WO2018218242A1 - Méthodes et compositions pour polythérapie - Google Patents

Méthodes et compositions pour polythérapie Download PDF

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Publication number
WO2018218242A1
WO2018218242A1 PCT/US2018/034890 US2018034890W WO2018218242A1 WO 2018218242 A1 WO2018218242 A1 WO 2018218242A1 US 2018034890 W US2018034890 W US 2018034890W WO 2018218242 A1 WO2018218242 A1 WO 2018218242A1
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patient
agent
inhibitor
erlotinib
administered
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PCT/US2018/034890
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English (en)
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Bryan ORONSKY
Tony R. REID
Scott CAROEN
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Epicentrx, Inc.
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Publication of WO2018218242A1 publication Critical patent/WO2018218242A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7052—Fibrosis

Definitions

  • the invention provides therapeutic methods, kits, and pharmaceutical compositions for treating cancer using a combination of (i) a first anti-cancer agent or a pharmaceutically acceptable salt thereof, (ii) an agent that increases the rate of clearance (such as metabolism) of the anti-cancer agent by a patient, and (iii) optionally a second anti-cancer agent.
  • the invention also provides therapeutic methods, kits, and pharmaceutical compositions for treating cutaneous abnormalities using a combination of an angiogenesis inhibitor and an agent capable of enhancing the efficacy of the angiogenesis inhibitor, such as a retinoid.
  • the invention also provides therapeutic methods, kits, and pharmaceutical compositions for treating conditions in immunologically privileged sites, such as central nervous system (CNS), eyes, placenta and the fetus, and testicles.
  • immunologically privileged sites such as central nervous system (CNS), eyes, placenta and the fetus, and testicles.
  • the invention also provides therapeutic methods and pharmaceutical compositions for treating conditions associated with abnormal extracellular matrix (ECM), and methods for identifying agents capable of modulating the abnormal ECM.
  • ECM extracellular matrix
  • Cancer is a significant health problem despite the many advances made for detecting and treating this disease.
  • Current strategies for managing cancer rely on early diagnosis and aggressive treatment. Treatment options often include surgery, radiotherapy, chemotherapy, hormone therapy, or a combination thereof. While such therapies provide a benefit to many patients, there is still a need for better therapeutic agents to treat various types of cancer.
  • Prostate cancer, breast cancer, and lung cancer are leading causes of cancer-related death. Prostate cancer is the most common form of cancer among males, with an estimated incidence of 30% in men over the age of 50. Moreover, clinical evidence indicates that human prostate cancer has the propensity to metastasize to bone, and the disease appears to progress inevitably from androgen dependent to androgen refractory status, leading to increased patient mortality.
  • Cutaneous abnormalities e.g., skin disorders
  • Cutaneous abnormalities vary greatly in symptoms and severity. They can be temporary or permanent and may be painless or painful. Some have situational causes, while others may be genetic. Some cutaneous abnormalities are minor, and others can be life- threatening.
  • ECM extracellular matrix
  • Tightly controlled ECM homeostasis is essential for development, wound healing and normal organ homeostasis.
  • pathological conditions including fibrotic disease, tumor progression and metastasis, may result.
  • ECM composition and remodeling are known to promote tumorigenesis and metastatic progression.
  • various fibrotic diseases such as pulmonary fibrosis, systemic sclerosis, liver cirrhosis, and cardiovascular disease. (Cox and Erler, Dis. Model. Mech. (2011) 4(2): 165-178) are associated with disruption of normal ECM homeostasis.
  • new treatment methods and pharmaceutical compositions are required to treat these pathological conditions, which are responsible for millions of deaths worldwide and for which adequate therapies are lacking.
  • the present disclosure provides a method for treating cancer in a patient in need thereof.
  • the method comprises administering to the patient (i) a therapeutically effective amount of an angiogenesis inhibitor, wherein the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor, and (ii) an effective amount of an agent that increases the rate of metabolism of the angiogenesis inhibitor.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • the agent that increases the rate of metabolism of the angiogenesis inhibitor is administered to the patient prior to administration of the angiogenesis inhibitor to the patient. In some embodiments, the agent that increases the rate of metabolism of the angiogenesis inhibitor is administered to the patient concurrently with or after administration of the angiogenesis inhibitor to the patient.
  • the agent that increases the rate of metabolism of the angiogenesis inhibitor is administered on (i) the same day as the last administration of the angiogenesis inhibitor in any treatment cycle of the angiogenesis inhibitor or (ii) within 6 hours after the last administration of the angiogenesis inhibitor in any treatment cycle of the angiogenesis inhibitor.
  • the rate of metabolism of the angiogenesis inhibitor administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of the angiogenesis inhibitor.
  • the agent that increases the rate of metabolism of the angiogenesis inhibitor is an agent that increases the activity of a cytochrome P450.
  • the angiogenesis inhibitor has a blood plasma half-life of more than 35 hours when the patient is not administered an agent that increases the rate of metabolism of the angiogenesis inhibitor.
  • the angiogenesis inhibitor is administered at a daily dose in an amount sufficient to reduce blood flow in a tumor in the patient.
  • a second or subsequent dose of the angiogenesis inhibitor is administered to the patient after about 4-6 half-lives after administration of the prior dose of the angiogenesis inhibitor to the patient.
  • the angiogenesis inhibitor is administered to the patient for two or three consecutive days.
  • the angiogenesis inhibitor is administered to the patient for 2 or 3 consecutive days, then after a period of at least 7 days during which the angiogenesis inhibitor is not administered to the patient, the angiogenesis inhibitor is administered to the patient for at least 2 consecutive days.
  • the angiogenesis inhibitor is administered to the patient for 2 or 3 consecutive days, then after a period of about 11 days during which the angiogenesis inhibitor is not administered to the patient, the angiogenesis inhibitor is administered to the patient for 2 or 3 consecutive days.
  • the method comprises administering the TKI or the VEGF inhibitor to the patient daily for two, three, four, or five consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient for another two, three, four, or five consecutive days.
  • administering the TKI or the VEGF inhibitor to the patient daily for two, three, four, or five consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient for another two, three, four, or five consecutive days.
  • the method comprises administering the TKI or the VEGF inhibitor to the patient for two, three, four, or five times within a week, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient for another two, three, four, or five times within another week.
  • the method comprises administering the TKI or the VEGF inhibitor to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient not more than 5 times in another week.
  • the TKI is an epidermal growth factor inhibitor (EGFR inhibitor), wherein the EGFR inhibitor is an antibody or a small molecule.
  • the EGFR inhibitor is cetuximab, erlotinib, gefitinib, afatinib or panitumumab.
  • the VEGF inhibitor is an antibody or antibody-like decoy trap.
  • the VEGF inhibitor is axitinib, bevacizumab, ramucirumab or aflibercept.
  • the angiogenesis inhibitor is erlotinib, gefitinib, afatinib, cetuximab, panitumumab, nintedanib, vandetanib, lapatinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, dovitinib, dasatinib, bosutinib, imatinib, regorafenib, cabozantinib, apatinib, lenvatinib, or nilotinib.
  • the angiogenesis inhibitor is erlotinib, and erlotinib is administered at a daily dose in the range of about 750 mg per day to about 5,000 mg per day.
  • the daily dose of erlotinib for adults (e.g., 750 mg per day to about 5,000 mg) is reduced by 75%, 50% and 25% for preterms, neonates and children respectively.
  • the angiogenesis inhibitor is erlotinib, and erlotinib is administered at a daily dose of about 2000 mg per day.
  • the angiogenesis inhibitor is erlotinib
  • the patient is orally administered a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 250 mg of erlotinib.
  • the angiogenesis inhibitor is erlotinib
  • the patient is orally administered a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 250-20,000 mg of erlotinib; and thereafter not administering any erlotinib to the patient for a period of at least about 10 days.
  • the method further comprises administering to the patient a second anti-cancer agent.
  • the second anti-cancer agent is a chemotherapeutic agent.
  • the second anti-cancer agent is gemcitabine or a pharmaceutically acceptable salt thereof.
  • the second anti-cancer agent is gemcitabine hydrochloride.
  • the second anti-cancer agent is administered at a dose providing at least 500 mg/m 2 of gemcitabine on each day it is administered to the patient. In some embodiments, the second anti-cancer agent is administered at a dose providing at least 1 ,000 mg/m 2 of gemcitabine on each day it is administered to the patient. In some embodiments, the second anti-cancer agent is administered at a dose providing about 1 ,000 mg/m 2 of gemcitabine on each day it is administered to the patient. In some embodiments, the second anti-cancer agent is administered on about day 1 and about day 8 of each 28-day cycle. In some embodiments, the second anti-cancer agent is administered on about day 1, about day 8, and about day 15 of each 28-day cycle. In some embodiments, the second anti-cancer agent is administered by intravenous injection to the patient.
  • the second anti-cancer agent is radiation therapy, doxorubicin, cyclophosphamide, bleomycin, fluorouracil, methotrexate, mitoxantrone, vincristine, etoposide, cisplatin, carboplatin, oxaliplatin, irinotecan, temozolomide, a taxane, or an interferon.
  • the second anti-cancer agent is an oncolytic virus.
  • the present disclosure also provides a method of treating cancer in a patient, comprising the steps of:
  • step (b) beginning on the day following the administration in step (a), orally administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 250 mg of erlotinib;
  • step (c) administering to the patient an effective amount of an agent that increases the rate of metabolism of erlotinib, so that erlotinib administered to the patient in step (b) undergoes metabolism at an accelerated rate;
  • step (d) on the seventh day after the administration in step (a), intravenously administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising gemcitabine;
  • step (e) on the fourteenth day after the administration in step (a), intravenously administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising gemcitabine; and (f) beginning on the fifteenth day following the administration in step (a), orally administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 250 mg of erlotinib; to thereby treat the cancer.
  • the present disclosure also provides a method of treating cancer in a patient, comprising the steps of:
  • step (b) beginning on the day following the administration in step (a), orally administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 2,000 mg of erlotinib; and thereafter not administering any erlotinib to the patient for a period of at least about 10 days;
  • step (c) administering to the patient an effective amount of an agent that increases the rate of metabolism of erlotinib, so that erlotinib administered to the patient in step (b) undergoes metabolism at an accelerated rate;
  • step (d) on the seventh day after the administration in step (a), intravenously administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising gemcitabine; and thereafter not administering any gemcitabine to the patient for a period of at least 6 days;
  • step (e) on the fourteenth day after the administration in step (a), intravenously administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising gemcitabine;
  • step (f) beginning on the fifteenth day following the administration in step (a), orally administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 2,000 mg of erlotinib; to thereby treat the cancer.
  • the formulation of the method described herein comprises gemcitabine, such as gemcitabine hydrochloride.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of cytochrome P450 CYP3A4.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of cytochrome P450 CYP1 A1/3A.
  • the agent that increases the rate of metabolism of erlotinib is selected from the group consisting of corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglitazone, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the agent that increases the rate of metabolism of erlotinib is administered to the patient in an amount that increases the rate of metabolism of erlotinib by the patient by at least 15%, at least 10%, at least 5%, at least 25%, or at least 50%.
  • the cancer is a solid tumor.
  • the cancer is pancreatic cancer, lung cancer, breast cancer, ovarian cancer, a primary melanoma, a metastatic melanoma, liver cancer, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, or prostate cancer.
  • the cancer is pancreatic cancer.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is a hematological malignancy.
  • the cancer is a leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.
  • the present disclosure also provides a method for treating a cutaneous abnormality in a patient in need thereof.
  • the method comprises administering to the patient (i) a therapeutically effective amount of an angiogenesis inhibitor, wherein the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor, and (ii) a therapeutically effective amount of one or more agents capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the TKI is an EGFR inhibitor, wherein the EGFR inhibitor is an antibody or a small molecule.
  • the EGFR inhibitor is cetuximab, erlotinib, gefitinib, afatinib or panitumumab.
  • the VEGF inhibitor is an antibody or antibody -like decoy trap.
  • the VEGF inhibitor is axitinib, bevacizumab, ramucirumab or aflibercept.
  • angiogenesis inhibitor is erlotinib, gefitinib, afatinib, cetuximab, panitumumab, nintedanib, vandetanib, lapatinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, dovitinib, dasatinib, bosutinib, imatinib, regorafenib, cabozantinib, apatinib, lenvatinib, or nilotinib.
  • the method for treating a cutaneous abnormality comprises administering the TKI or the VEGF inhibitor to the patient daily for two, three, four, or five consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient for another two, three, four, or five consecutive days.
  • the method for treating a cutaneous abnormality comprises administering the TKI or the VEGF inhibitor to the patient for two, three, four, or five times within a week, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient for another two, three, four, or five times within another week.
  • the method for treating a cutaneous abnormality comprises administering the TKI or the VEGF inhibitor to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient not more than 5 times in another week.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is administered to the patient prior to, concurrently with, or after administration of the TKI or the VEGF inhibitor.
  • the angiogenesis inhibitor for treating cutaneous abnormality is erlotinib, and erlotinib is administered at a daily dose in the range of about 1,500 mg per day to about 2,500 mg per day, such as a daily dose in the range of about 1,800 mg per day to about 2,200 mg per day, or a daily dose of about 2000 mg per day.
  • the angiogenesis inhibitor for treating cutaneous abnormality is erlotinib
  • the patient is orally administered a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 1,500 mg of erlotinib.
  • erlotinib is administered once per day for three consecutive days at a daily dose of about 2,000-20,000 mg of erlotinib; and thereafter not administering any erlotinib to the patient for a period of at least about 10 day.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor for treating cutaneous abnormality is administered to the patient prior to administration of the angiogenesis inhibitor to the patient.
  • the angiogenesis inhibitor for treating cutaneous abnormality is administered to the patient concurrently with or after administration of the angiogenesis inhibitor to the patient.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor for treating cutaneous abnormality is a retinoid.
  • the retinoid is selected from the group consisting of tazarotene, retinoic acid, tretinoin, isotretinoin, adapalene, bexarotene, alitretinoin, vitamin A, retinol, retinoic acid, retinal, retinyl palmitate, retinyl acetate, ethyl 5-(2-(4,4- dimethylthiochroman-6-yl)ethynyl)thiophene-2-carboxylate, 6- (2-4,4- dimethylthiochroman- 6-yl)-ethynyl)-3-pyridylmethanol, and 2-(2-(4,4- dimethylthiochroman-6-yl)-ethynyl)-5- pyridinecarboxaldehyde.
  • the method for treating cutaneous abnormality comprises administering the retinoid to the patient daily for three consecutive days, then after a period of at least 7, 10, 14, or 21 days during which retinoid is not administered to the patient, administering retinoid to the patient for another three consecutive days.
  • the method for treating cutaneous abnormality comprises administering the retinoid to the patient daily for three consecutive days in a week for two consecutive weeks, then after a period of at least 7, 10, 14, or 21 days during which retinoid is not administered to the patient, administering retinoid to the patient for another three consecutive days in a week for two consecutive weeks.
  • the method for treating cutaneous abnormality comprises administering the retinoid to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the retinoid is not administered to the patient, administering the retinoid to the patient not more than 5 times in another week.
  • the retinoid is isotretinoin.
  • isotretinoin is administered to the patient at an initial dosage of about 10 mg/day or 40 mg/day for the first two to four weeks, then at a dosage of about 1 mg/kg/day after the first two to four weeks.
  • the total dosage of isotretinoin is about 120 mg/kg to 200 mg/kg.
  • isotretinoin is administered to the patient at 160 mg/m 2 /day in 2 divided doses.
  • the retinoid is tretinoin, and wherein tretinoin is administered at 45 mg/m 2 /day in 2 divided doses. In some embodiments, the total dosage of tretinoin is about 630 mg to 1000 mg.
  • the method for treating cutaneous abnormality further comprises administering to the patient an agent capable of increasing the rate of metabolism of the angiogenesis inhibitor, and/or the metabolism of the agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the angiogenesis inhibitor for treating cutaneous abnormality, is erlotinib, and wherein the rate of metabolism of erlotinib administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the angiogenesis inhibitor is erlotinib, and the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the agent capable of increasing the rate of metabolism of the angiogenesis inhibitor is selected from the group consisting of tetracycline, corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglitazone, and any combination thereof.
  • the corticosteroid is dexamethasone.
  • the method for treating cutaneous abnormality further comprises administering to a patient in need thereof a therapeutically effective amount of an agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor.
  • the agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor for treating cutaneous abnormality is an antibiotic.
  • the antibiotic is azithromycin.
  • azithromycin is administered to the patient at a dosage of 500-2000 mg for three days every week.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is selected from the group consisting of cardiac glycoside, clindamycin, erythromycin, benzoyl peroxide, azelaic acid, dapsone, clotrimazole, psoralen plus ultraviolet A (PUVA), permethrin, calcipotriene, adalimumab, coal tar, etanercept, infliximab, tazarotene, and alefacept.
  • PUVA psoralen plus ultraviolet A
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is a cardiac glycoside.
  • the cardiac glycoside is digoxin.
  • digoxin is administered at 0.125-0.5 mg/day orally.
  • the angiogenesis inhibitor and/or the agent capable of enhancing the efficacy of the angiogenesis inhibitor are administered to the patient topically, orally, intravenously, intramuscularly, subcutaneously, intradermally, or any combination thereof.
  • the cutaneous abnormality is selected from the group consisting of benign skin conditions, inflammatory skin conditions, precancerous skin conditions, autoimmune skin conditions, and cancerous skin conditions.
  • the benign skin condition is selected from the group consisting of skin rash, acne, herpes zoster (shingles), post herpetic neuralgia (PNH) and rosacea.
  • the autoimmune skin condition is psoriasis.
  • the precancerous skin condition is actinic keratosis.
  • the cancerous skin condition is selected from the group consisting of melanoma, squamous cell carcinoma, and basal cell carcinoma.
  • the cutaneous abnormality is a noncancerous condition
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is not administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the cutaneous abnormality is a cancerous condition
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is optionally administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the present disclosure also provides a method for treating a condition in an immunologically privileged site in a patient in need thereof.
  • the method for treating a condition in an immunologically privileged site comprises administering to the patient a therapeutically effective amount of one or more agents capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the immunologically privileged site is selected from the group consisting of central nervous system (CNS), eyes, placenta and fetus, and testicles.
  • the method for treating a condition in an immunologically privileged site comprises administering to the patient a therapeutically effective amount of an angiogenesis inhibitor, wherein the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor, wherein the immunologically privileged site is selected from the group consisting of central nervous system (CNS), eyes, placenta and fetus, and testicles.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • the methods for treating a condition in an immunologically privileged site comprises administering to the patient (i) a therapeutically effective amount of an angiogenesis inhibitor, wherein the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor, and/or (ii) a therapeutically effective amount of one or more agents capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or the Platelet-Derived Growth Factor (PDGF) signaling pathway, wherein the immunologically privileged site is selected from the group consisting of central nervous system (CNS), eyes, placenta and fetus, and testicles.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the method for treating a condition in an immunologically privileged site further comprises administering to the patient a therapeutically effective amount of one or more agents capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the TKI for treating a condition in an immunologically privileged site, is an EGFR inhibitor, wherein the EGFR inhibitor is an antibody or a small molecule.
  • the EGFR inhibitor is cetuximab, erlotinib, gefitinib, or panitumumab.
  • the VEGF inhibitor for treating a condition in an immunologically privileged site, is an antibody or antibody-like decoy trap.
  • the VEGF inhibitor is axitinib, bevacizumab, ramucirumab or aflibercept.
  • the angiogenesis inhibitor is erlotinib, gefitinib, afatinib, cetuximab, panitumumab, nintedanib, vandetanib, lapatinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, dovitinib, dasatinib, bosutinib, imatinib, regorafenib, cabozantinib, apatinib, lenvatinib, or nilotinib.
  • the method comprises administering the TKI or the VEGF inhibitor to the patient daily for two, three, four, or five consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient for another two, three, four, or five consecutive days.
  • the method comprises administering the TKI or the VEGF inhibitor to the patient for two, three, four, or five times within a week, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient for another two, three, four, or five times within another week.
  • the method comprises administering the TKI or the VEGF inhibitor to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient not more than 5 times in another week.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is administered to the patient prior to, concurrently with, or after administration of the angiogenesis inhibitor.
  • the angiogenesis inhibitor is erlotinib, and erlotinib is administered at a daily dose in the range of about 1,500 mg per day to about 2,500 mg per day, such as a daily dose in the range of about 1,800 mg per day to about 2,200 mg per day, or a daily dose of about 2000 mg per day.
  • the angiogenesis inhibitor is erlotinib
  • the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 1,500 mg of erlotinib.
  • the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 2,000-20,000 mg of erlotinib; and thereafter not administering any erlotinib to the patient for a period of at least about 10 days.
  • the method further comprises administering to the patient an agent capable of increasing the rate of metabolism of the angiogenesis inhibitor, and/or the metabolism of the agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the angiogenesis inhibitor is erlotinib, and wherein the rate of metabolism of erlotinib administered to the patient is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% or more due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the angiogenesis inhibitor is erlotinib
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the agent capable of increasing the rate of metabolism of the angiogenesis inhibitor is selected from the group consisting of tetracycline, corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglitazone, and any combination thereof.
  • the corticosteroid is dexamethasone.
  • the method further comprises administering to a patient in need thereof a therapeutically effective amount of an agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor.
  • the agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor is an antibiotic.
  • the antibiotic is azithromycin.
  • azithromycin is administered to the patient at a dosage of 500-2000 mg for three days every week.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is selected from the group consisting of cardiac glycoside, clindamycin, erythromycin, benzoyl peroxide, azelaic acid, dapsone, clotrimazole, psoralen plus ultraviolet A (PUVA), permethrin, calcipotriene, adalimumab, coal tar, etanercept, infliximab, tazarotene, and alefacept.
  • PUVA psoralen plus ultraviolet A
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is a cardiac glycoside.
  • the cardiac glycoside is digoxin.
  • digoxin is administered at 0.125-0.5 mg/day orally.
  • the angiogenesis inhibitor and/or the agent capable of enhancing the efficacy of the angiogenesis inhibitor are administered to the patient topically, orally, intravenously, intramuscularly, subcutaneously, intradermally, or any combination thereof.
  • the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway is an agent capable of inhibiting the interaction of a TGF- ⁇ ligand protein and a TGFfi receptor protein.
  • the TGF- ⁇ ligand protein is TGF- ⁇ - ⁇ .
  • the agent is a TGF- ⁇ - ⁇ ligandtrap.
  • the agent is an anti-TGF- ⁇ antibody.
  • the agent is an anti-TGF- ⁇ receptorantibody.
  • the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway is an agent capable of inhibiting a component in the downstream of TGF- ⁇ signaling pathway.
  • the agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway is an agent capable of inhibiting the interaction of a PDGF ligand protein and a PDGF receptor protein.
  • the PDGF ligand protein is PDGF-AA, PDGF-BB, PDGF- AB, PDGF-CC, and/or PDGF-DD.
  • the agent is a PDGF ligand trap.
  • the agent is an anti-PDGF antibody.
  • the agent is an anti- PDGF receptorantibody.
  • the agent capable of inhibiting the PDGF signaling pathway is an agent capable of inhibiting a component in the downstream of PDGF signaling pathway.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway is a protein.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway is a virus comprising a recombinant gene encoding a protein capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway.
  • the condition for treating a condition in an immunologically privileged site, is cancerous or non-cancerous.
  • the condition comprises symptom of inflammation.
  • the condition disrupts or breaks down Blood-Brain-Barrier, Blood- Ocular-Barrier, Placental Blood Barrier, and/or the Blood Testis Barrier.
  • condition leads to tissue fibrosis and/or desmoplasia in the immunologically privileged site.
  • condition for treating a condition in an immunologically privileged site, condition triggers tissue fibrosis or scar formation in the immunologically privileged site.
  • fibrous extracellular matrix and/or fibrotic/desmoplastic scar forms in the immunologically privileged site.
  • the condition for treating a condition in an immunologically privileged site, is a neurological disorder.
  • the neurological disorder is stroke, spinal cord injury, multiple sclerosis or Alzheimer's disease (AD).
  • the method further comprises administering an additional therapeutic agent for neurological disorder to the patient in need thereof.
  • the present disclosure also provides a method for improving penetration of a drug through Blood-Brain-Barrier, Blood-Ocular- Barrier, Placental Blood Barrier, and/or the Blood Testis Barrier in a patient in need thereof.
  • the method comprises administering the drug to the patient, and:
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the present disclosure also provides a method for cell regeneration in a central nervous system of a patient in need thereof.
  • the method comprises: (a) administering to the patient a therapeutically effective amount of an angiogenesis inhibitor and optionally a therapeutically effective amount of an angiogenesis inhibitor and an agent capable of enhancing the efficacy of the angiogenesis inhibitor; and/or
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the method further comprises administering a chemotherapy, a radiotherapy, a hormone therapy, a surgery of any combination thereof to the patient.
  • the method comprises administering to the patient a therapeutically effective amount of a first agent and a therapeutically effective amount of a second agent, wherein the first agent is capable of decreasing connective tissue in the immunologically privileged site, and the second agent can increase blood flow in the immunologically privileged site.
  • the immunologically privileged site is selected from the group consisting of central nervous system (CNS), eyes, placenta and fetus, and testicles.
  • the first agent for treating a condition in an immunologically privileged site, is an angiogenesis inhibitor, wherein the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor.
  • the first agent is erlotinib or axitinib.
  • the present disclosure also provides a method for treating a condition associated with abnormal extracellular matrix (ECM) in a patient in need thereof.
  • the method comprises administering to the patient a therapeutically effective amount of one or more agents capable of modulating the abnormal ECM.
  • the agent capable of modulating the abnormal ECM is selected from the group consisting of an angiogenesis inhibitor, an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway, and an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway, wherein the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the method for treating a condition associated with abnormal ECM further comprises administering to the patient a therapeutically effective amount of one or more agents capable of ameliorating the condition.
  • the method comprises the steps of:
  • the agent capable of modulating the abnormal ECM is selected from the group consisting of an angiogenesis inhibitor, an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway, and an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway, wherein the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the method further comprises administering to the patient a therapeutically effective amount of one or more agents capable of ameliorating the condition.
  • the agent capable of modulating the abnormal ECM improves the delivery and/or efficacy of the agent capable of ameliorating the condition.
  • the agent capable of modulating the abnormal ECM is administered to the patient prior to, concurrently with, or after administration of the agent capable of ameliorating the condition.
  • the agent capable of modulating the abnormal ECM decreases the level of one or more ECM proteins selected from the group consisting of collagen, elastin, fibrillin, fibronectin, vitronectin, laminins, integrins, and proteoglycan.
  • a second or subsequent dose of the angiogenesis inhibitor is administered to the patient after about 4-6 half-lives after administration of the prior dose of the angiogenesis inhibitor to the patient.
  • the angiogenesis inhibitor is administered to the patient for two or three consecutive days.
  • the angiogenesis inhibitor for treating a condition associated with abnormal ECM, is administered to the patient for 2 or 3 consecutive days, then after a period of at least 7 days during which the angiogenesis inhibitor is not administered to the patient, the angiogenesis inhibitor is administered to the patient for at least 2 consecutive days.
  • the angiogenesis inhibitor for treating a condition associated with abnormal ECM, is administered to the patient for 2 or 3 consecutive days, then after a period of about 11 days during which the angiogenesis inhibitor is not administered to the patient, the angiogenesis inhibitor is administered to the patient for 2 or 3 consecutive days.
  • the method comprises administering the TKI or the VEGF inhibitor to the patient daily for two, three, four, or five consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient for another two, three, four, or five consecutive days.
  • the method comprises administering the TKI or the VEGF inhibitor to the patient for two, three, four, or five times within a week, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient for another two, three, four, or five times within another week.
  • the method comprises administering the TKI or the VEGF inhibitor to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the TKI or the VEGF inhibitor is not administered to the patient, administering the TKI or the VEGF inhibitor to the patient not more than 5 times in another week.
  • the TKI for treating a condition associated with abnormal ECM, is an EGFR inhibitor, wherein the EGFR inhibitor is an antibody or a small molecule.
  • the EGFR inhibitor is cetuximab, erlotinib, gefitinib, or panitumumab.
  • the VEGF inhibitor for treating a condition associated with abnormal ECM, is an antibody or antibody-like decoy trap.
  • the VEGF inhibitor is axitinib, bevacizumab, ramucirumab or aflibercept.
  • the angiogenesis inhibitor is erlotinib, gefitinib, afatinib, cetuximab, panitumumab, nintedanib, vandetanib, lapatinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, dovitinib, dasatinib, bosutinib, imatinib, regorafenib, cabozantinib, apatinib, lenvatinib, or nilotinib.
  • the angiogenesis inhibitor is erlotinib, and erlotinib is administered at a daily dose in the range of about 1,500 mg per day to about 2,500 mg per day, such as about 1,800 mg per day to about 2,200 mg per day.
  • the angiogenesis inhibitor is erlotinib, and erlotinib is administered at a daily of about 2000 mg per day.
  • the angiogenesis inhibitor is erlotinib
  • the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 1,500 mg of erlotinib.
  • the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 2,000- 20,000 mg of erlotinib; and thereafter not administering any erlotinib to the patient for a period of at least about 10 days.
  • the method further comprises administering to the patient a therapeutically effective amount of one or more agents capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is administered to the patient prior to, concurrently with, or after administration of the angiogenesis inhibitor.
  • the method further comprises administering to the patient an agent capable of increasing the rate of metabolism of the angiogenesis inhibitor, and/or the metabolism of the agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the angiogenesis inhibitor for treating a condition associated with abnormal ECM, is erlotinib, and wherein the rate of metabolism of erlotinib administered to the patient is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or more due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the angiogenesis inhibitor is erlotinib, and the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the angiogenesis inhibitor is a TKI or a VEGF inhibitor
  • the agent capable of increasing the rate of metabolism of the TKI or a VEGF inhibitor is selected from the group consisting of tetracycline, corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglitazone, and any combination thereof.
  • the corticosteroid is dexamet
  • the method further comprises administering to a patient in need thereof a therapeutically effective amount of an agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor.
  • the agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor is an antibiotic.
  • the angiogenesis inhibitor and/or the agent capable of enhancing the efficacy of the angiogenesis inhibitor are administered to the patient topically, orally, intravenously, intramuscularly, subcutaneously, intradermally, or any combination thereof.
  • the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway is an agent capable of inhibiting the interaction of a TGF- ⁇ ligand protein and a TGFfi receptor protein.
  • the TGF- ⁇ ligand protein is TGF- ⁇ - ⁇ , TGF ⁇ -2, or TGF ⁇ -3.
  • the agent is a TGF- ⁇ ligand trap.
  • the agent is an anti-TGF- ⁇ antibody.
  • the agent is an anti-TGF- ⁇ receptor antibody.
  • the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway is an agent capable of inhibiting a component in the downstream of TGF- ⁇ signaling pathway.
  • the agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway is an agent capable of inhibiting the interaction of a PDGF ligand protein and a PDGF receptor protein.
  • the PDGF ligand protein is PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and/or PDGF-DD.
  • the agent is a PDGF ligand trap.
  • the agent is an anti-PDGF antibody.
  • the agent is an anti-PDGF receptor antibody.
  • the agent capable of inhibiting the PDGF signaling pathway is an agent capable of inhibiting a component in the downstream of PDGF signaling pathway.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway is a polypeptide.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway is a virus comprising a recombinant gene encoding a protein capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway.
  • the condition is cancerous or non-cancerous.
  • the condition is selected from the group consisting of pancreatitis, cirrhosis, liver fibrosis, hepatitis B, hepatitis C, primary biliary cirrhosis, glial scar tissue, fibrocystic disease, Dupuytren's contracture, lung fibrosis, gingival hypertrophy, uterine or ovarian fibroids, endometriosis, silicosis, keloidosis, uterine fibrosis, cystic fibrosis, osteosclerosis, kidney fibrosis, diabetic nephropathy, scleroderma, glomerulosclerosis, asbestosis, exophthalmos of Grave's disease, proliferative vitreoretinopathy, anterior capsule cataract, corneal fibrosis, corneal scarring due to surgery, trabeculectomy-induced fibrosis, progressive subretinal fibrosis, and multif
  • the condition is cancer
  • the agent capable of ameliorating the condition is a chemotherapy, radiotherapy, tyrosine kinase inhibitor, an antihypertensive, a TGF- ⁇ trap, an anti-oxidant, a PPAR gamma agonist, an integrin antagonist, a TIMP-1 or TIMP-2 inhibitor, a Farnesoid X receptor agonist, a caspase inhibitor, an ACE inhibitor, a RAGE inhibitor, LMW heparin, a PKC inhibitor, an ADAM- 10 inhibitor, a copper chelator, an anti-fibrotic cytokine, or a rho kinase inhibitor.
  • the antihypertensive is an ACE inhibitor or a calcium channel blocker.
  • the anti-fibrotic cytokine is HGF, BMP-7, or IL-10.
  • the condition for treating a condition associated with abnormal ECM, the condition comprises symptom of inflammation.
  • the condition disrupts or breaks down blood-tissue barriers such as the Blood-Brain-Barrier, Blood-Ocular-Barrier, Placental Blood Barrier, Blood Thymus Barrier and/or the Blood Testis Barrier.
  • the condition is in the patient's brain, the eye, pancreas, prostate, adrenal cortex, heart, blood vessels, GI tract, appendix, gallbladder, bile duct, liver, skin, spleen, lungs, prostate, testis, ovary, placenta, uterus, renal tubule, extremities, and/or joints.
  • the condition triggers tissue fibrosis or scar formation in the patient.
  • fibrous extracellular matrix and/or fibrotic/desmoplastic scar forms in an immunologically privileged site in the patient.
  • the condition is a neurological disorder.
  • the neurological disorder is stroke, spinal cord injury, multiple sclerosis or Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • the method comprises
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • the abnormal extracellular matrix manifests as fibrosis, scarring and/or desmoplasia in the patient.
  • the method comprises determining whether the patient has an abnormal extracellular matrix (ECM), which comprises the steps of:
  • the biomarker is selected from the group consisting of a2- MG, A2M, HA, TIMP-1 , tumor necrosis factor-a (TNF-a), and transforming growth factor- ⁇ (TGF- ⁇ ), PIIINP; laminin, tenascin, adipokines, MT1-MMP, Migration-stimulating factor (MSF), YKL-40, MMP-2, MMP-3, MMP-9/TIMP-1 complex, MMP-13, MMP-14, sFas ligand, TGF- ⁇ , TGF- ⁇ receptor 1, TGF- ⁇ receptor 2, TGF- ⁇ receptor 3, Smad 3, Smad 4, Smad 7, IL-10, apoAl, apoA2, apoB, integrin 1 ⁇ , TNF- ⁇ , MCP-1, leptin, VEGF, PDGF, collagen type I, collagen type III, collagen type IV, collagen type VI, collagen type XIV, e
  • the agent capable of stimulate the fibroblast cells to differentiate into myofibroblasts is selected from the group consisting of TGF- ⁇ , fibroblast growth factor (FGF), IL- ⁇ , interleukin-6 (IL-6), IL-13, IL-33, leukotrienes, CXC, and CC chemokines, IGFBP-3 and -5, IGF-II, reactive oxygen and nitrogen species and connective tissue growth factor (CTGF).
  • composition comprising:
  • angiogenesis inhibitor a therapeutically effective amount of an angiogenesis inhibitor, wherein the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor; and
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet- Derived Growth Factor
  • the agent capable of modulating the abnormal ECM and the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway are in a unified dosage form or in separate dosage forms.
  • TKI is an EGFR inhibitor.
  • the angiogenesis inhibitor is erlotinib, gefitinib, afatinib, cetuximab, panitumumab, nintedanib, vandetanib, lapatinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, dovitinib, dasatinib, bosutinib, imatinib, regorafenib, cabozantinib, apatinib, lenvatinib, or nilotinib.
  • the composition further comprises a therapeutically effective amount of an agent capable of increasing the rate of metabolism of the angiogenesis inhibitor.
  • Figure 1A depicts a model of traditional dosing and its effects on drug concentration in blood and toxicity.
  • Figure IB depicts a model of pulsed dosing and its effects on drug concentration in blood and toxicity.
  • Figure 2 depicts four similar processes/concepts involved in cancer desmoplasia
  • the 4 processes/concepts shown are: (1) the fibroblast-to- myofibroblast transdifferentiation by recruiter cytokines (e.g. TGF- ⁇ ), either by cancer cells or platelets; (2) induction of desmoplasia (EMT transition) around the tumor or the damaged epithelium; (3) paracrine signaling from the cancer-associated fibroblasts (CAFs) or myofibroblastic niche on the tumor invasion front cancer cells or wound edge respectively; (4) induction of stromal reactions such as neoangiogenesis.
  • recruiter cytokines e.g. TGF- ⁇
  • EMT transition desmoplasia
  • CAFs cancer-associated fibroblasts
  • myofibroblastic niche on the tumor invasion front cancer cells or wound edge respectively
  • stromal reactions such as neoangiogenesis.
  • the invention provides therapeutic methods, kits, and pharmaceutical compositions for treating cancer.
  • the methods comprise using a combination of (i) a first anti-cancer agent selected from the group consisting of an angiogenesis inhibitor or a pharmaceutically acceptable salt thereof, (ii) an agent that increases the rate of clearance (such as metabolism) of the angiogenesis inhibitor by a patient, and (iii) optionally a second anticancer agent.
  • the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor.
  • Administration of the first anti-cancer agent, for example an angiogenesis inhibitor, in combination with an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent desirably provides a superior anti-cancer effect relative to administration of the first anti-cancer agent without an agent that increases the rate of clearance (such as metabolism) of the angiogenesis inhibitor.
  • the agent that increases the rate of clearance (such as metabolism) of the angiogenesis inhibitor may be, for example, an agent that increases the activity of a cytochrome P450, such as cytochrome P450 3A4 (CPY3A4).
  • the therapeutic methods may be used to treat a variety of cancers including, but are not limited to, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, a primary melanoma, a metastatic melanoma, liver cancer, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, or prostate cancer.
  • the cancer is pancreatic cancer, lung cancer, breast cancer, ovarian cancer, a primary melanoma, a metastatic melanoma, liver cancer, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, or prostate cancer.
  • the cancer is pancreatic cancer.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is a hematological malignancy.
  • the cancer is a leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.
  • the cancer is brain cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, stomach cancer, testicular cancer, or uterine cancer.
  • the cancer is brain cancer.
  • the cancer is a vascularized tumor, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma (e.g.
  • an angiosarcoma or chondrosarcoma larynx cancer, parotid cancer, bilary tract cancer, thyroid cancer, acral lentiginous melanoma, actinic keratoses, acute lymphocytic leukemia, acute myeloid leukemia, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, anal canal cancer, anal cancer, anorectum cancer, astrocytic tumor, bartholin gland carcinoma, basal cell carcinoma, biliary cancer, bone cancer, bone marrow cancer, bronchial cancer, bronchial gland carcinoma, carcinoid, cholangiocarcinoma, chondosarcoma, choroid plexus papilloma/carcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell carcinoma, connective tissue cancer, cystadenoma, digestive system
  • the cancer is non- Hodgkin's lymphoma, such as a B-cell lymphoma or a T-cell lymphoma.
  • the non-Hodgkin's lymphoma is a B-cell lymphoma, such as a diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, or primary central nervous system (CNS) lymphoma.
  • B-cell lymphoma such as a diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphom
  • the non-Hodgkin's lymphoma is a T-cell lymphoma, such as a precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T- cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, or peripheral T-cell lymphoma.
  • T-cell lymphoma such as a precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T- cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, or
  • the first anti-cancer agent may be administered to the patient according to a particular dosing regimen, such as a pulse-type dosing regimen where the first anti-cancer agent is administered for two or three consecutive days, then thereafter no first anti-cancer agent is administered to the patient for several days (e.g., at least 10 days), and then the first anti-cancer agent is administered for two or three consecutive days.
  • a pulse-type dosing regimen where the first anti-cancer agent is administered for two or three consecutive days, then thereafter no first anti-cancer agent is administered to the patient for several days (e.g., at least 10 days), and then the first anti-cancer agent is administered for two or three consecutive days.
  • Numerous anti-cancer agents may be used as the second anti-cancer agent.
  • the second anti-cancer agent comprises gemcitabine.
  • Exemplary benefits of such therapeutic methods include (i) superior anti-cancer effects, (ii) induction of ischemia-reperfusion in a tumor in the patient, and/or (iii) reduction in adverse side effects associated with the second anti-cancer agent.
  • Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.
  • the invention provides therapeutic methods for treating cancer using a combination of (i) a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof, and (ii) an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent by the patient, and (iii) optionally a second anti-cancer agent.
  • a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof
  • an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent by the patient and (iii) optionally a second anti-cancer agent.
  • the invention provides methods for treating cancer using a combination of (i) erlotinib, (ii) an agent that increases the rate of clearance (such as metabolism) of erlotinib by a patient, and (iii) optionally a second anti-cancer agent.
  • erlotinib includes erlotinib free base and pharmaceutical acceptable salts of erlotinib, including erlotinib hydrochloride.
  • One aspect of the invention provides a method of treating cancer in a patient, wherein the method comprises administering to a patient in need thereof (i) a therapeutically effective amount of a first anti-cancer agent selected from the group consisting of erlotinib, and (ii) an effective amount of an agent that increases the rate of clearance (such as metabolism) of erlotinib by the patient, to treat the cancer.
  • Administration of the first anti-cancer agent in combination with an agent that increases the rate of clearance (such as metabolism) of erlotinib desirably provides a superior anti-cancer effect relative to administration of the first anti-cancer agent without an agent that increases the rate of clearance (such as metabolism) of erlotinib.
  • the agent that increases the rate of clearance of the first anti-cancer agent may be, for example, (i) an agent that increases the rate of metabolism of the first anti-cancer agent by the patient or (i) an agent that increases the rate of excretion of the first anti-cancer agent from the patient.
  • the therapeutic method may be used to treat a variety of cancers, as described in more detail.
  • a more specific aspect of the invention provides a method of treating cancer in a patient, wherein the method comprises administering to a patient in need thereof (i) a therapeutically effective amount of a first anti-cancer agent selected from the group consisting of erlotinib, and (ii) an effective amount of an agent that increases the rate of metabolism of erlotinib by the patient, to treat the cancer.
  • Administration of the first anti-cancer agent in combination with an agent that increases the rate of metabolism of erlotinib desirably provides a superior anti-cancer effect relative to administration of the first anti-cancer agent without an agent that increases the rate of metabolism of erlotinib.
  • Another more specific aspect of the invention provides a method of treating cancer in a patient, wherein the method comprises the steps of:
  • step (b) beginning on the day following the administration in step (a), orally administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 1 ,500 mg of erlotinib;
  • step (c) administering to the patient an effective amount of an agent that increases the rate of clearance (such as metabolism) of erlotinib, so that erlotinib administered to the patient in step (b) undergoes clearance (such as metabolism) at an accelerated rate;
  • step (f) beginning on the fifteenth day following the administration in step (a), orally administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 1,500 mg of erlotinib; to thereby treat the cancer.
  • Administration of the first anti-cancer agent in combination with an agent that increases the rate of clearance (such as metabolism) of erlotinib desirably provides a superior anti-cancer effect relative to administration of the first anti-cancer agent without an agent that increases the rate of clearance (such as metabolism) of erlotinib.
  • the therapeutic method may be used to treat a variety of cancers, as described in more detail below.
  • Another more specific aspect of the invention provides a method for treating cancer in a patient, wherein the method comprises the steps of:
  • step (b) beginning on the day following the administration in step (a), orally administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 2,000 mg of erlotinib; and thereafter not administering any erlotinib to the patient for a period of at least about 10 days;
  • step (c) administering to the patient an effective amount of an agent that increases the rate of clearance (such as metabolism) of erlotinib, so that erlotinib administered to the patient in step (b) undergoes clearance (such as metabolism) at an accelerated rate;
  • step (f) beginning on the fifteenth day following the administration in step (a), orally administering to the patient in need thereof a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 2,000 mg of erlotinib; to thereby treat the cancer.
  • Administration of the first anti-cancer agent in combination with an agent that increases the rate of clearance (such as metabolism) of erlotinib desirably provides a superior anti-cancer effect relative to administration of the first anti-cancer agent without an agent that increases the rate of clearance (such as metabolism) of erlotinib.
  • the therapeutic method may be used to treat a variety of cancers, as described in more detail below.
  • Another aspect of the invention provides a method of inducing ischemia- reperfusion in a tumor in a patient, wherein the method comprises administering to a patient in need thereof: (i) at least two doses on consecutive days of a therapeutically effective amount of a first anti- cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof, and a pharmaceutically acceptable salt thereof, and (ii) an effective amount of an agent that increases the rate of clearance of the anti-cancer agent from the patient, to induce ischemia-reperfusion in a tumor in a patient.
  • a first anti- cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof, and a pharmaceutically acceptable salt thereof
  • the agent that increases the rate of clearance of the first anti-cancer agent may be, for example, (i) an agent that increases the rate of metabolism of the first anticancer agent by the patient or (ii) an agent that increases the rate of excretion of the first anticancer agent from the patient.
  • Another aspect of the invention provides a method of inducing ischemia- reperfusion in a tumor in a patient, wherein the method comprises administering to a patient in need thereof (i) at least two doses on consecutive days of a therapeutically effective amount of a first anti-cancer agent selected from the group consisting of erlotinib, and (ii) an effective amount of an agent that increases the rate of clearance (such as metabolism) of erlotinib by the patient, to induce ischemia-reperfusion in a tumor in a patient.
  • a first anti-cancer agent selected from the group consisting of erlotinib
  • an agent that increases the rate of clearance such as metabolism
  • Another aspect of the invention provides a method for treating cancer in a patient.
  • the method comprises administering to a patient in need thereof (i) a therapeutically effective amount of a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof, and (ii) an effective amount of an agent that increases the rate of clearance of the first anti-cancer agent from the patient, to treat the cancer.
  • a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof.
  • the agent that increases the rate of clearance of the first anti-cancer agent may be, for example, (i) an agent that increases the rate of metabolism of the first anti-cancer agent by the patient or (ii) an agent that increases the rate of excretion of the first anti-cancer agent from the patient.
  • Another aspect of the invention provides a method for treating cancer in a patient.
  • the method comprises administering to a patient in need thereof (i) a therapeutically effective amount of a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof, and (ii) an effective amount of an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent by the patient, to treat the cancer.
  • a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof
  • an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent by the patient to treat the cancer.
  • Another aspect of the invention provides a method for inducing ischemia- reperfusion in a tumor in a patient.
  • the method comprises administering to a patient in need thereof (i) a therapeutically effective amount of a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof, and (ii) an effective amount of an agent that increases the rate of clearance of the first anti-cancer agent from the patient, to induce ischemia-reperfusion in a tumor in a patient.
  • a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof
  • an agent that increases the rate of clearance of the first anti-cancer agent from the patient to induce ischemia-reperfusion in a tumor in a patient.
  • the agent that increases the rate of clearance of the first anti-cancer agent may be, for example, (i) an agent that increases the rate of metabolism of the first anti-cancer agent by the patient or (i) an agent that increases the rate of excretion of the first anti-cancer agent from the patient.
  • a more specific aspect of the invention provides a method for inducing ischemia- reperfusion in a tumor in a patient.
  • the method comprises administering to a patient in need thereof (i) a therapeutically effective amount of a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof, and (ii) an effective amount of an agent that increases the rate of metabolism of the first anti-cancer agent by the patient, to induce ischemia-reperfusion in a tumor in a patient.
  • a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof
  • an agent that increases the rate of metabolism of the first anti-cancer agent by the patient to induce ischemia-reperfusion in a tumor in a patient.
  • Another aspect of the invention provides a method for treating cancer in a patient.
  • the method comprises administering to a patient in need thereof (i) a therapeutically effective amount of a first anti-cancer agent selected from the group consisting of bevacizumab, aflibercept, ramucirumab, and combinations thereof, and (ii) an effective amount of an agent that increases the rate of clearance of the first anti-cancer agent from the patient, to treat the cancer.
  • the first anti-cancer agent is bevacizumab.
  • a further embodiment involves further comprising administering to the patient a second anti-cancer agent.
  • the second anti-cancer agent comprises erlotinib.
  • the above therapeutic methods may be further characterized by additional features, such as the timing for administering the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent (e.g. erlotinib), and the dose amount of the first anticancer agent.
  • the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent e.g. erlotinib
  • the dose amount of the first anticancer agent e.g. erlotinib
  • a further embodiment involves further comprising administering to the patient a second anti-cancer agent.
  • the second anti-cancer agent comprises erlotinib.
  • the therapeutic methods may be characterized according to the timing for administering the agent that increases the rate of clearance of the first anti-cancer agent.
  • the agent that increases the rate of clearance of the first anti- cancer agent is administered to the patient prior to administration of the first anticancer agent to the patient.
  • the agent that increases the rate of clearance of the first anti-cancer agent is administered to the patient concurrently with or after administration of the first anti-cancer agent to the patient.
  • the agent that increases the rate of clearance of the first anti-cancer agent is administered at a time such that at least some of the first anti-cancer agent administered to the patient will undergo more rapid clearance due to administration of the agent that increases the rate of clearance of the first anticancer agent.
  • the method further comprises administering to the patient an effective amount of an agent that increases the rate of clearance of the first anticancer agent on (i) the same day as the last administration of the first anti-cancer agent in any treatment cycle of the first anti-cancer agent or (ii) within 6 hours after the last administration of the first anti-cancer agent in any treatment cycle of the first anti-cancer agent.
  • Rate of clearance and/or metabolism of an angiogenesis inhibitor i.e., a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor
  • angiogenesis inhibitor i.e., a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor
  • Metabolism routes for TKIs and VEGF inhibitors are also known in the art, as as reviewed by Hartmann et al, Curr Drug Metab. 10(5):470-81. (2009).
  • the main cytochrome P450 (CYP) enzyme, CYP3A4 is implicated in the metabolism of almost all of the tyrosine kinase inhibitors (TKIs).
  • erlotinib is metabolized in the liver by cytochrome P450s, primarily by CYP3A4 and CYPlAl, but CYP3A5 also plays a minor role in erlotinib metabolism. Metabolism rate of erlotinib can be measured by methods described in Li et al., Clin. Cancer Res. 13(12):3731-7 (2007) and Ling et al, Drug Metab. Dispos. 34(3):420-6 (2006), each of which are here incorapted by reference.
  • the therapeutic method may be characterized according to the timing for administering the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent.
  • the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer is administered to the patient prior to administration of the first anti-cancer agent to the patient.
  • the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer is administered to the patient concurrently with or after administration of the first anti-cancer agent to the patient.
  • the key feature is that the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer is administered at a time such that at least some of the first anti-cancer administered to the patient will undergo more rapid metabolism due to administration of the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer.
  • the method further comprises administering to the patient an effective amount of an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer on (i) the same day as the last administration of the first anti-cancer agent in any treatment cycle of the first anti-cancer agent or (ii) within 6 hours after the last administration of the first anti-cancer agent in any treatment cycle of the first anti-cancer agent.
  • an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer on (i) the same day as the last administration of the first anti-cancer agent in any treatment cycle of the first anti-cancer agent or (ii) within 6 hours after the last administration of the first anti-cancer agent in any treatment cycle of the first anti-cancer agent.
  • the therapeutic method may be characterized according to the timing for administering the agent that increases the rate of clearance (such as metabolism) of erlotinib.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib is administered to the patient prior to administration of the first anti-cancer agent to the patient.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib is administered to the patient concurrently with or after administration of the first anti-cancer agent to the patient.
  • the key feature is that the agent that increases the rate of clearance (such as metabolism) of erlotinib is administered at a time such that at least some of the erlotinib administered to the patient will undergo more rapid metabolism due to administration of the agent that increases the rate of clearance (such as metabolism) of erlotinib.
  • the therapeutic method may be characterized according to the amount of increase in the rate of clearance (such as metabolism) of the first anti-cancer agent.
  • the rate of clearance (such as metabolism) of the first anti-cancer agent administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent.
  • the rate of clearance (such as metabolism) of the first anti-cancer agent administered to the patient is increased by at least 20% due to administration of the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent.
  • the rate of clearance (such as metabolism) of the first anti-cancer agent administered to the patient is increased by at least 40% due to administration of the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent. In certain embodiments, the rate of clearance (such as metabolism) of the first anti-cancer agent administered to the patient is increased by at least 60% due to administration of the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent. In certain embodiments, the rate of clearance (such as metabolism) of the first anti-cancer agent administered to the patient is increased by at least 100% due to administration of the agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent.
  • the rate of clearance (such as metabolism) of the first anti-cancer agent may be characterized and analyzed according to procedures described in the literature.
  • One approach for measuring the rate of clearance (such as metabolism) of the first anti-cancer agent is to determine the half-life of the first anti-cancer agent based on blood plasma samples taken from the patient.
  • the therapeutic method may be characterized according to the amount of increase in the rate of metabolism of the first anticancer agent.
  • the rate of metabolism of the first anticancer administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of the first anti-cancer.
  • the rate of metabolism of the first anti-cancer administered to the patient is increased by at least 20% due to administration of the agent that increases the rate of metabolism of the first anticancer.
  • the rate of metabolism of the first anti-cancer administered to the patient is increased by at least 40% due to administration of the agent that increases the rate of metabolism of the first anti-cancer. In certain embodiments, the rate of metabolism of the first anti-cancer administered to the patient is increased by at least 60% due to administration of the agent that increases the rate of metabolism of the first anti-cancer. In certain embodiments, the rate of metabolism of the first anti-cancer administered to the patient is increased by at least 100% due to administration of the agent that increases the rate of metabolism of the first anti-cancer.
  • the rate of metabolism of the first anti-cancer may be characterized and analyzed according to procedures described in the literature. One approach for measuring the rate of metabolism of the first anti-cancer is to determine the half-life of the first anti-cancer based on blood plasma samples taken from the patient.
  • the therapeutic methods may be characterized according to the identity of the agent that increases the rate of clearance of the first anti-cancer agent.
  • the agent that increases the rate of clearance of the first anti-cancer agent is selected from (i) an agent that increases the rate of metabolism of the first anti-cancer agent by the patient and (i) an agent that increases the rate of excretion of the first anti-cancer agent from the patient.
  • the agent that increases the rate of clearance of the first anti-cancer agent is an agent that increases the rate of metabolism of the first anti-cancer agent by the patient.
  • the therapeutic method may be characterized according to the identity of the agent that increases the rate of metabolism of erlotinib.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the therapeutic method may be characterized according to the identity of the agent that increases the rate of metabolism of erlotinib.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the therapeutic method may be characterized according to the amount of increase in the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 20% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 40% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 60% due to administration of the agent that increases the rate of metabolism of erlotinib. In certain embodiments, the rate of metabolism of erlotinib administered to the patient is increased by at least 100% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib may be characterized and analyzed according to procedures described in the literature. One approach for measuring the rate of metabolism of erlotinib is to determine the half-life of erlotinib based on blood plasma samples taken from the patient.
  • the therapeutic method may be characterized according to the dose amount of the first anti-cancer agent.
  • any administration of the first anti-cancer agent is administered at a daily dose in an amount sufficient to reduce blood flow in a tumor in the patient.
  • the therapeutic method may be characterized according to the dose amount of erlotinib.
  • any administration of the first anti-cancer agent is administered at a daily dose of at least 500 mg of erlotinib.
  • any administration of the first anticancer agent is administered at a daily dose of at least 1000 mg of erlotinib.
  • any administration of the first anti-cancer agent is administered at a daily dose of at least 2000 mg of erlotinib.
  • any administration of the first anticancer agent is administered at a daily dose in the range of about 1,000 mg per day to about 3,000 mg per day of erlotinib.
  • any administration of the first anticancer agent is administered at a daily dose in the range of about 1,500 mg per day to about 2,500 mg per day of erlotinib. In certain embodiments, any administration of the first anticancer agent is administered at a daily dose in the range of about 1,800 mg per day to about 2,200 mg per day of erlotinib. In certain embodiments, any administration of the first anticancer agent is administered at a daily dose of about 2000 mg per day of erlotinib.
  • the first anti-cancer agent comprises erlotinib, and any administration of the first anti-cancer agent is administered at a daily dose in the range of about 1,500 mg per day to about 2,500 mg per day of erlotinib. In certain embodiments, the first anticancer agent comprises erlotinib, and any administration of the first anti-cancer agent is administered at a daily dose in the range of about 1,800 mg per day to about 2,200 mg per day of erlotinib. In certain embodiments, the first anti-cancer agent comprises erlotinib, and any administration of the first anti-cancer agent is administered at a daily dose of about 2000 mg per day of erlotinib.
  • the therapeutic method may be characterized according to the timing and route for administration of the first anti-cancer agent.
  • the first anti-cancer agent is administered to the patient for two or three consecutive days.
  • the first anti-cancer agent is administered to the patient for 2 or 3 consecutive days, then after a period of at least 7 days during which the first anti-cancer agent is not administered to the patient, the first anti-cancer agent is administered to the patient for at least 2 consecutive days.
  • the first anti-cancer agent is administered to the patient for 2 or 3 consecutive days, then after a period of about 11 days during which the first anti-cancer agent is not administered to the patient, the first anti-cancer agent is administered to the patient for 2 or 3 consecutive days.
  • a second or subsequent dose of the first anti-cancer agent is administered to the patient after about 4-6 half-lives after administration of the prior dose of first anti-cancer agent to the patient.
  • the first anti-cancer agent is administered to the patient for two or three consecutive days.
  • the first anti-cancer agent is administered to the patient for 2 or 3 consecutive days, then after a period of at least 7 days during which the first anti-cancer agent is not administered to the patient, the first anti-cancer agent is administered to the patient for at least 2 consecutive days.
  • the first anti-cancer agent is administered to the patient for 2 or 3 consecutive days, then after a period of about 1 1 days during which the first anti-cancer agent is not administered to the patient, the first anti-cancer agent is administered to the patient for 2 or 3 consecutive days.
  • the first anti-cancer agent comprises gefitinib, and a 1000 mg dose of gefitinib is administered on days 2, 3, 4, 16, 17, and 18 of a 28-day cycle.
  • the first anti-cancer agent comprises imatinib, and a 800 mg dose of imatinib is administered on days 2, 3, 4, 16, 17, and 18 of a 28-day cycle.
  • the first anti-cancer agent comprises dasatinib, and a 140 mg dose of dasatinib is administered on days 2, 3, 4, 16, 17, and 18 of a 28-day cycle.
  • the first anti-cancer agent comprises nilotinib, and a 800 mg dose of nilotinib is administered on days 2, 3, 4, 16, 17, and 18 of a 28-day cycle.
  • the first anti-cancer agent comprises axitinib, and a 7 mg or 10 mg dose of axitinib is administered twice daily for 7 days on an alternating one-week-on then one-week-off schedule.
  • the first anticancer agent comprises apatinib, and a 750 mg dose of apatinib is administered twice daily for 7 days on an alternating one-week-on then one-week-off schedule.
  • the first anti-cancer agent is administered orally to the patient.
  • the therapeutic method may be characterized according to the identity of the first anti-cancer agent.
  • the first anti-cancer agent has a blood plasma half-life of less than 37 hours when the patient is not administered an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent.
  • the first anti-cancer agent is a VEGF inhibitor.
  • the first anti-cancer agent comprises erlotinib, gefitinib, afatinib, cetuximab, panitumumab, nintedanib, vandetanib, lapatinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, dovitinib, dasatinib, bosutinib, imatinib, regorafenib, cabozantinib, apatinib, or nilotinib.
  • the first anti-cancer agent comprises erlotinib.
  • the first anti-cancer agent is erlotinib hydrochloride.
  • the therapeutic method may be characterized according to whether a second anticancer agent is administered to the patient.
  • the method further comprises administering to the patient a second anti-cancer agent.
  • the second anti-cancer agent is a chemotherapeutic agent.
  • the second anti-cancer agent is gemcitabine or a pharmaceutically acceptable salt thereof.
  • the second anti-cancer agent is gemcitabine hydrochloride.
  • the second anti-cancer agent comprises radiation therapy, doxorubicin, cyclophosphamide, bleomycin, fluorouracil, methotrexate, mitoxantrone, vincristine, atoposide, cisplatin, carboplatin, oxaliplatin, irinotecan, temozolomide, a taxane, or an interferon.
  • the second anti-cancer agent is an oncolytic virus.
  • exemplary oncolytic viruses contemplated for use in the therapeutic methods described herein include those described in U.S. Patent Application Publication 201 1/031831 1, which is hereby incorporated by reference.
  • the second anti-cancer agent is an oncolytic virus that expresses a cytokine, such as GM-CSF, an interleukin (e.g., IL-1 , IL-2, IL-4, IL-12, IL-10, IL-19, or IL-20), or an interferon (e.g., interferon-alpha, interferon-beta, or interferon- gamma).
  • a cytokine such as GM-CSF
  • an interleukin e.g., IL-1 , IL-2, IL-4, IL-12, IL-10, IL-19, or IL-20
  • an interferon e.g., interferon-alpha, interferon-
  • additional anti-cancer agents include, for example, azacitidine, azathioprine, bleomycin, capecitabine, carmustine, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, fulvestrant, hydroxyurea, idarubicin, imatinib, lomustine, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raloxifene, teniposide, thiotepa, tioguanine, tamoxifen, toremifene, valrubicin, vinblast
  • the additional anti-cancer agent is abraxane; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amrubicin; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate: bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefmgol:
  • the therapeutic method may be characterized according to features of administration when the second anti-cancer agent administered to the patient comprises gemcitabine.
  • the therapeutic method may be characterized according to the dose of gemcitabine administered to the patient.
  • the second anti-cancer agent is administered at a dose providing at least 500 mg/m 2 of gemcitabine on each day it is administered to the patient.
  • the second anti-cancer agent is administered at a dose providing at least 1,000 mg/m 2 of gemcitabine on each day it is administered to the patient.
  • the second anti-cancer agent is administered at a dose providing about 1,000 mg/m 2 of gemcitabine on each day it is administered to the patient.
  • the therapeutic method may also be characterized according to the dosing schedule of the second therapeutic agent.
  • the second anti-cancer agent is administered on about day 1 and about day 8 of each 28-day cycle.
  • the second anti-cancer agent is administered on about day 1, about day 8, and about day 15 of each 28-day cycle.
  • the therapeutic method may be further characterized according to the route of administration of the second therapeutic agent.
  • the second anti-cancer agent e.g., comprising gemcitabine
  • the second anti-cancer agent is administered by intravenous injection to the patient.
  • the second anti-cancer agent is gemcitabine or a pharmaceutically acceptable salt thereof.
  • the second anti-cancer agent is gemcitabine hydrochloride.
  • the above second and third methods may be further characterized by additional features, such as (i) the number of doses of agent that increases the rate of clearance (such as metabolism) of erlotinib that are administered to the patient and/or (ii) the identity of the agent that increases the rate of clearance (such as metabolism) of erlotinib.
  • the method further comprises administering to the patient one or more additional doses of the agent that increases the rate of clearance (such as metabolism) of erlotinib.
  • the method further comprises administering to the patient one or more additional doses of the agent that increases the rate of clearance (such as metabolism) of erlotinib, so that erlotinib administered to the patient in step (f) undergoes metabolism at an accelerated rate.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib
  • the methods may be further characterized by the identity of active components used in the methods.
  • the formulation comprising gemcitabine contains gemcitabine hydrochloride.
  • the formulation comprising erlotinib contains erlotinib hydrochloride.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib is an agent that increases the activity of a cytochrome P450.
  • first, second, and third methods may be further characterized by additional features, such as the identity of the agent that increases the rate of clearance (such as metabolism) of erlotinib and/or the type of cancer treated.
  • the methods may be further characterized by the identity of the agent that increases the rate of clearance (such as metabolism) of erlotinib.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib is an agent that increases the activity of cytochrome P450 3A4.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib is selected from the group consisting of a corticosteroid, nicotine, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib is selected from the group consisting of nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglitazone, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the methods may be further characterized by the impact that the agent that increases the rate of clearance (such as metabolism) of erlotinib has on rate of clearance (such as metabolism) of erlotinib by the patient.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib is administered to the patient in an amount that increases the rate of clearance (such as metabolism) of erlotinib by the patient by at least 15%.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib is administered to the patient in an amount that increases the rate of clearance (such as metabolism) of erlotinib by the patient by at least 25%.
  • the agent that increases the rate of clearance (such as metabolism) of erlotinib is administered to the patient in an amount that increases the rate of clearance (such as metabolism) of erlotinib by the patient by at least 50%.
  • the cancer is a solid tumor.
  • the cancer is pancreatic cancer, lung cancer, breast cancer, ovarian cancer, a primary melanoma, a metastatic melanoma, liver cancer, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, or prostate cancer.
  • the cancer is pancreatic cancer.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is a hematological malignancy.
  • the cancer is a leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.
  • the cancer is brain cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, stomach cancer, testicular cancer, or uterine cancer.
  • the cancer is brain cancer.
  • the cancer is a vascularized tumor, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma (e.g.
  • an angiosarcoma or chondrosarcoma larynx cancer, parotid cancer, bilary tract cancer, thyroid cancer, acral lentiginous melanoma, actinic keratoses, acute lymphocytic leukemia, acute myeloid leukemia, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, anal canal cancer, anal cancer, anorectum cancer, astrocytic tumor, bartholin gland carcinoma, basal cell carcinoma, biliary cancer, bone cancer, bone marrow cancer, bronchial cancer, bronchial gland carcinoma, carcinoid, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell carcinoma, connective tissue cancer, cystadenoma,
  • the cancer is non-Hodgkin's lymphoma, such as a B- cell lymphoma or a T-cell lymphoma.
  • the non-Hodgkin's lymphoma is a B-cell lymphoma, such as a diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, or primary central nervous system (CNS) lymphoma.
  • B-cell lymphoma such as a diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphom
  • the non-Hodgkin's lymphoma is a T-cell lymphoma, such as a precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, or peripheral T-cell lymphoma.
  • T-cell lymphoma such as a precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, or
  • the therapeutic methods may be further characterized according to the therapeutic benefit provided by the method relative to monotherapy using just the first anti-cancer agent.
  • the improvement in anti-cancer activity achieved by the therapeutic method is at least a 10%, 25%, or 50% improvement in cancer-cell kill rate relative to administration of the first anti-cancer agent without administration of agent that increases the rate of clearance (such as metabolism) of erlotinib.
  • the therapeutic methods may be further characterized according to the patient to be treated.
  • the patient is an adult human. In certain other embodiments, the patient is a pediatric human.
  • Additional exemplary benefits of therapeutic methods described herein include (i) induction of ischemia-reperfusion and/or (ii) reduction in adverse side effects associated with the second anti-cancer agent. These are described in more detail below.
  • Ischemia-reperfusion may occur when the first anti-cancer agent is dosed in a pulsatile manner to the patient. Upon administration of the first anti-cancer agent, blood flow to the tumor is reduced, resulting in ischemic conditions in at least some of the tumor. Once the effect of the first-anti-cancer agent wears off, blood flow to the tumor increases - this is characterized as reperfusion. This ischemia-reperfusion can provide benefits to patients suffering from cancer.
  • a benefit of the therapeutics methods may include a reduction in adverse side effects associated with the second anti-cancer agent. This can include a reduction in the magnitude of the adverse event and/or reduction in the frequency of the adverse event.
  • the second anti-cancer agent is a chemotherapeutic agent
  • one benefit of the therapeutic methods may include chemo-protection, which means that the patient suffers reduced adverse side effects from the chemotherapy.
  • the second anti-cancer agent is radiotherapy
  • one benefit of the therapeutic methods may include radioprotection, which means that the patient suffers reduced adverse side effects from the radiation therapy.
  • kits for treating cancer comprises: (i) a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof, or an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent by the patient, and (ii) instructions for treating a cancer according to procedures described herein, such as administering to a patient in need thereof (a) a therapeutically effective amount of a first anticancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof, and (b) an effective amount of an agent that increases the rate of clearance (such as metabolism) of the first anti-cancer agent by the patient.
  • a first anti-cancer agent selected from the group consisting of a VEGF inhibitor, VEGF receptor inhibitor, a tyrosine kinase inhibitor, and combinations thereof
  • kits for treating cancer comprises: (i) a first anti-cancer agent selected from the group consisting of erlotinib, or an agent that increases the rate of clearance (such as metabolism) of erlotinib by a patient, and (ii) instructions for treating a cancer according to procedures described herein, such as administering to a patient in need thereof (a) a first anti-cancer agent selected from the group consisting of erlotinib, and (b) an effective amount of an agent that increases the rate of clearance (such as metabolism) of erlotinib by the patient.
  • the kit comprises (i) a formulation comprising erlotinib or a pharmaceutically acceptable salt thereof, (ii) a formulation comprising an agent that increases the rate of clearance (such as metabolism) of erlotinib, and (iii) instructions for treating cancer according to procedures described herein, such as administering to a patient in need thereof (a) a dose of a therapeutically effective amount of a formulation comprising erlotinib or a pharmaceutically acceptable salt thereof, and (b) a dose of an effective amount of a formulation comprising an agent that increases the rate of clearance (such as metabolism) of erlotinib by the patient.
  • the present invention relates to methods, kits and pharmaceutical compositions for treating or preventing a cutaneous abnormality in a patient.
  • a cutaneous abnormality refers to a condition having abnormality of development or an epithelial anomaly of growth and differentiation.
  • the present invention provides a method for treating a cutaneous abnormality in a subject in need thereof, such as a human patient.
  • the method comprises administering to the patient a therapeutically effective amount of an angiogenesis inhibitor, and an therapeutically effective amount of one or more agents capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • the TKI is an epidermal growth factor receptor (EGFR) inhibitor.
  • the EGFR inhibitor is an anti-EGFR antibody or small molecule EGFR inhibitor.
  • the EGFR inhibitor is cetuximab, erlotinib, gefitinib, or panitumumab.
  • the TKI inhibitor is sunitinib, sorafenib, pazopanib, axitinib, tivozanib, regorafenib, nintedanib, cabozantinib, lenvatinib or vandetanib.
  • the TKI is erlotinib.
  • erlotinib is administered at a dose in the range of about 500 mg to about 5000 mg per day.
  • the VEGF inhibitor is an antibody or antibody-like decoy trap. In some embodiments, the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept. [00243] In some embodiments, the TKI is erlotinib, and the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 1,500 mg of erlotinib.
  • the TKI is erlotinib
  • the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 2,000-5,000 mg of erlotinib; and thereafter not administering any erlotinib to the patient for a period of at least about 10 days.
  • the method comprises administering the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) to the patient daily for two, three, four, or five consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient, administering the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) to the patient for another two, three, four, or five consecutive days.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the method comprises administering angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) to the patient for two, three, four, or five times within a week, then after a period of at least 7, 10, 14, or 21 days during which the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient, administering the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) to the patient for another two, three, four, or five times within another week.
  • angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the method comprises administering the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient, administering the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) to the patient not more than 5 times in another week.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the agent capable of enhancing therapeutic efficacy of the angiogenesis inhibitor is administered to the patient prior to, concurrently with, or after administration of angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor).
  • angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor.
  • the agent capable of enhancing efficacy of the angiogenesis inhibitor is a retinoid.
  • the retinoid is selected from the group consisting of tazarotene, retinoic acid, tretinoin, isotretinoin, adapalene, bexarotene, alitretinoin, vitamin A, retinol, retinoic acid, retinal, retinyl palmitate, retinyl acetate, ethyl 5-(2-(4,4- dimethylthiochroman-6-yl)ethynyl)thiophene-2-carboxylate, 6- (2-4,4- dimethylthiochroman-6-yl)-ethynyl)-3-pyridylmethanol, and 2-(2-(4,4- dimethylthiochroman-6- yl)-ethynyl)-ethynyl)
  • agents capable of enhancing efficacy of the angiogenesis inhibitor include, but are not limited to, cardiac glycoside, clindamycin, erythromycin, benzoyl peroxide, azelaic acid, dapsone, clotrimazole, psoralen plus ultraviolet A (PUVA), permethrin, calcipotriene, adalimumab, coal tar, etanercept, infliximab, tazarotene, and alefacept.
  • cardiac glycoside clindamycin, erythromycin, benzoyl peroxide, azelaic acid, dapsone, clotrimazole, psoralen plus ultraviolet A (PUVA), permethrin, calcipotriene, adalimumab, coal tar, etanercept, infliximab, tazarotene, and alefacept.
  • PUVA psoralen plus ultraviolet A
  • the method comprises administering the retinoid to the patient daily for three consecutive days, then after a period of at least 7, 10, 14, or 21 days during which retinoid is not administered to the patient, administering retinoid to the patient for another three consecutive days.
  • the method comprises administering a retinoid to the patient daily for three consecutive days in a week for two consecutive weeks, then after a period of at least 7, 10, 14, or 21 days during which retinoid is not administered to the patient, administering retinoid to the patient for another three consecutive days in a week for two consecutive weeks.
  • the method comprises administering a retinoid to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the retinoid is not administered to the patient, administering the retinoid to the patient not more than 5 times in another week.
  • the retinoid is isotretinoin, and wherein isotretinoin is administered to the patient at an initial dosage of about 10 mg/day or 40 mg/day for the first two to four weeks, then at a dosage of about 1 mg/kg/day after the first two to four weeks.
  • the retinoid is isotretinoin, and wherein the total dosage of isotretinoin is about 120 mg/kg to 200 mg/kg. In some embodiments, the retinoid is isotretinoin, and isotretinoin is administered to the patient at 160 mg/m 2 /day in 2 divided doses. In some embodiments, the retinoid is tretinoin, and wherein tretinoin is administered at 45 mg/m 2 /day in 2 divided doses.
  • the retinoid is tretinoin, and wherein the total dosage of tretinoin is about 630 mg to 1000 mg.
  • the method further comprises administering to the patient an agent capable of increasing the rate of metabolism of the angiogenesis inhibitor, and/or the metabolism of the agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the angiogenesis inhibitor is erlotinib
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the angiogenesis inhibitor is erlotinib
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the angiogenesis inhibitor is a TKI or a VEGF inhibitor
  • the agent capable of increasing the rate of metabolism of the TKI or a VEGF inhibitor is selected from the group consisting of tetracycline, corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglitazone, and any combination thereof.
  • the corticosteroid is dexamethasone.
  • the method further comprises administering to a patient in need thereof a therapeutically effective amount of an agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor and /or the metabolism of the agent capable of enhancing efficacy of the angiogenesis inhibitor.
  • the agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor is an antibiotic.
  • the method further comprises administering to the patient a therapeutically effective amount of azithromycin.
  • azithromycin refers to (2R,3S,4R,5R,8R,10R,l lR, 12S, 13S, 14R)-2-ethyl-3,4, 10-trihydroxy-3,5,6,8, 10, 12,14- heptamethyl-15-oxo-l l- ⁇ [3,4,6 rideoxy-3-(dimethylamino)- -D-xylo-hexopyranosyl]oxy ⁇ - l -oxa-6-azacyclopentadec-13-yl2,6-dideoxy-3C-methyl-3-0-methyl-a-L-ribo- hexopyranoside, any salts thereof, and any functional derivatives thereof.
  • azithromycin is administered to the patient at a dosage of 500-2000 mg for three days every week.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is selected from the group consisting of cardiac glycoside, clindamycin, erythromycin, benzoyl peroxide, azelaic acid, dapsone, clotrimazole, psoralen plus ultraviolet A (PUVA), permethrin, calcipotriene, adalimumab, coal tar, etanercept, infliximab, tazarotene, alefacept, and combinations thereof.
  • PUVA psoralen plus ultraviolet A
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is a cardiac glycoside.
  • the cardiac glycoside is selected from digoxin.
  • the digoxin is administered at 0.125-0.5 mg/day orally.
  • the angiogenesis inhibitor and/or the agent capable of enhancing the efficacy of the angiogenesis inhibitor are administered to the patient topically, orally, intravenously, intramuscularly, subcutaneously, intradermally, or any combination thereof.
  • the cutaneous abnormality is selected from the group consisting of benign skin conditions, inflammatory skin conditions, precancerous skin conditions, autoimmune skin conditions and cancerous skin conditions.
  • the benign skin condition is selected from the group consisting of skin rash, acne, herpes zoster (shingles), post herpetic neuralgia (PNH) and rosacea.
  • the autoimmune skin condition is psoriasis.
  • the precancerous skin condition is actinic keratosis.
  • the cancerous skin condition is selected from the group consisting of melanoma, squamous cell carcinoma, and basal cell carcinoma.
  • the cutaneous abnormality is a noncancerous condition
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is not administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the cutaneous abnormality is a cancerous condition
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is optionally administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the cutaneous abnormalities to be treated or prevented include, but are not limited to, benign skin conditions, inflammatory skin conditions, autoimmune skin conditions, dysplastic skin conditions (precancerous), and malignant skin conditions (cancerous).
  • the cutaneous abnormality to be treated or prevented is noncancerous. In some embodiments, the cutaneous abnormality to be treated or prevented is cancerous. In some embodiments, the cutaneous abnormality to be treated or prevented has a risk of developing into cancer.
  • the cutaneous abnormalities to be treated of the present invention include, but are not limited to, skin rash, acne, psoriasis, rosacea, seborrhea, atopic dermatitis (which is really eczema), parasitic infections such as scabies, urticaria and drug eruptions, pityriasis, dermatomyositis, hidradenitis suppurative, pompholyx, behcet's disease, sarcoidosis, scalp folliculitis, folliculitis, tinea infections, Candida infections, shingles, vitiligo, warts, keloids, corns, lichen planus, corns and calluses, pemphigoid, chemotherapy -induced stomatitis, mouth ulcers, canker sores, herpes stomatitis, fungal nail infection, cold sore, ichthyosis vulgaris, molluscum cont
  • the cutaneous abnormality is a side effect of a cancer treatment.
  • the condition is skin rash due to an EGFR inhibitor treatment of a cancer.
  • the cancer is a solid tumor.
  • the cancer is pancreatic cancer, lung cancer, breast cancer, ovarian cancer, a primary melanoma, a metastatic melanoma, liver cancer, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, or prostate cancer.
  • the cancer is pancreatic cancer.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is a hematological malignancy.
  • the cancer is a leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.
  • the cancer is brain cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, stomach cancer, testicular cancer, or uterine cancer.
  • the cancer is brain cancer.
  • the cancer is a vascularized tumor, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma (e.g.
  • an angiosarcoma or chondrosarcoma larynx cancer, parotid cancer, bilary tract cancer, thyroid cancer, acral lentiginous melanoma, actinic keratoses, acute lymphocytic leukemia, acute myeloid leukemia, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, anal canal cancer, anal cancer, anorectum cancer, astrocytic tumor, bartholin gland carcinoma, basal cell carcinoma, biliary cancer, bone cancer, bone marrow cancer, bronchial cancer, bronchial gland carcinoma, carcinoid, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell carcinoma, connective tissue cancer, cystadenoma,
  • the cancer is non- Hodgkin's lymphoma, such as a B-cell lymphoma or a T-cell lymphoma.
  • the non-Hodgkin's lymphoma is a B-cell lymphoma, such as a diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, or primary central nervous system (CNS) lymphoma.
  • B-cell lymphoma such as a diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphom
  • the non-Hodgkin's lymphoma is a T-cell lymphoma, such as a precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T- cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, or peripheral T-cell lymphoma.
  • T-cell lymphoma such as a precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T- cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, or
  • methods of the present invention comprise administering to a patient in need of a therapeutically effective amount of an angiogenesis inhibitor.
  • an angiogenesis inhibitor of the present invention can inhibit the VEFG pathway.
  • the angiogenesis inhibitor is a VEGF inhibitor, or a tyrosine kinase inhibitor.
  • the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI).
  • TKI tyrosine kinase inhibitor
  • EGFR epidermal growth factor receptor
  • the agent is an inhibitor against a heterodimer formed by EGFR and another member of the ErbB receptor family such as EfbB2/Her2/neu, or a homodimmer formed by two EGFR molecules.
  • the agent is against the signaling pathway downstream of EGFR.
  • the EGFR inhibitor comprises a small molecule.
  • small molecule refers to a molecule having a molecular weight of less than 500 MW, wherein the drug is a non-peptidyl or peptide agent.
  • the EGFR inhibitor comprises a protein or a polypeptide.
  • the EGFR inhibitor comprises a hybrid molecule.
  • the EGFR inhibitor is an antibody. In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the EGFR inhibitor is an anti-EGFR ligand antibody. In some embodiments, the EGFR inhibitor is a humanized anti-EGFR ligand antibody. In some embodiments, the antibody is a monoclonal antibody. [00280] In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the drug is erlotinib. In some embodiments, the erlotinib is erlotinib hydrochloride or erlotinib in other form of pharmaceutically acceptable salt.
  • methods of the present invention comprise administering to a patient in need of a therapeutically effective amount of an agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the agent is capable of regulating epithelial cell growth.
  • the agent is a vitamin or a vitamer of a particular vitamin.
  • a vitamer is any of a number of chemical compounds, generally having a similar molecular structure, each of which shows vitamin-activity in a vitamin-deficient biological system.
  • the agent is a retinoid.
  • therapeutically effective amounts of a formulation comprising an angiogenesis inhibitor are amounts that are effective to inhibit the growth of abnormal cell growth.
  • angiogenesis inhibitor is a TKI, such as an EGFR inhibitor.
  • the EGFR inhibitor is erlotinib
  • the amount of erlotinib may be dosage units within a range corresponding to of about 500 mg to about 3000 mg per day, such as about 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1 100 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1 100 mg, 1800 mg, 1900mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg per day.
  • erlotinib is administered at a daily dose of at least 500 mg. In some embodiments, erlotinib is administered at a daily dose of at least 1000 mg. In some embodiments, erlotinib is administered at a daily dose of at least 2000 mg. In some embodiments, erlotinib is administered at a daily dose in the range of about 1 ,000 mg per day to about 3,000 mg per day. In some embodiments, erlotinib is administered at a daily dose in the range of about 1,500 mg per day to about 2,500 mg per day. In some embodiments, erlotinib is administered at a daily dose in the range of about 1,800 mg per day to about 2,200 mg per day. In some embodiments, erlotinib is administered at a daily dose of about 2000 mg per day.
  • the retinoid is isotretinoin.
  • the amount of isotretinoin may be dosage units within a range corresponding to about 10 mg/day or 40 mg/day for the first two to four weeks, then at a dosage of about 1 mg/kg/day after the first two to four weeks.
  • the total dosage of isotretinoin is about 120 mg/kg to 200 mg/kg, such as about 100 mg/kg, 110 mg/kg, 120 mg/kg, 130 mg/kg, 140 mg/kg, 150 mg/kg, 160 mg/kg, 170 mg/kg, 180 mg/kg, 190 mg/kg, 200 mg/kg or more.
  • the total dosage of isotretinoin is about 630 mg to 1000 mg. In some embodiments, the amount of isotretinoin is about 160 mg/m 2 /day in 2 divided doses. In some embodiments, the amount of isotretinoin is about 45 mg/m 2 /day in 2 divided doses.
  • the methods comprise topical application of the composition to skin of a subject.
  • the formulation is applied to facial, neck, hands, feet skin of the subject or other parts of the body as needed.
  • an angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • a pulse dose regimen Traditional dosing regimens are usually based on constant effect of the drug (e.g., constant target inhibition) and/or long half life of drug. Such regimens can only reach an optimal dose interval, but never a supra- therapeutic dose interval (see FIG. 1A).
  • a pulsed dosing regimen of the present invention is based on intermittent dosing and/or short half life of drug. Such regimens can reach not only optimal dose interval, but also a supra-therapeutic dose interval (see FIG. IB).
  • intermittent pulsed supra-therapeutic doses and an acceleration of metabolism of the drug lead to higher treatment efficacy, less treatment resistance, and/or less toxicity.
  • a dose of a therapeutically effective amount of an angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor is not administered to the patient for a second period of time.
  • Such administration and non-administration form a cycle of the regimen.
  • the cycle is repeated for once, twice, three times, four times, five times, six times, seven times, eight times, night times, ten times, or more, or until a desired end point is reached.
  • the dose of the angiogenesis inhibitor can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of the angiogenesis inhibitor.
  • the dose of the angiogenesis inhibitor is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times or more of an FDA-approved safe dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of the angiogenesis inhibitor can be administered prior to, during, or after administration of the angiogenesis inhibitor.
  • the significantly higher dose as described herein is reduced by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more.
  • the significantly higher dose reduced by 75%, 50%, and 25% for preterms, neonates and children, respectively.
  • the impaired cytochrome p450 activity in patient is due to cancer.
  • the patient having impaired cytochrome p450 activity has inflammation.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor is administered to the patient once, twice, three times or more per day.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the EGFR inhibitor is administered to the patient for once another day, and the administration time lasts for four days, six days, eight days, ten days or more.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor is administered to the patient for two, three, four, or five times within a week. Each of the two, three, four, or five times of administration can be consecutive to each other, equally separated, randomly separated, or combinations thereof.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient.
  • the second period of time can last at least about 7 days, 10 days, 14 days, 21 days, 28 days, or more.
  • the second period of time is long enough for the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) in the patient to be partially or completely metabolized, such as that about 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more of the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) in the patient has been metabolized.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor is administered to the patient again for another two, three, four, five, or more consecutive days.
  • an agent capable of enhancing the efficacy of the angiogenesis inhibitor is administered to the patient prior to, concurrently with, or after administration of the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor).
  • the agent is administered to the patient also based on a pulse dose regimen.
  • a dose of a therapeutically effective amount of the agent is administered to a patient one or more times within a third period of time so that the dose provides a supra- therapeutic dose within the third period of time, then the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient for a fourth period of time.
  • Such administration and non-administration form a cycle of the regimen.
  • the cycle is repeated for once, twice, three times, four times, five times, six times, seven times, eight times, night times, ten times, or more, or until a desired end point is reached.
  • the agent is administered to the patient once, twice, three times or more per day.
  • the agent is administered to the patient for several consecutive days, such as two consecutive days, three consecutive days, four consecutive days, five consecutive days, or more.
  • the agent is administered to the patient for once per day three consecutive days.
  • the agent is administered to the patient for once another day, and the administration time lasts for four days, six days, eight days, ten days or more.
  • the agent is administered to the patient for two, three, four, or five times within a week. Each of the two, three, four, or five times of administration can be consecutive to each other, equally separated, randomly separated, or combinations thereof.
  • the agent is administered to the patient for not more than three, four, or five times within a given week.
  • the agent is not administered to the patient.
  • the fourth period of time can last at least about 7 days, 10 days, 14 days, 21 days, 28 days, or more.
  • the fourth period of time is long enough for the agent in the patient to be partially or completely metabolized, such as that about 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more of the agent in the patient has been metabolized.
  • the agent is administered to the patient again according to the regimen described herein. In some embodiments, the agent is administered to the patient again for another two, three, four, five, or more consecutive days.
  • the regimen for the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the regimen for the agent capable of enhancing the efficacy of the angiogenesis inhibitor match with each other.
  • the first period of time is equal to the third period of time
  • the second period of time equal to the fourth period of time.
  • the schedule for administering the EGFR inhibitor and the schedule for administering the agent match with each other.
  • the EGFR inhibitor is administered to the patient on the same day when the agent capable of enhancing the efficacy of the angiogenesis inhibitor is administered to the patient.
  • the schedule for the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the regimen for the agent capable of capable of enhancing the efficacy of the angiogenesis inhibitor partially match (overlap) with each other.
  • the schedule for the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the schedule for the agent capable of enhancing the efficacy of the angiogenesis inhibitor do not overlap each other.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is not administered to the patient during the time when the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is optionally administered to the patient during the time when the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • a method of the present invention further comprises administering a therapeutically effective amount of an agent capable of increasing the rate of metabolism of angiogenesis inhibitor, and/or the metabolism of the agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • Agents capable of increasing the rate of metabolism of an angiogenesis inhibitor such as a TKI or a VEGF inhibitor include, but are not limited to tetracycline, corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglitazone, and any combination thereof.
  • corticosteroids that can be used in the present invention include, but are not limited to, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone a
  • the corticosteroid is dexamethasone. In some embodiments, the corticosteroid is a topical steroid, an inhaled steroid, an oral form steroid, or a systemic form steroid.
  • the agent is capable of increasing the metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 20% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 40% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 60% due to administration of the agent that increases the rate of metabolism of erlotinib. In some embodiments, the rate of metabolism of erlotinib administered to the patient is increased by at least 100% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib may be characterized and analyzed according to procedures described in the literature. One approach for measuring the rate of metabolism of erlotinib is to determine the half-life of erlotinib based on blood plasma samples taken from the patient.
  • an agent that increases the rate of metabolism of the angiogenesis inhibitor is administered on (i) the same day as the last administration of the angiogenesis inhibitor in any treatment cycle, or (ii) within about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 hours or more after the last administration of angiogenesis inhibitor in any treatment cycle.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450. Additional agent that can increase the rate of metabolism of an angiogenesis inhibitor can be screened and identified according to literatures.
  • the method of the present invention further comprises administering to the patient in need of one or more agents capable of reducing or preventing inhibitory effect on the metabolism rate of the angiogenesis inhibitor. In some embodiments, the method of the present invention further comprises administering to the patient in need of a cosmetic treatment or modality.
  • such agents include, but are not limited to, anti-fungals (e.g., fluconazole, itraconazole, micafungin, terbinafine, miconazole, and voriconazole), antifungal creams (e.g., ketoconazole, miconazole, terbinafine), antibiotics (e.g., cephalexin, dicl oxacillin, trovafloxacin, augmentin, penicillin, cyclosporin, dapsone), mycophenolate mofetil, PUVA phototherapy, biologies (e.g., Infliximab (Remicade®), Etanercept (Enbrel®), Adalimumab (Humira®), Ustekinumab (Stelara®), Secukinumb (Cosentxy®), Ixekizumab (Taltz®), Brodalumab (Siliq®)), chemotherapy (e.g., 5- FU
  • anti-fungals e
  • benzoyl peroxide tretinoin cream, oral or topical metronidazole, topical azaleic acid (e.g., gel, foam, cream), topical ivermectin, minocycline, doxycycline, topical brimonidine, pulsed dye laser, liquid nitrogen, dermabrasion, chemical peels, botox and disport, dermal fillers, antihistamines, sunscreen, aspirin and NSAIDs.
  • the invention also provides pharmaceutical compositions, which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated separately or together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g.
  • parenteral administration for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation
  • parenteral application for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin
  • topical application for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin
  • intravaginally or intrarectally for example, as a pessary, cream or foam
  • sublingually (6) ocularly; (7) trans dermally; or (8) nasally.
  • the invention also provides a kit for treating a cutaneous abnormality condition.
  • the kit comprises an angiogenesis inhibitor.
  • the kit comprises an agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the kit comprises an agent capable of increasing the metabolism rate of the angiogenesis inhibitor.
  • the kit comprises an agent capable of reducing or preventing inhibitory effect on the metabolism rate of the angiogenesis inhibitor.
  • the kit further comprises an instruction a cutaneous abnormality condition according to procedures described herein, such as administering to a patient in need thereof an angiogenesis inhibitor and an agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the instruction provides guidance to administering other agents as described herein, such as an agent capable of increasing the metabolism rate of the angiogenesis inhibitor, and/or an agent capable of reducing or preventing inhibitory effect on the metabolism rate of the angiogenesis inhibitor.
  • the invention provides therapeutic methods, kits, and pharmaceutical compositions for treating conditions in immunologically privileged sites, such as central nervous system (CNS), eyes, placenta and the fetus, and testicles.
  • immunologically privileged sites such as central nervous system (CNS), eyes, placenta and the fetus, and testicles.
  • the term "immunologically privileged site” refers to certain sites of a subject that they are able to tolerate the introduction of antigens without eliciting an inflammatory immune response, such as central nervous system (including brains and spinal cord), eyes, placenta and the fetus, and testes. Physical structures surrounding privileged sites cause a lack of lymphatic drainage, limiting the immune system's ability to enter the site.
  • Other conditions to be treated may include conditions related to certain endocrine organs (e.g., prostate, adrenal cortex, testis, ovary), placenta, uterus, renal tubule, and joints.
  • endocrine organs e.g., prostate, adrenal cortex, testis, ovary
  • placenta e.g., uterus, renal tubule, and joints.
  • inflammatory immune response can be used to refer to any specific types, including but not limited to, appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, RSD/CRPS, rhinitis, tendonitis, tonsillitis, and vasculitis.
  • a condition to be treated by a method of the present invention lead to inflammation (e.g., inflammation due to a tumor) in the immunologically privileged sites.
  • inflammation e.g., inflammation due to a tumor
  • the barrier around these sites e.g., Blood-Brain- Barrier, Blood-Ocular-Barrier, Placental Blood Barrier, and/or the Blood Testis Barrier
  • the barrier around these sites e.g., Blood-Brain- Barrier, Blood-Ocular-Barrier, Placental Blood Barrier, and/or the Blood Testis Barrier
  • Inflammation and disruption of the barrier can unleash stromal cells and trigger tissue fibrosis or scar formation.
  • BBB blood brain barrier
  • perivascular fibroblasts and other precursor cells are activated to generate a transient fibrous extracellular matrix in the CNS.
  • the stromal cells sense inflammation and attract immune cells, which in turn drive myofibroblast differentiation.
  • This fibrotic/desmoplastic scar is a major barrier to entry of therapies such as chemotherapy as well as a major barrier to CNS regeneration.
  • Targeting of fibrosis/desmoplasia with use of methods of the present invention e.g., erlotinib
  • a TGF-beta trap and/or a PDGF trap may be used to improve penetration of other therapeutic agents for in treating a condition in immunologically privileged sites (e.g., a cancer).
  • the methods can also be used to treat neurological disorders, such as stroke, spinal cord injury, multiple sclerosis and Alzheimer's diseases.
  • a pharmaceutical composition of the present invention can decrease the scar-like tissue (fibrosis and desmoplasia) that retards or prevents entry of the pharmaceutical composition, or other therapies (e.g., chemotherapy).
  • therapies e.g., chemotherapy.
  • the present invention provides a method for treating a condition in an immunologically privileged site in a patient in need thereof.
  • the method comprises administering to the patient a therapeutically effective amount of an angiogenesis inhibitor; a therapeutically effective amount of one or more agents capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or the Platelet-Derived Growth Factor (PDGF) signaling pathway; or a therapeutically effective amount of an angiogenesis inhibitor, and a therapeutically effective amount of one or more agents capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the method for treating a condition in an immunologically privileged site comprises administering to the patient a therapeutically effective amount of a first agent, wherein the first agent is capable of decreasing connective tissue in the immunologically privileged site.
  • the method comprises administering to the patient a therapeutically effective amount of a second agent, wherein the second agent can increase blood flow in the immunologically privileged site.
  • the first agent and the second agent are administered to the patient, regardless orders.
  • the combination of the first agent and the second agent may be beneficial, as it increases drug delivery by land (e.g., decreased connective tissue) and by sea (e.g., increased blood flow).
  • the method further comprises administering to the patient a therapeutically effective amount of a third agent, wherein the third agent has increased delivery to its target due to the administration of the first agent and/or the second agent.
  • the first agent is an angiogenesis inhibitor.
  • the first agent is erlotinib.
  • the second agent is a TKI.
  • the second agent is axitinib.
  • the first agent is capable of targeting to abnormal fibroblasts and to reduce connective tissue or kill fibroblasts that are stimulated by TGFfi or connective tissue growth factor.
  • the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • the TKI is an epidermal growth factor receptor (EGFR) inhibitor.
  • the EGFR inhibitor is an anti-EGFR antibody or small molecule EGFR inhibitor.
  • the EGFR inhibitor is cetuximab, erlotinib, gefitinib, or panitumumab.
  • small molecule refers to a molecule having a molecular weight of less than 500 MW, wherein the drug is a non-peptidyl or peptide agent.
  • the EGFR inhibitor comprises a protein or a polypeptide.
  • the EGFR inhibitor comprises a hybrid molecule.
  • the EGFR inhibitor is an antibody. In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the EGFR inhibitor is an anti-EGFR ligand antibody. In some embodiments, the EGFR inhibitor is a humanized anti-EGFR ligand antibody. In some embodiments, the antibody is a monoclonal antibody.
  • the EGFR inhibitor is an anti-EGFR antibody.
  • the drug is erlotinib.
  • the erlotinib is erlotinib hydrochloride.
  • the term erlotinib refers to Tarceva® or any functional variants or derivatives thereof.
  • the angiogenesis inhibitor is erlotinib, gefitinib, afatinib, cetuximab, panitumumab, nintedanib, vandetanib, lapatinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, dovitinib, dasatinib, bosutinib, imatinib, regorafenib, cabozantinib, apatinib, or nilotinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, regorafenib, nintedanib, cabozantinib, lenvatinib, vandetanib, or any combination thereof, such as a combination of erlotinib and axitin
  • the TKI is erlotinib.
  • erlotinib is administered at a dose in the range of about 500 mg to about 5000 mg per day.
  • the VEGF inhibitor is an antibody or antibody-like decoy trap. In some embodiments, the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept.
  • the TKI is erlotinib
  • the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 1 ,500 mg of erlotinib.
  • the TKI is erlotinib
  • the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 2,000-5,000 mg of erlotinib; and thereafter not administering any erlotinib to the patient for a period of at least about 10 days.
  • the method comprises administering the angiogenesis inhibitor (e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof) to the patient daily for two, three, four, or five consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the angiogenesis inhibitor is not administered to the patient, administering the angiogenesis inhibitor to the patient for another two, three, four, or five consecutive days.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • the method comprises administering angiogenesis inhibitor (e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof) to the patient for two, three, four, or five times within a week, then after a period of at least 7, 10, 14, or 21 days during which the angiogenesis inhibitor is not administered to the patient, administering the angiogenesis inhibitor to the patient for another two, three, four, or five times within another week.
  • angiogenesis inhibitor e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof
  • the method comprises administering the angiogenesis inhibitor (e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof) to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the angiogenesis inhibitor is not administered to the patient, administering the angiogenesis inhibitor to the patient not more than 5 times in another week.
  • the angiogenesis inhibitor e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof
  • the agent capable of enhancing therapeutic efficacy of the angiogenesis inhibitor is administered to the patient prior to, concurrently with, or after administration of angiogenesis inhibitor (e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof).
  • angiogenesis inhibitor e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof.
  • the method comprises administering an agent capable of enhancing efficacy of the angiogenesis inhibitor to the patient daily for three consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the agent is not administered to the patient, administering the agent to the patient for another three consecutive days.
  • the method comprises administering an agent capable of enhancing efficacy of the angiogenesis inhibitor to the patient daily for three consecutive days in a week for two consecutive weeks, then after a period of at least 7, 10, 14, or 21 days during which the agent is not administered to the patient, administering the agent to the patient for another three consecutive days in a week for two consecutive weeks.
  • the method comprises administering an agent capable of enhancing efficacy of the angiogenesis inhibitor to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the agent is not administered to the patient, administering the agent to the patient not more than 5 times in another week.
  • the method further comprises administering to the patient an agent capable of increasing the rate of metabolism of the angiogenesis inhibitor, and/or the metabolism of the agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the angiogenesis inhibitor is erlotinib
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the angiogenesis inhibitor is erlotinib
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof, and wherein the agent capable of increasing the rate of metabolism of one or more of these angiogenesis inhibitor is selected from the group consisting of tetracycline, corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglit
  • TKI tyros
  • the method further comprises administering to a patient in need thereof a therapeutically effective amount of an agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor and /or the metabolism of the agent capable of enhancing efficacy of the angiogenesis inhibitor.
  • the agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor is an antibiotic.
  • the angiogenesis inhibitor and/or the agent capable of enhancing the efficacy of the angiogenesis inhibitor are administered to the patient topically, orally, intravenously, intramuscularly, subcutaneously, intradermally, or any combination thereof.
  • the condition is a noncancerous condition
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is not administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the condition is a cancerous condition
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is optionally administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway is an agent capable of inhibiting the interaction of a TGF- ⁇ ligand protein and a TGFfi receptor protein.
  • the TGF- ⁇ ligand protein is TGF- ⁇ - 1, TGF ⁇ -2, TGF ⁇ -3, or a combination thereof.
  • the agent is a TGF- ⁇ ligand trap, such as a TGF- ⁇ - ⁇ ligand trap.
  • the agent is an anti- TGF- ⁇ antibody.
  • the agent is an anti-TGF- ⁇ receptor antibody.
  • the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway is an agent capable of inhibiting a component in the downstream of TGF- ⁇ signaling pathway.
  • the agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway is an agent capable of inhibiting the interaction of a PDGF ligand protein and a PDGF receptor protein.
  • the PDGF ligand protein is PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and/or PDGF-DD.
  • the agent is a PDGF ligand trap.
  • the agent is an anti-PDGF antibody.
  • the agent is an anti-PDGF receptor antibody.
  • the PDGF ligand protein is PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and/or PDGF-DD.
  • the agent is a PDGF ligand trap.
  • the agent is an anti-PDGF antibody.
  • the agent is an anti-PDGF receptor antibody.
  • the PDGF ligand protein is PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC
  • agent capable of inhibiting the PDGF signaling pathway is an agent capable of inhibiting a component in the downstream of PDGF signaling pathway.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway is a protein, a small molecule, or combinations thereof.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway is a virus comprising a recombinant gene encoding a protein capable of inhibiting the TGF- ⁇ signaling pathway and/ or the PDGF signaling pathway .
  • the immunologically privileged site is selected from the group consisting of central nervous system (CNS), eyes, placenta and fetus, testicles, or any combination thereof.
  • CNS central nervous system
  • the condition to be treated is cancerous or non-cancerous.
  • the condition is a brain cancer.
  • Brain cancers include, but are not limited to, astrocytoma, Atypical Teratoid Rhaboid Tumor (ATRT), chondrosarcoma, choroid plexus, craniopharyngioma, cysts, ependymoma, germ cell tumor, glioblastoma, glioma, hemangioma, juvenile pilocytic astrocytoma, lipoma, lymphoma, medulloblastoma, meningioma, metastatic, neurofibroma, meuronal & mixed neuronal-glial tumors, oligoastrocytoma, oligodendroglioma, pineal tumor, pituitary tumor, PNET, and schwannoma.
  • Atypical Teratoid Rhaboid Tumor ATRT
  • chondrosarcoma choroid plexus
  • craniopharyngioma cysts
  • the condition is an intraocular cancer.
  • Intraocular cancers include, but are not limited to, melanoma, intraocular lymphoma, retinoblastoma, hemangioma, conjunctival melanoma, eyelid carcinoma, lacrimal gland tumor.
  • the condition is a noncancerous intraocular condition, including but not limited to, glaucoma, age- related macular degeneration such as wet age-related macular degeneration, diabetic macular edema, geographic atrophy, choroidal neovascularization, uveitis, diabetic retinopathy, retinovascular disease and other types of retinal degenerations.
  • the condition is a testicular cancer.
  • Testicular cancers include, but are not limited to, seminoma (e.g., typical seminomas and spermatocytic seminomas), non- seminoma (e.g., embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, and teratoma), and stromal tumors (e.g., leydig cell tumors and Sertoli cell tumors).
  • seminoma e.g., typical seminomas and spermatocytic seminomas
  • non- seminoma e.g., embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, and teratoma
  • stromal tumors e.g., leydig cell tumors and Sertoli cell tumors.
  • the condition is a noncancerous condition, including but not limited to, varicocele, hydrocele testis, spermatocele, endocrinedisorders, bell-clapper deformity, orchitis, epididymitis, anorchia, cryptorchidism, blue balls, and testicular prostheses.
  • the condition is a noncancerous neurological disease.
  • the condition is a neurodegenerative disease.
  • the neurological disease is a condition involving inflammation.
  • the neurological disease is a condition involving infection.
  • the neurological disease is an autoimmune disease.
  • the neurodegenerative diseases include, but are not limited to, ataxia-telangiectasia, autosomal dominant cerebellar ataxia, autosomal recessive spastic ataxia of Charlevoix-Saguenay, Baggio-Yoshinari syndrome, Batten disease, Alzheimer's Disease, Corticobasal degeneration, Creutzfeldt-Jakob disease, Estrogen and neurodegenerative diseases, Fatal familial insomnia, Frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), batten disease, hereditary motor and sensory neuropathy with proximal dominance, infantile refsum disease, Kufs disease, locomotor ataxia, lyme disease, Machado-Joseph disease, Mental retardation and microcephaly with pontine and cerebellar hypoplasia, Mitochondria associated membranes (MAM), Multiple system atrophy, neuroacanthocyto
  • the CNS infection diseases include, but are not limited to, fungal infections (Cryptococcal meningitis, Brain abscess, Spinal epidural infection), protozoal infections (e.g., toxoplasmosis, Malaria, Primary amoebic meningoencephalitis), bacterial infections (e.g., tuberculosis, Leprosy, neurosyphilis, bacterial meningitis, lyme disease, brain abscess, neuroborreliosis), viral infections (e.g., viral meningitis, Eastern equine encephalitis, St Louis encephalitis, Japanese encephalitis, West Nile encephalitis, Herpes simplex encephalitis, Rabies, California encephalitis virus, Varicella-zoster encephalitis, La Crosse encephalitis, Measles encephalitis, poliomyelitis, slow virus infections, which include Subacute sclerosing panence
  • the CNS inflammatory diseases include, but are not limited to, CNS vasculitis, antibody-mediated inflammatory brain disease, demyelinating conditions (e.g., multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM)), Rasmussen's encephalitis, neurosarcoidosis, and secondary inflammation.
  • demyelinating conditions e.g., multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM)
  • Rasmussen's encephalitis e.g., multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM)
  • Rasmussen's encephalitis e.g., sen's encephalitis
  • neurosarcoidosis e.g., asarcoidosis
  • secondary inflammation e.
  • the neurological disorder is stroke, spinal cord injury, multiple sclerosis or Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • the condition to be treated disrupts or breakdowns Blood- Brain- Barrier, Blood-Ocular-Barrier, Placental Blood Barrier, and/or the Blood Testis Barrier.
  • the condition to be treated leads to tissue fibrosis and/or desmoplasia in the immunologically privileged site.
  • the condition to be treated triggers tissue fibrosis or scar formation in the immunologically privileged site.
  • the condition to be treated lead to formation of fibrous extracellular matrix and/or fibrotic/desmoplastic scar in the immunologically privileged site.
  • the method further comprises administering an additional therapeutic agent for neurological disorder to the patient in need thereof.
  • the present invention also provides a method for improving penetration of a drug through Blood-Brain-Barrier, Blood-Ocular-Barrier, Placental Blood Barrier, and/or the Blood Testis Barrier in a patient in need thereof.
  • the method comprises administering the drug to the patient, and: administering to the patient a therapeutically effective amount of an angiogenesis inhibitor; administering to the patient a therapeutically effective amount of an angiogenesis inhibitor and an agent capable of enhancing the efficacy of the angiogenesis inhibitor; and/or administering to the patient a therapeutically effective amount of one or more agents capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or the Platelet- Derived Growth Factor (PDGF) signaling pathway.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet- Derived Growth Factor
  • the method comprises administering an additional drug to the patient.
  • the additional drug has increased access to its target and/or increased delivery due to the administration of the angiogenesis inhibitor, and/or the administration of the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway is a TGF- ⁇ trap molecule as described herein.
  • the agent capable of inhibiting the PDGF signaling pathway is a PDGF trap molecule as described herein.
  • the additional drug is an anti- cancer agent.
  • the present invention also provides a method for cell regeneration in a central nervous system (CNS) of a patient in need thereof.
  • the method comprises: administering to the patient a therapeutically effective amount of an angiogenesis inhibitor; administering to the patient a therapeutically effective amount of an angiogenesis inhibitor and an agent capable of enhancing the efficacy of the angiogenesis inhibitor; and/or administering to the patient a therapeutically effective amount of one or more agents capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or the Platelet- Derived Growth Factor (PDGF) signaling pathway.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet- Derived Growth Factor
  • the method comprises administering an additional drug to the patient.
  • the additional drug has increased access to its target and/or increased delivery due to the administration of the angiogenesis inhibitor, and/or the administration of the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • the additional drug is capable of promote cell regeneration in CNS.
  • the additional drug is capable of treating a neurological disease.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway is a TGF- ⁇ trap molecule as described herein.
  • the agent capable of inhibiting the PDGF signaling pathway is a PDGF trap molecule as described herein.
  • a method of the present invention further comprises administering a chemotherapy, a radiotherapy, a hormone therapy, a surgery of any combination thereof to the patient.
  • a method of the present invention further comprises administering an anti-cancer agent to the patient who received or will receive an angiogenesis inhibitor, and/or an agent capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway.
  • the anti-cancer agent is gemcitabine, doxorubicin, cyclophosphamide, bleomycin, fluorouracil, methotrexate, mitoxantrone, vincristine, atoposide, cisplatin, carboplatin, oxaliplatin, irinotecan, temozolomide, a taxane, an interferon, or a combination thereof.
  • a method of the present invention further comprises administering a second anti-cancer agent to the patient in need thereof.
  • the second anti-cancer agent is an oncolytic virus.
  • Exemplary oncolytic viruses contemplated for use in the therapeutic methods described herein include those described in U.S. Patent Application Publication 2011/0318311, which is hereby incorporated by reference.
  • the second anti-cancer agent is an oncolytic virus that expresses a cytokine, such as GM-CSF, an interleukin (e.g., IL-1, IL-2, IL-4, IL-12, IL-10, IL-19, or IL-20), or an interferon (e.g., interferon- alpha, interferon-beta, or interferon-gamma).
  • a cytokine such as GM-CSF
  • an interleukin e.g., IL-1, IL-2, IL-4, IL-12, IL-10, IL-19, or IL-20
  • an interferon e.g., interferon- alpha, interferon-beta, or interferon-gamma
  • additional anti-cancer agents include, but are not limited to, azacitidine, azathioprine, bleomycin, capecitabine, carmustine, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, fulvestrant, hydroxyurea, idarubicin, imatinib, lomustine, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raloxifene, teniposide, thiotepa, tioguanine, tamoxifen, toremifene, valrubicin, vinblastine,
  • the present invention also provides a method for treating a condition in an immunologically privileged site in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first agent and a therapeutically effective amount of a second agent, wherein the first agent is capable of decreasing connective tissue in the immunologically privileged site, and the second agent can increase blood flow in the immunologically privileged site.
  • the first agent is an angiogenesis inhibitor.
  • the first agent is erlotinib.
  • the second agent is a TKI.
  • the second agent is axitinib.
  • therapeutically effective amounts of a formulation comprising an angiogenesis inhibitor for treating a condition in an immunologically privileged site are amounts that are effective to inhibit the growth of abnormal cell growth.
  • the angiogenesis inhibitor is a TKI, such as an EGFR inhibitor.
  • the EGFR inhibitor is erlotinib
  • the amount of erlotinib may be dosage units within a range corresponding to of about 500 mg to about 3000 mg per day, such as about 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1100 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1100 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg per day.
  • erlotinib is administered at a daily dose of at least 500 mg. In some embodiments, erlotinib is administered at a daily dose of at least 1000 mg. In some embodiments, erlotinib is administered at a daily dose of at least 2000 mg. In some embodiments, erlotinib is administered at a daily dose in the range of about 1 ,000 mg per day to about 3,000 mg per day. In some embodiments, erlotinib is administered at a daily dose in the range of about 1,500 mg per day to about 2,500 mg per day. In some embodiments, erlotinib is administered at a daily dose in the range of about 1 ,800 mg per day to about 2,200 mg per day. In some embodiments, erlotinib is administered at a daily dose of about 2000 mg per day.
  • an angiogenesis inhibitor is administered to the patient based on a pulse dose regimen.
  • Traditional dosing regimens are usually based on constant effect of the drug (e.g., constant target inhibition) and/or long half-life of drug. Such regimens can only reach an optimal dose interval, but never a supra-therapeutic dose interval (see FIG. 1 A).
  • a pulsed dosing regimen of the present invention is based on intermittent dosing and/or short half-life of drug. Such regimens can reach not only optimal dose interval, but also a supra-therapeutic dose interval (see FIG. IB).
  • intermittent pulsed supra- therapeutic doses and an acceleration of metabolism of the drug lead to higher treatment efficacy, less treatment resistance, and/or less toxicity.
  • a dose of a therapeutically effective amount of an angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • Such administration and non-administration form a cycle of the regimen.
  • the cycle is repeated for once, twice, three times, four times, five times, six times, seven times, eight times, night times, ten times, or more, or until a desired end point is reached.
  • the angiogenesis inhibitor for treating a condition in an immunologically privileged site, during the first period of time, is administered to the patient once, twice, three times or more per day.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the EGFR inhibitor is administered to the patient for once another day, and the administration time lasts for four days, six days, eight days, ten days or more.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor is administered to the patient for two, three, four, or five times within a week. Each of the two, three, four, or five times of administration can be consecutive to each other, equally separated, randomly separated, or combinations thereof.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the second period of time can last at least about 7 days, 10 days, 14 days, 21 days, 28 days, or more.
  • the second period of time is long enough for the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) in the patient to be partially or completely metabolized, such as that about 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more of the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) in the patient has been metabolized.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor is administered to the patient again for another two, three, four, five, or more consecutive days.
  • an agent capable of enhancing the efficacy of the angiogenesis inhibitor is administered to the patient prior to, concurrently with, or after administration of the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor).
  • the agent is administered to the patient also based on a pulse dose regimen.
  • a dose of a therapeutically effective amount of the agent is administered to a patient one or more times within a third period of time so that the dose provides a supra-therapeutic dose within the third period of time, then the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient for a fourth period of time.
  • Such administration and non-administration form a cycle of the regimen.
  • the cycle is repeated for once, twice, three times, four times, five times, six times, seven times, eight times, night times, ten times, or more, or until a desired end point is reached.
  • the agent for treating a condition in an immunologically privileged site, during the third period of time, is administered to the patient once, twice, three times or more per day.
  • the agent is administered to the patient for several consecutive days, such as two consecutive days, three consecutive days, four consecutive days, five consecutive days, or more.
  • the agent is administered to the patient for once per day three consecutive days.
  • the agent is administered to the patient for once another day, and the administration time lasts for four days, six days, eight days, ten days or more.
  • the agent is administered to the patient for two, three, four, or five times within a week. Each of the two, three, four, or five times of administration can be consecutive to each other, equally separated, randomly separated,or combinations thereof.
  • the agent is administered to the patient for not more than three, four, or five times within a given week.
  • the agent for treating a condition in an immunologically privileged site, during the fourth period of time, is not administered to the patient.
  • the fourth period of time can last at least about 7 days, 10 days, 14 days, 21 days, 28 days, or more.
  • the fourth period of time is long enough for the agent in the patient to be partially or completely metabolized, such as that about 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more of the agent in the patient has been metabolized.
  • the agent for treating a condition in an immunologically privileged site, after the third period of time (e.g., after a cycle of the regimen is finished), the agent is administered to the patient again according to the regimen described herein. In some embodiments, the agent is administered to the patient again for another two, three, four, five, or more consecutive days.
  • the regimen for the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the regimen for the agent capable of enhancing the efficacy of the angiogenesis inhibitor match with each other.
  • the first period of time is equal to the third period of time
  • the second period of time equal to the fourth period of time.
  • the schedule for administering the angiogenesis inhibitor and the schedule for administering the agent match with each other.
  • the angiogenesis inhibitor is administered to the patient on the same day when the agent capable of enhancing the efficacy of the angiogenesis inhibitor is administered to the patient.
  • the schedule for the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the regimen for the agent capable of capable of enhancing the efficacy of the angiogenesis inhibitor partially match (overlap) with each other.
  • the schedule for the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the schedule for the agent capable of enhancing the efficacy of the angiogenesis inhibitor do not overlap each other.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is not administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is optionally administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • a method for treating a condition in an immunologically privileged site further comprises administering a therapeutically effective amount of an agent capable of increasing the rate of metabolism of angiogenesis inhibitor, and/or the metabolism of the agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • Agents capable of increasing the rate of metabolism of an angiogenesis inhibitor include, but are not limited to tetracycline, corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglitazone, and any combination thereof.
  • corticosteroids that can be used in the present invention include, but are not limited to, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone a
  • the corticosteroid is dexamethasone. In some embodiments, the corticosteroid is a topical steroid, an inhaled steroid, an oral form steroid, or a systemic form steroid.
  • the agent is capable of increasing the metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 20% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 40% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 60% due to administration of the agent that increases the rate of metabolism of erlotinib. In some embodiments, the rate of metabolism of erlotinib administered to the patient is increased by at least 100% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib may be characterized and analyzed according to procedures described in the literature. One approach for measuring the rate of metabolism of erlotinib is to determine the half-life of erlotinib based on blood plasma samples taken from the patient.
  • an agent that increases the rate of metabolism of the angiogenesis inhibitor is administered on (i) the same day as the last administration of the angiogenesis inhibitor in any treatment cycle, or (ii) within about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 hours or more after the last administration of angiogenesis inhibitor in any treatment cycle.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450. Additional agent that can increase the rate of metabolism of an angiogenesis inhibitor can be screened and identified according to literatures.
  • the method for treating a condition in an immunologically privileged site further comprises administering to the patient in need of one or more agents capable of reducing or preventing inhibitory effect on the metabolism rate of the angiogenesis inhibitor.
  • the method of the present invention further comprises administering to the patient in need of a cosmetic treatment or modality.
  • such agents include, but are not limited to, anti-fungals (e.g., fluconazole, itraconazole, micafungin, terbinafine, miconazole, and voriconazole), antifungal creams (e.g., ketoconazole, miconazole, terbinafine), antibiotics (e.g., cephalexin, dicloxacillin, trovafloxacin, augmentin, penicillin, cyclosporin, dapsone), mycophenolate mofetil, PUVA phototherapy, biologies (e.g., Infliximab (Remicade®), Etanercept (Enbrel®), Adalimumab (Humira®), Ustekinumab (Stelara®), Secukinumb (Cosentxy®), Ixekizumab (Taltz®), Brodalumab (Siliq®)), chemotherapy (e.g., 5- FU, Methotidib, X-
  • benzoyl peroxide tretinoin cream, oral or topical metronidazole, topical azaleic acid (e.g., gel, foam, cream), topical ivermectin, minocycline, doxycycline, topical brimonidine, pulsed dye laser, liquid nitrogen, dermabrasion, chemical peels, botox and disport, dermal fillers, antihistamines, sunscreen, aspirin and NSAIDs.
  • the invention also provides a kit for treating a condition as described herein.
  • the kit comprises an angiogenesis inhibitor.
  • the kit comprises an agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the kit comprises an agent capable of increasing the metabolism rate of the angiogenesis inhibitor.
  • the kit comprises an agent capable of reducing or preventing inhibitory effect on the metabolism rate of the angiogenesis inhibitor.
  • the kit further comprises an instruction for treating a condition according to procedures described herein, such as administering to a patient in need thereof an angiogenesis inhibitor and an agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the instruction provides guidance to administering other agents as described herein, such as an agent capable of increasing the metabolism rate of the angiogenesis inhibitor, and/or an agent capable of reducing or preventing inhibitory effect on the metabolism rate of the angiogenesis inhibitor.
  • the present invention relates to methods and pharmaceutical compositions for treating conditions associated with abnormal extracellular matrix (ECM).
  • ECM extracellular matrix
  • the abnormal ECM manifests as fibrosis, scarring and/or desmoplasia (growth of fibrous tissue around a neoplasm) in the patient.
  • the condition may be cancerous or non-cancerous.
  • the condition is in the patient's brain, the eye, pancreas, prostate, adrenal cortex, heart, blood vessels, GI tract, appendix, gallbladder, bile duct, liver, skin, spleen, lungs, prostate, testis, ovary, placenta, uterus, renal tubule, extremities, and/or joints.
  • the condition to be treated or prevented is cancer.
  • the condition to be treated or prevented has a risk of developing into cancer.
  • ECM composition and remodeling is known to be crucial for tumorigenesis and metastatic progression in cancer. Tumors have also been likened to wounds that fail to heal (Schafer and Wemer, (2008) Nat. Rev. Mol. Cell Biol. 9: 628-638). Thus, the tumor stroma exhibits some of the characteristics found in an unresolved wound (Bissell and Radisky, (2001) Nat. Rev. Cancer 1 : 46-54). Tumors are characteristically suffer than the surrounding normal tissue, which is induced by ECM deposition and remodeling by resident fibroblasts. (Butcher et al, (2009) Nat. Rev. Cancer 9: 108-122).
  • the condition is a pancreatic cancer. It is known that patients with pancreatic cancer show a marked stromal desmoplasia that often associates with tumor progression and poor disease outcome. (Pandol et al, Clin. Gastroenterol. Hepatol. (2009) 7: S44 - S47) Expression of matrix remodeling genes such as MMPs and collagen cross- linkers have also been shown to be predictive of a poor prognosis for breast cancer patients. (Erler et al.
  • Fibrosis can also predispose a tissue to malignancy; patients with cirrhosis of the liver or cystic fibrosis, conditions that are characterized by abnormal accumulation of collagen, have an increased risk of developing cancer. (Sorensen et al. Hepatology (1998) 28: 921 - 925).
  • the condition is a brain cancer.
  • Brain cancers include, but are not limited to, astrocytoma, Atypical Teratoid Rhaboid Tumor (ATRT), chondrosarcoma, choroid plexus, craniopharyngioma, cysts, ependymoma, germ cell tumor, glioblastoma, glioma, hemangioma, juvenile pilocytic astrocytoma, lipoma, lymphoma, medulloblastoma, meningioma, metastatic, neurofibroma, meuronal & mixed neuronal-glial tumors, oligoastrocytoma, oligodendroglioma, pineal tumor, pituitary tumor, PNET, and schwannoma.
  • Atypical Teratoid Rhaboid Tumor ATRT
  • chondrosarcoma choroid plexus
  • craniopharyngioma cysts
  • the condition is an intraocular cancer.
  • Intraocular cancers include, but are not limited to, melanoma, intraocular lymphoma, retinoblastoma, hemangioma, conjunctival melanoma, eyelid carcinoma, lacrimal gland tumor.
  • the condition is a noncancerous intraocular condition, including but not limited to, glaucoma, age- related macular degeneration such as wet age-related macular degeneration, diabetic macular edema, geographic atrophy, choroidal neovascularization, uveitis, diabetic retinopathy, retinovascular disease and other types of retinal degenerations.
  • the condition is a testicular cancer.
  • Testicular cancers include, but are not limited to, seminoma (e.g., typical seminomas and spermatocytic seminomas), non- seminoma (e.g., embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, and teratoma), and stromal tumors (e.g., leydig cell tumors and Sertoli cell tumors).
  • seminoma e.g., typical seminomas and spermatocytic seminomas
  • non- seminoma e.g., embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, and teratoma
  • stromal tumors e.g., leydig cell tumors and Sertoli cell tumors.
  • the condition is a noncancerous condition, including but not limited to, varicocele, hydrocele testis, spermatocele, endocrinedisorders, bell-clapper deformity, orchitis, epididymitis, anorchia, cryptorchidism, blue balls, and testicular prostheses.
  • the condition associated with abnormal ECM is selected from the group consisting of pancreatitis, cirrhosis, liver fibrosis, hepatitis B, hepatitis C, primary biliary cirrhosis, glial scar tissue, fibrocystic disease, Dupuytren's contracture, lung fibrosis, gingival hypertrophy, uterine or ovarian fibroids, endometriosis, silicosis, keloidosis, uterine fibrosis, cystic fibrosis, osteosclerosis, kidney fibrosis, diabetic nephropathy, scleroderma, glomerulosclerosis, asbestosis, exophthalmos of Grave's disease, proliferative vitreoretinopathy, anterior capsule cataract, corneal fibrosis, corneal scarring due to surgery, trabeculectomy- induced fibrosis, progressive subretinal fibrosis, and multifocal gran
  • the condition is a noncancerous neurological disease.
  • the condition is a neurodegenerative disease.
  • the neurological disease is a condition involving inflammation.
  • the neurological disease is a condition involving infection.
  • the neurological disease is an autoimmune disease.
  • the neurodegenerative diseases include, but are not limited to, ataxia-telangiectasia, autosomal dominant cerebellar ataxia, autosomal recessive spastic ataxia of Charlevoix-Saguenay, Baggio-Yoshinari syndrome, Batten disease, Alzheimer's Disease, Corticobasal degeneration, Creutzfeldt-Jakob disease, Estrogen and neurodegenerative diseases, Fatal familial insomnia, Frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), batten disease, hereditary motor and sensory neuropathy with proximal dominance, infantile refsum disease, Kufs disease, locomotor ataxia, lyme disease, Machado-Joseph disease, Mental retardation and microcephaly with pontine and cerebellar hypoplasia, Mitochondria associated membranes (MAM), Multiple system atrophy, neuroacanthocyto
  • the CNS infection diseases include, but are not limited to, fungal infections (Cryptococcal meningitis, Brain abscess, Spinal epidural infection), protozoal infections (e.g., toxoplasmosis, Malaria, Primary amoebic meningoencephalitis), bacterial infections (e.g., tuberculosis, Leprosy, neurosyphilis, bacterial meningitis, lyme disease, brain abscess, neuroborreliosis), viral infections (e.g., viral meningitis, Eastern equine encephalitis, St Louis encephalitis, Japanese encephalitis, West Nile encephalitis, Herpes simplex encephalitis, Rabies, California encephalitis virus, Varicella-zoster encephalitis, La Crosse encephalitis, Measles encephalitis, poliomyelitis, slow virus infections, which include Subacute sclerosing panence
  • the CNS inflammatory diseases include, but are not limited to, CNS vasculitis, antibody-mediated inflammatory brain disease, demyelinating conditions (e.g., multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM)), Rasmussen's encephalitis, neurosarcoidosis, and secondary inflammation.
  • demyelinating conditions e.g., multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM)
  • Rasmussen's encephalitis e.g., multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM)
  • Rasmussen's encephalitis e.g., sen's encephalitis
  • neurosarcoidosis e.g., neurosarcoidosis
  • secondary inflammation e.g., the condition comprises symptom of inflammation.
  • the neurological disorder is stroke, spinal cord injury, multiple sclerosis or Alzheimer
  • the condition to be treated by a method of the present invention lead to inflammation (e.g., inflammation due to a tumor) in the immunologically privileged sites.
  • inflammation e.g., inflammation due to a tumor
  • the barrier around these sites e.g., Blood-Brain-Barrier, Blood- Ocular-Barrier, Placental Blood Barrier, Blood Thymus Barrier and/or the Blood Testis Barrier
  • BBB blood brain barrier
  • perivascular fibroblasts and other precursor cells are activated to generate a transient fibrous extracellular matrix in the CNS.
  • the stromal cells sense inflammation and attract immune cells, which in turn drive myofibroblast differentiation.
  • This fibrotic/desmoplastic scar is a major barrier to entry of therapies such as chemotherapy as well as a major barrier to CNS regeneration.
  • Targeting of fibrosis/desmoplasia with use of methods of the present invention e.g., erlotinib
  • a TGF- ⁇ trap and/or a PDGF trap may be used to improve penetration of other therapeutic agents for in treating a condition in immunologically privileged sites (e.g., a cancer).
  • the methods can also be used to treat neurological disorders, such as stroke, spinal cord injury, multiple sclerosis and Alzheimer's diseases.
  • the condition to be treated disrupts or breaks down Blood-Brain-Barrier, Blood-Ocular-Barrier, Placental Blood Barrier, Blood Thymus Barrier and/or the Blood Testis Barrier.
  • the condition to be treated leads to tissue fibrosis and/or desmoplasia in an immunologically privileged site.
  • the condition to be treated triggers tissue fibrosis or scar formation in an immunologically privileged site.
  • the condition to be treated lead to formation of fibrous extracellular matrix and/or fibrotic/desmoplastic scar in an immunologically privileged site.
  • the abnormal ECM manifests as fibrosis/scarring and/or desmoplasia (growth of fibrous tissue around a neoplasm) in the patient.
  • Pathological ECM dysregulation mimicks an aberrant or overexuberant wound healing response.
  • CAFs cancer-associated fibroblasts
  • Disease associated fibroblasts mimic the wound healing response in at least 4 processes, as illustrated in FIG. 2. Accordingly, an agent capable of modulating the abnormal ECM may disrupt or hinder one or more of these four processes.
  • the myofibroblastic response during wound healing or tumorigenesis is potentially a reversible process; once the recruiter cytokine production (e.g.
  • TGF- ⁇ -l and PDGF is reduced with a TGF- ⁇ -l or PDGF traps the myofibroblastic cohort has the potential to undergo apoptosis.
  • Induction of desmoplasia During wound healing or tumorigenesis myofibroblasts secrete collagens type I and III, fibronectin, proteoglycans, and gly cos aminogly cans, which all provide a supportive or structural framework for wound healing. Targeting the disease associated fibroblasts with an angiogenesis inhibitor, such as an EGFR tyrosine kinase inhibitor, optionally along with additional agents, has the potential to decrease or inhibit the induction of desmoplasia.
  • angiogenesis inhibitor such as an EGFR tyrosine kinase inhibitor
  • EMT Endothelial to mesenchymal transition
  • VEGF inhibition either with a tyrosine kinase inhibitor such as erlotinib that also interferes with VEGF signaling or a primary VEGF-inhibitor such as Avastin or axitinib or a CXCL12-trap will prevent or decrease neoangiogenesis.
  • a tyrosine kinase inhibitor such as erlotinib that also interferes with VEGF signaling
  • a primary VEGF-inhibitor such as Avastin or axitinib or a CXCL12-trap
  • the present inventors discovered that modulating abnormal ECM as observed in tissue fibrosis and desmoplasia using a first agent capable of modulating the abnormal ECM improves the delivery and/or efficacy of a second agent in ameliorating a condition that is associated with the abnormal ECM.
  • an angiogenesis inhibitor such as a tyrosine kinase inhibitor (TKI) or a vascular endothelial growth factor (VEGF) inhibitor, reduces abnormal ECM, particularly when they are administered in a pulse-dosing regimen.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • the present invention provides a method for treating a condition associated with abnormal extracellular matrix (ECM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of one or more agents capable of modulating the abnormal ECM, and a therapeutically effective amount of one or more agents capable of ameliorating the condition.
  • ECM extracellular matrix
  • the present invention provides a method for treating a condition associated with abnormal extracellular matrix (ECM) in a patient in need thereof, the method comprising steps of: a) determining the whether the patient has an abnormal ECM; and b) administering to the patient a therapeutically effective amount of one or more agents capable of modulating the abnormal ECM, and a therapeutically effective amount of one or more agents capable of ameliorating the condition.
  • ECM extracellular matrix
  • the condition associated with abnormal extracellular matrix is cancer, and wherein the agent capable of ameliorating the condition is an anti-cancer agent.
  • the anti-cancer agent is gemcitabine, doxorubicin, cyclophosphamide, bleomycin, fluorouracil, methotrexate, mitoxantrone, vincristine, etoposide, cisplatin, carboplatin, oxaliplatin, irinotecan, temozolomide, a taxane, an interferon, or a combination thereof.
  • the anti- cancer agent is a chemotherapy, radiotherapy, tyrosine kinase inhibitor, an antihypertensive, a TGF- ⁇ trap, an anti-oxidant, a PPAR gamma agonist, an integrin antagonist, a TIMP-1 or TIMP- 2 inhibitor, a Farnesoid X receptor agonist, a caspase inhibitor, an AGE inhibitor, a RAGE inhibitor, LMW heparin, a PKC inhibitor, an ADAM- 10 inhibitor, a copper chelator, an anti- fibrotic cytokine, or a rho kinase inhibitor.
  • the antihypertensive is an ACE inhibitor or a calcium channel blocker.
  • the anti-fibrotic cytokine is HGF, BMP-7, or IL-10.
  • the anti-cancer agent is an oncolytic virus.
  • exemplary oncolytic vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; viruses contemplated for use in the therapeutic methods described herein include those described in U.S. Patent Application Publication 201 1/031831 1, which is hereby incorporated by reference.
  • the second anti-cancer agent is an oncolytic virus that expresses a cytokine, such as GM-CSF, an interleukin (e.g., IL-1 , IL-2, IL-4, IL-12, IL-10, IL- 19, or IL-20), or an interferon (e.g., interferon-alpha, interferon-beta, or interferon- gamma).
  • a cytokine such as GM-CSF
  • an interleukin e.g., IL-1 , IL-2, IL-4, IL-12, IL-10, IL- 19, or IL-20
  • an interferon e.g., interferon-alpha, interferon-beta, or interferon- gamma
  • additional anti-cancer agents include, but are not limited to, azacitidine, azathioprine, bleomycin, capecitabine, carmustine, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, fulvestrant, hydroxyurea, idarubicin, imatinib, lomustine, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raloxifene, teniposide, thiotepa, tioguanine, tamoxifen, toremifene, valrubicin, vinblastine,
  • the agent capable of modulating the abnormal ECM improves the delivery and/or efficacy of the agent capable of ameliorating the condition.
  • the combination of the agents is beneficial to the patient, as the agents increase drug delivery by land (e.g., decreased connective tissues) and by sea (e.g., increased blood flow).
  • the agent capable of modulating the abnormal ECM is administered to the patient prior to, concurrently with, or after administration of the agent capable of ameliorating the condition.
  • the agent capable of modulating the abnormal ECM is selected from the group consisting of an angiogenesis inhibitor, an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway, and an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • angiogenesis inhibitor an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the condition is selected from the group consisting of pancreatitis, cirrhosis, liver fibrosis, hepatitis B, hepatitis C, primary biliary cirrhosis, glial scar tissue, fibrocystic disease, Dupuytren's contracture, lung fibrosis, gingival hypertrophy, uterine or ovarian fibroids, endometriosis, silicosis, keloidosis, uterine fibrosis, cystic fibrosis, osteosclerosis, kidney fibrosis, diabetic nephropathy, scleroderma, glomerulosclerosis, asbestosis, exophthalmos of Grave's disease, proliferative vitreoretinopathy, anterior capsule cataract, corneal fibrosis, corneal scarring due to surgery, trabeculectomy-induced fibrosis, progressive subretinal fibrosis, and multifocal granulomatous chori
  • the condition comprises symptom of inflammation.
  • the condition disrupts or breaks down blood-tissue barriers such as the Blood- Brain-Barrier, Blood-Ocular-Barrier, Placental Blood Barrier, Blood Thymus Barrier and/or the Blood Testis Barrier.
  • the condition is in the patient's brain, the eye, pancreas, prostate, adrenal cortex, heart, blood vessels, GI tract, appendix, gallbladder, bile duct, liver, skin, spleen, lungs, prostate, testis, ovary, placenta, uterus, renal tubule, extremities, and/or joints.
  • the condition triggers tissue fibrosis or scar formation in the patient.
  • fibrous extracellular matrix and/or fibrotic/desmoplastic scar forms in an immunologically privileged site in the patient.
  • the condition is a neurological disorder.
  • the neurological disorder is stroke, spinal cord injury, multiple sclerosis or Alzheimer's disease (AD).
  • the condition is cancer
  • the agent capable of ameliorating the condition is an anti-cancer agent.
  • the anti-cancer agent is gemcitabine, doxorubicin, cyclophosphamide, bleomycin, fluorouracil, methotrexate, mitoxantrone, vincristine, atoposide, cisplatin, carboplatin, oxaliplatin, irinotecan, temozolomide, a taxane, an interferon, or a combination thereof.
  • the condition is cancer
  • the agent capable of ameliorating the condition is a chemotherapy, radiotherapy, tyrosine kinase inhibitor, an antihypertensive, a TGF- ⁇ trap, an anti-oxidant, a PPAR gamma agonist, an integrin antagonist, a TIMP-1 or TIMP-2 inhibitor, a Farnesoid X receptor agonist, a caspase inhibitor, an ACE inhibitor, a RAGE inhibitor, LMW heparin, a PKC inhibitor, an ADAM- 10 inhibitor, a copper chelator, an anti-fibrotic cytokine, or a rho kinase inhibitor.
  • the antihypertensive is an ACE inhibitor or a calcium channel blocker.
  • the anti-fibrotic cytokine is HGF, BMP-7, or IL-10.
  • the anti-cancer agent is an oncolytic virus.
  • exemplary oncolytic viruses contemplated for use in the therapeutic methods described herein include those described in U. S. Patent Application Publication 201 1/0318311 , which is hereby incorporated by reference.
  • the second anti-cancer agent is an oncolytic virus that expresses a cytokine, such as GM-CSF, an interleukin (e.g., IL-1 , IL-2, IL-4, IL-12, IL-10, IL- 19, or IL-20), or an interferon (e.g., interferon-alpha, interferon-beta, or interferon- gamma).
  • a cytokine such as GM-CSF
  • an interleukin e.g., IL-1 , IL-2, IL-4, IL-12, IL-10, IL- 19, or IL-20
  • an interferon e.g., interferon-alpha, interferon-
  • additional anti-cancer agents include, but are not limited to, azacitidine, azathioprine, bleomycin, capecitabine, carmustine, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, fulvestrant, hydroxyurea, idarubicin, imatinib, lomustine, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raloxifene, teniposide, thiotepa, tioguanine, tamoxifen, toremifene, valrubicin, vinblastine,
  • the present invention provides a method for modulating abnormal extracellular matrix (ECM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an agent capable of modulating the abnormal ECM, wherein the agent is selected from the group consisting of an angiogenesis inhibitor, an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway, and an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • ECM extracellular matrix
  • the present invention provides a method for modulating abnormal extracellular matrix (ECM) in a patient in need thereof, comprising: a) determining the whether the patient has an abnormal extracellular matrix (ECM); and b) administering to the patient a therapeutically effective amount of an agent capable of modulating the abnormal ECM, wherein the agent is selected from the group consisting of an angiogenesis inhibitor, an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway, and an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • ECM abnormal extracellular matrix
  • present invention provides a method for modulating abnormal extracellular matrix (ECM) in a patient in need thereof, comprising: a) administering to the patient a therapeutically effective amount of an angiogenesis inhibitor; b) administering to the patient a therapeutically effective amount of an angiogenesis inhibitor and an agent capable of enhancing the efficacy of the angiogenesis inhibitor; and/or c) administering to the patient a therapeutically effective amount of one or more agents capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the abnormal extracellular matrix manifests as fibrosis, scarring and/or desmoplasia in the patient.
  • the agent capable of modulating the abnormal ECM decreases the level of one or more ECM proteins selected from the group consisting of collagen, elastin, fibrillin, fibronectin, vitronectin, laminins, integrins, and proteoglycan.
  • level of the ECM proteins is determined at protein expression level.
  • protein expression level is analyzed using a specific antibody and a protein assay. Any suitable method or assay can be used to measure the level of the ECM protein expression in the biological sample of a subject. Numerous antibody-based detection formats arewell known in the art, and include ELISA (enzyme linked immunosorbent assay), radioimmunoassays, immunoblots, Western blots, flow cytometry, immunofluorescence assays, immunoprecipitation, protein A assays, Immunoelectrophoresis assays, and other related techniques.
  • antibody binding is detected by detecting a label on the primary antibody.
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody.
  • the secondary antibody is labeled.
  • Antibodies specific for the biomarkers may be provided in a diagnostic kit that incorporates at least one of these procedures to quantitate the biomarkers' expression.
  • the kit may contain other components, packaging, instructions, or other material to aid the quantitation of the protein and use of the kit.
  • Antibodies against the biomarkers can be obtained commercially or routinely made according to methods such as, but not limited to, inoculation of an appropriate animal with the polypeptide or an antigenic fragment, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or recombinant cells expressing nucleic acid encoding such antibodies.
  • level of the ECM proteins is analyzed at the mRNA level.
  • RT-PCR and a pair of specific primers may be used.
  • mRNA are prepared and analyzed according to well-established protocols.
  • the control level is the level of corresponding ECM protein in the patient before the administration of the agent capable of modulating the abnormal ECM.
  • the control level is a normal level, and/or a level not observed in patients having abnormal ECM.
  • the level of ECM protein decreases by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to the control level.
  • the agent capable of modulating the abnormal ECM is selected from the group consisting of an angiogenesis inhibitor, an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway, and an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • angiogenesis inhibitor an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • the TKI is an epidermal growth factor receptor (EGFR) inhibitor.
  • the EGFR inhibitor is an anti-EGFR antibody or small molecule EGFR inhibitor.
  • the EGFR inhibitor is cetuximab, erlotinib, gefitinib, or panitumumab.
  • the agent is against a heterodimer formed by EGFR and another member of the ErbB receptor family such as EfbB2/Her2/neu, or a homodimmer formed by two EGFR molecules.
  • the agent is against the signaling pathway downstream of EGFR.
  • the EGFR inhibitor comprises a small molecule.
  • the EGFR inhibitor comprises a protein or a polypeptide. In some embodiments, the EGFR inhibitor comprises a hybrid molecule. In some embodiments, the EGFR inhibitor is an antibody. In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the EGFR inhibitor is an anti-EGFR ligand antibody. In some embodiments, the EGFR inhibitor is a humanized anti-EGFR ligand antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the drug is erlotinib.
  • the angiogenesis inhibitor is erlotinib, gefitinib, afatinib, cetuximab, panitumumab, nintedanib, vandetanib, lapatinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, dovitinib, dasatinib, bosutinib, imatinib, regorafenib, cabozantinib, apatinib, nilotinib, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, regorafenib, nintedanib, cabozantinib, lenvatinib, vandetanib, or any combination thereof, such as a combination of erlotinib and axitini
  • the VEGF inhibitor is an antibody or antibody-like decoy trap. In some embodiments, the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept.
  • the TKI is erlotinib.
  • erlotinib is administered at a dose in the range of about 500 mg to about 5000 mg per day.
  • the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for at least two consecutive days at a daily dose that provides at least 1,500 mg of erlotinib.
  • the TKI is erlotinib
  • the patient is orally administered a dose of a therapeutically effective amount of a formulation comprising erlotinib once per day for three consecutive days at a daily dose of about 2,000-5,000 mg of erlotinib; and thereafter not administering any erlotinib to the patient for a period of at least about 10 days.
  • the method comprises administering the angiogenesis inhibitor (e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof) to the patient daily for two, three, four, or five consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the angiogenesis inhibitor is not administered to the patient, administering the angiogenesis inhibitor to the patient for another two, three, four, or five consecutive days.
  • TKI tyrosine kinase inhibitor
  • VEGF vascular endothelial growth factor
  • the method comprises administering angiogenesis inhibitor (e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof) to the patient for two, three, four, or five times within a week, then after a period of at least 7, 10, 14, or 21 days during which the angiogenesis inhibitor is not administered to the patient, administering the angiogenesis inhibitor to the patient for another two, three, four, or five times within another week.
  • angiogenesis inhibitor e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof
  • the method comprises administering the angiogenesis inhibitor (e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof) to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the angiogenesis inhibitor is not administered to the patient, administering the angiogenesis inhibitor to the patient not more than 5 times in another week.
  • the angiogenesis inhibitor e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof
  • the agent capable of enhancing therapeutic efficacy of the angiogenesis inhibitor is administered to the patient prior to, concurrently with, or after administration of angiogenesis inhibitor (e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof).
  • angiogenesis inhibitor e.g., a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof.
  • the method comprises administering an agent capable of enhancing efficacy of the angiogenesis inhibitor to the patient daily for three consecutive days, then after a period of at least 7, 10, 14, or 21 days during which the agent is not administered to the patient, administering the agent to the patient for another three consecutive days.
  • the method comprises administering an agent capable of enhancing efficacy of the angiogenesis inhibitor to the patient daily for three consecutive days in a week for two consecutive weeks, then after a period of at least 7, 10, 14, or 21 days during which the agent is not administered to the patient, administering the agent to the patient for another three consecutive days in a week for two consecutive weeks.
  • the method comprises administering an agent capable of enhancing efficacy of the angiogenesis inhibitor to the patient daily for three consecutive days in a week for two consecutive weeks, then after a period of at least 7, 10, 14, or 21 days during which the agent is not administered to the patient, administering the agent to the patient for another three consecutive days in a week for two consecutive weeks.
  • the method comprises administering an agent capable of enhancing efficacy of the angiogenesis inhibitor to the patient not more than 5 times in a week, then after a period of at least 7, 10, 14, or 21 days during which the agent is not administered to the patient, administering the agent to the patient not more than 5 times in another week.
  • the method further comprises administering to the patient an agent capable of increasing the rate of metabolism of the angiogenesis inhibitor, and/or the metabolism of the agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • the angiogenesis inhibitor is erlotinib
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the angiogenesis inhibitor is erlotinib
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the angiogenesis inhibitor is a tyrosine kinase inhibitor (TKI), a vascular endothelial growth factor (VEGF) inhibitor, a VEGF receptor inhibitor, or any combination thereof, and wherein the agent capable of increasing the rate of metabolism of one or more of these angiogenesis inhibitor is selected from the group consisting of tetracycline, corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglita
  • TKI ty
  • the method further comprises administering to a patient in need thereof a therapeutically effective amount of an agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor and /or the metabolism of the agent capable of enhancing efficacy of the angiogenesis inhibitor.
  • the agent capable of preventing an inhibition of metabolism of the angiogenesis inhibitor is an antibiotic.
  • the angiogenesis inhibitor and/or the agent capable of enhancing the efficacy of the angiogenesis inhibitor are administered to the patient topically, orally, intravenously, intramuscularly, subcutaneously, intradermally, or any combination thereof.
  • the condition is a noncancerous condition
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is not administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the condition is a cancerous condition
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is optionally administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway is an agent capable of inhibiting the interaction of a TGF- ⁇ ligand protein and a TGFfi receptor protein.
  • the TGF- ⁇ ligand protein is TGF- ⁇ - ⁇ , TGF ⁇ -2, TGF ⁇ -3, or a combination thereof.
  • the agent is a TGF- ⁇ ligand trap, such as a TGF- ⁇ - ⁇ ligand trap.
  • the agent is an anti- TGF- ⁇ antibody.
  • the agent is an anti-TGF- ⁇ receptor antibody.
  • the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway is an agent capable of inhibiting a component in the downstream of TGF- ⁇ signaling pathway.
  • the agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway is an agent capable of inhibiting the interaction of a PDGF ligand protein and a PDGF receptor protein.
  • the PDGF ligand protein is PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and/or PDGF-DD.
  • the agent is a PDGF ligand trap.
  • the agent is an anti-PDGF antibody.
  • the agent is an anti-PDGF receptor antibody.
  • the agent capable of inhibiting the PDGF signaling pathway is an agent capable of inhibiting a component in the downstream of PDGF signaling pathway.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway is a protein, a small molecule, or combinations thereof.
  • the agent capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway is a virus comprising a recombinant gene encoding a protein capable of inhibiting the TGF- ⁇ signaling pathway and/or the PDGF signaling pathway.
  • the present invention provides a pharmaceutical combination comprising a) a therapeutically effective amount of an agent capable of modulating the abnormal ECM, wherein the agent is selected from the group consisting of an angiogenesis inhibitor; and b) a therapeutically effective amount of an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the agent capable of modulating the abnormal ECM and the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway are in a unified dosage form or in separate dosage forms.
  • the forgoing pharmaceutical combination further comprises a therapeutically effective amount of an agent capable of increasing the rate of metabolism of the angiogenesis inhibitor.
  • the present invention provides a method of identifying an agent capable of modulating the abnormal extracellular matrix (ECM), the method including the steps of: a) providing a plurality of fibroblast cells; b) contacting the fibroblast cells with one or more of agents capable of stimulate the fibroblast cells to differentiate into myofibroblasts; c) contacting the fibroblast cells with a test agent; and d) comparing the ability of the fibroblast cells to differentiate in the presence of the test agent to the ability of a plurality of fibroblast cells to differentiate in the absence of the test agent, wherein a difference in the differentiation ability of the fibroblast cells is indicative of the test agent's capability to modulating the abnormal ECM.
  • ECM extracellular matrix
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a) a therapeutically effective amount of an angiogenesis inhibitor; and b) a therapeutically effective amount of an agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • PDGF Platelet-Derived Growth Factor
  • the agent capable of modulating the abnormal ECM and the agent capable of inhibiting the Transforming Growth Factor- ⁇ (TGF- ⁇ ) signaling pathway and/or an agent capable of inhibiting the Platelet-Derived Growth Factor (PDGF) signaling pathway are in a unified dosage form or in separate dosage forms.
  • the forgoing pharmaceutical composition further comprises a therapeutically effective amount of an agent capable of increasing the rate of metabolism of the angiogenesis inhibitor.
  • therapeutically effective amounts of a formulation comprising an angiogenesis inhibitor are amounts that are effective to inhibit the growth of abnormal cell growth.
  • the angiogenesis inhibitor is a TKI, such as an EGFR inhibitor.
  • the EGFR inhibitor is erlotinib, and the amount of erlotinib may be dosage units within a range corresponding to of about 500 mg to about 3000 mg per day, such as about 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, l lOO mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, l lOO mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg per day.
  • erlotinib is administered at a daily dose of at least 500 mg. In some embodiments, erlotinib is administered at a daily dose of at least 1000 mg. In some embodiments, erlotinib is administered at a daily dose of at least 2000 mg. In some embodiments, erlotinib is administered at a daily dose in the range of about 1 ,000 mg per day to about 3,000 mg per day. In some embodiments, erlotinib is administered at a daily dose in the range of about 1 ,500 mg per day to about 2,500 mg per day. In some embodiments, erlotinib is administered at a daily dose in the range of about 1 ,800 mg per day to about 2,200 mg per day. In some embodiments, erlotinib is administered at a daily dose of about 2000 mg per day.
  • an angiogenesis inhibitor is administered to the patient based on a pulse dose regimen.
  • Traditional dosing regimens are usually based on constant effect of the drug (e.g., constant target inhibition) and/or long half-life of drug. Such regimens can only reach an optimal dose interval, but never a supra-therapeutic dose interval (see FIG. 1A).
  • a pulsed dosing regimen of the present invention is based on intermittent dosing and/or short half-life of drug. Such regimens can reach not only optimal dose interval, but also a supra-therapeutic dose interval (see FIG. IB).
  • intermittent pulsed supra-therapeutic doses and an acceleration of metabolism of the drug lead to higher treatment efficacy, less treatment resistance, and/or less toxicity.
  • a dose of a therapeutically effective amount of an angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • Such administration and non-administration form a cycle of the regimen.
  • the cycle is repeated for once, twice, three times, four times, five times, six times, seven times, eight times, night times, ten times, or more, or until a desired end point is reached.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor is administered to the patient once, twice, three times or more per day.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the EGFR inhibitor is administered to the patient for once another day, and the administration time lasts for four days, six days, eight days, ten days or more.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor is administered to the patient for two, three, four, or five times within a week. Each of the two, three, four, or five times of administration can be consecutive to each other, equally separated, randomly separated, or combinations thereof.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient.
  • the second period of time can last at least about 7 days, 10 days, 14 days, 21 days, 28 days, or more.
  • the second period of time is long enough for the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) in the patient to be partially or completely metabolized, such as that about 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more of the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) in the patient has been metabolized.
  • the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the angiogenesis inhibitor is administered to the patient again for another two, three, four, five, or more consecutive days.
  • an agent capable of enhancing the efficacy of the angiogenesis inhibitor is administered to the patient prior to, concurrently with, or after administration of the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor).
  • the agent is administered to the patient also based on a pulse dose regimen.
  • a dose of a therapeutically effective amount of the agent is administered to a patient one or more times within a third period of time so that the dose provide a supra- therapeutic dose within the third period of time, then the angiogenesis inhibitor (e.g., a TKI or a VEGF inhibitor) is not administered to the patient for a fourth period of time.
  • Such administration and non-administration form a cycle of the regimen.
  • the cycle is repeated for once, twice, three times, four times, five times, six times, seven times, eight times, night times, ten times, or more, or until a desired end point is reached.
  • the agent is administered to the patient once, twice, three times or more per day.
  • the agent is administered to the patient for several consecutive days, such as two consecutive days, three consecutive days, four consecutive days, five consecutive days, or more.
  • the agent is administered to the patient for once per day three consecutive days.
  • the agent is administered to the patient for once another day, and the administration time lasts for four days, six days, eight days, ten days or more.
  • the agent is administered to the patient for two, three, four, or five times within a week. Each of the two, three, four, or five times of administration can be consecutive to each other, equally separated, randomly separated, or combinations thereof.
  • the agent is administered to the patient for not more than three, four, or five times within a given week.
  • the agent is not administered to the patient.
  • the fourth period of time can last at least about 7 days, 10 days, 14 days, 21 days, 28 days, or more.
  • the fourth period of time is long enough for the agent in the patient to be partially or completely metabolized, such as that about 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more of the agent in the patient has been metabolized.
  • the agent is administered to the patient again according to the regimen described herein. In some embodiments, the agent is administered to the patient again for another two, three, four, five, or more consecutive days.
  • the regimen for the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the regimen for the agent capable of enhancing the efficacy of the angiogenesis inhibitor match with each other.
  • the first period of time is equal to the third period of time
  • the second period of time equal to the fourth period of time.
  • the schedule for administering the angiogenesis inhibitor and the schedule for administering the agent match with each other.
  • the angiogenesis inhibitor is administered to the patient on the same day when the agent capable of enhancing the efficacy of the angiogenesis inhibitor is administered to the patient.
  • the schedule for the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the regimen for the agent capable of capable of enhancing the efficacy of the angiogenesis inhibitor partially match (overlap) with each other.
  • the schedule for the angiogenesis inhibitor e.g., a TKI or a VEGF inhibitor
  • the schedule for the agent capable of enhancing the efficacy of the angiogenesis inhibitor do not overlap each other.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is not administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • the agent capable of enhancing the efficacy of the angiogenesis inhibitor is optionally administered to the patient during the time when the angiogenesis inhibitor is not administered to the patient.
  • a method of the present invention further comprises administering a therapeutically effective amount of an agent capable of increasing the rate of metabolism of angiogenesis inhibitor, and/or the metabolism of the agent capable of enhancing the efficacy of the angiogenesis inhibitor.
  • Agents capable of increasing the rate of metabolism of an angiogenesis inhibitor include, but are not limited to tetracycline, corticosteroid, nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John's wort, sulfadimidine, sulfinpyrazone, troglitazone, and any combination thereof.
  • corticosteroids that can be used in the present invention include, but are not limited to, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate
  • the corticosteroid is dexamethasone. In some embodiments, the corticosteroid is a topical steroid, an inhaled steroid, an oral form steroid, or a systemic form steroid.
  • the agent is capable of increasing the metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 10% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 20% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 40% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib administered to the patient is increased by at least 60% due to administration of the agent that increases the rate of metabolism of erlotinib. In some embodiments, the rate of metabolism of erlotinib administered to the patient is increased by at least 100% due to administration of the agent that increases the rate of metabolism of erlotinib.
  • the rate of metabolism of erlotinib may be characterized and analyzed according to procedures described in the literature. One approach for measuring the rate of metabolism of erlotinib is to determine the half-life of erlotinib based on blood plasma samples taken from the patient.
  • an agent that increases the rate of metabolism of the angiogenesis inhibitor is administered on (i) the same day as the last administration of the angiogenesis inhibitor in any treatment cycle, or (ii) within about 1 , 2,3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 hours or more after the last administration of angiogenesis inhibitor in any treatment cycle.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450. Additional agents that can increase the rate of metabolism of an angiogenesis inhibitor can be screened and identified according to the scientific literature.
  • the method of the present invention further comprises administering to the patient in need of one or more agents capable of reducing or preventing inhibitory effect on the metabolism rate of the angiogenesis inhibitor. In some embodiments, the method of the present invention further comprises administering to the patient in need of a cosmetic treatment or modality.
  • such agents include, but are not limited to, anti-fungals (e.g., fluconazole, itraconazole, micafungin, terbinafine, miconazole, and voriconazole), antifungal creams (e.g., ketoconazole, miconazole, terbinafine), antibiotics (e.g., cephalexin, dicloxacillin, trovafloxacin, augmentin, penicillin, cyclosporin, dapsone), mycophenolate mofetil, PUVA phototherapy, biologies (e.g., Infliximab (Remicade®), Etanercept (Enbrel®), Adalimumab (Humira®), Ustekinumab (Stelara®), Secukinumb (Cosentxy®), Ixekizumab (Taltz®), Brodalumab (Siliq®)), chemotherapy (e.g., 5- FU, Methotidib, X-
  • benzoyl peroxide tretinoin cream, oral or topical metronidazole, topical azaleic acid (e.g., gel, foam, cream), topical ivermectin, minocycline, doxycycline, topical brimonidine, pulsed dye laser, liquid nitrogen, dermabrasion, chemical peels, botox and disport, dermal fillers, antihistamines, sunscreen, aspirin and NSAIDs.
  • Whether the patient has an abnormal extracellular matrix can be determined by various diagnostic methods known in the art. Known methods for diagnosis and quantitation of fibrosis have been summarized in publications such as Manning and Afdhal, Gastroenterology, (2008)134: 1670-1681; Schiavon et al, World J. Gastroenterol. (2014) 20(11): 2854-2866, which are incorporated by reference herein in their entireties.
  • whether the patient has an abnormal ECM can be determined by biopsies or medical imaging for presence of inflammation and/or evidence of scar tissue.
  • whether the patient has an abnormal extracellular matrix is determined by analyzing the level of one or more biomarkers in a biological sample obtained from the patient.
  • the biological sample is selected from the group consisting of blood, saliva, serum, plasma, urine, stool, cerebral spinal fluid, cells, a cellular extract, a tissue sample, and a tissue biopsy.
  • determining the whether the patient has an abnormal extracellular matrix comprises the steps of: a) determining the level of one or more biomarkers of abnormal ECM in a biological sample obtained from the patient; and b) comparing the level of the biomarker with a control level, wherein a positive determination is made if the level of biomarker in the biological sample is statistically significantly higher or lower than the control level.
  • the biomarker is selected from the group consisting of a2- MG, A2M, HA, TIMP-1, tumor necrosis factor-a (TNF-a), and transforming growth factor- ⁇ (TGF- ⁇ ), PIIINP; laminin, tenascin, adipokines, MT1-MMP, Migration-stimulating factor (MSF), YKL-40, MMP-2, MMP-3, MMP-9/TIMP-1 complex, MMP-13, MMP-14, sFas ligand, TGF- ⁇ ,
  • level of the biomarkers is determined at protein expression level.
  • protein expression level is analyzed using a specific antibody and a protein assay. Any suitable method or assay can be used to measure the level of the biomarker protein expression in the biological sample of a subject. Numerous antibody-based detection formats are well known in the art, and include ELISA (enzyme linked immunosorbent assay), radioimmunoassays, immunoblots, Western blots, flow cytometry, immunofluorescence assays, immunoprecipitation, protein A assays, Immunoelectrophoresis assays, and other related techniques.
  • antibody binding is detected by detecting a label on the primary antibody.
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody.
  • the secondary antibody is labeled.
  • Antibodies specific for the biomarkers may be provided in a diagnostic kit that incorporates at least one of these procedures to quantitate the biomarkers' expression.
  • the kit may contain other components, packaging, instructions, or other material to aid the quantitation of the protein and use of the kit.
  • Antibodies against the biomarkers can be obtained commercially or routinely made according to methods such as, but not limited to, inoculation of an appropriate animal with the polypeptide or an antigenic fragment, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or recombinant cells expressing nucleic acid encoding such antibodies.
  • level of the biomarkers is analyzed at the mRNA level.
  • RT-PCR and a pair of specific primers may be used.
  • mRNA are prepared and analyzed according to well-established protocols.
  • the level of one or more of the markers is statistically significantly higher or lower in the biological sample is compared to a control level of expression of the corresponding biomarker.
  • the control level is a normal level in patients not having abnormal ECM (non-diseased tissue).
  • the level of biomarker decreases or increases by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to the control level.
  • the present invention provides a method for identifying an agent capable of modulating the abnormal extracellular matrix (ECM), the method including the steps of: a) providing a plurality of fibroblast cells; b) contacting the fibroblast cells with one or more of agents capable of stimulate the fibroblast cells to differentiate into myofibroblasts; c) contacting the fibroblast cells with a test agent; and d) comparing the ability of the fibroblast cells to differentiate in the presence of the test agent to the ability of a plurality of fibroblast cells to differentiate in the absence of the test agent, wherein a difference in the differentiation ability of the fibroblast cells is indicative of the test agent's capability to modulating the abnormal ECM.
  • the fibroblast cells are mixed with other cells, such as cancer cells.
  • the fibroblast cells are implanted in animal models, such as rodents.
  • the ability of the fibroblast cells to differentiate into myofibroblasts is determined by immunostaining of the cells for signature proteins of myofibroblasts, such as a-smooth muscle actin (a-SMA).
  • a-SMA a-smooth muscle actin
  • the ability of the fibroblast cells to differentiate is determined by analyzing the TGF- ⁇ signaling pathway activity, such as analyzing inhibition of expression of Smad2 and Smad4.
  • inhibition of fibroblast cells differentiation by a test agent can manifest as selective apoptosis of the treated fibroblasts.
  • the agent capable of stimulating the fibroblast cells to differentiate into myofibroblasts is selected from the group consisting of TGF- ⁇ , fibroblast growth factor (FGF), IL- ⁇ , interleukin-6 (IL-6), IL-13, IL-33, leukotrienes, CXC, and CC chemokines, IGFBP-3 and -5, IGF -II, reactive oxygen and nitrogen species and connective tissue growth factor (CTGF).
  • FGF fibroblast growth factor
  • IL-6 interleukin-6
  • IL-13 interleukin-6
  • IL-33 interleukin-6
  • leukotrienes CXC
  • CXC CC chemokines
  • IGFBP-3 and -5 IGF -II
  • CGF connective tissue growth factor
  • Test agents include, but are not limited to, small organic compounds (e.g., organic molecules having a molecular weight between about 50 and about 2,500 Da), nucleic acids or proteins, for example.
  • the compound or plurality of compounds can be chemically synthesized or microbiologically produced and/or comprised in, for example, samples, e.g., cell extracts from, e.g., plants, animals or microorganisms.
  • a plurality of compounds can be, e.g., added to a reaction mixture, added to a culture medium, injected into a cell or administered to a transgenic animal.
  • Several methods are known to the person skilled in the art for producing and screening large libraries to identify compounds having specific activity to inhibit or affect fibroblast cells' differentiation into myofibroblasts.
  • the invention provides pharmaceutical compositions, which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pess
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety -nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants,
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms, e.g., one administration per day.
  • Erlotinib the FDA-approved dose of erlotinib is 150 mg/day orally (NSCLC) or 100 mg/day (pancreatic cancer) orally.
  • the dose of erlotinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of Erlotinib.
  • the dose of erlotinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of Erlotinib can be administered prior to, during, or after administration of erlotinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Gefitinib the FDA-approved dose of gefitinib is 250 mg/day orally.
  • the dose of gefitinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of gefitinib.
  • the dose of gefitinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of gefitinib can be administered prior to, during, or after administration of gefitinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Afatinib the FDA-approved dose of afatinib is 40 mg/day orally.
  • the dose of afatinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of afatinib.
  • the dose of afatinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of afatinib can be administered prior to, during, or after administration of afatinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Cetuximab the FDA-approved dose of cetuximab is 400 mg/m2 as a 120-minute intravenous infusion followed by 250 mg/m2 weekly infused over 60 minutes.
  • the dose of cetuximab can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of cetuximab.
  • the dose of cetuximab is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of cetuximab can be administered prior to, during, or after administration of cetuximab.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Panitumumab the FDA-approved dose of panitumumab is 6 mg/kg every 14 days as an intravenous infusion over 60 minutes ( ⁇ 1000 mg) or 90 minutes (> 1000 mg).
  • the dose of panitumumab can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of panitumumab.
  • the dose of afatinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times,
  • the agent that is capable of increasing the clearance (such as metabolism) of panitumumab can be administered prior to, during, or after administration of panitumumab.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • the FDA-approved dose of nintedanib is 150 mg twice daily approximately 12 hours.
  • the dose of nintedanib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of nintedanib.
  • the dose of nintedanib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of nintedanib can be administered prior to, during, or after administration of nintedanib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Vandetanib the FDA-approved dose of vandetanib is 300 mg once daily.
  • the dose of vandetanib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of vandetanib.
  • the dose of vandetanib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times,
  • the agent that is capable of increasing the clearance (such as metabolism) of vandetanib can be administered prior to, during, or after administration of vandetanib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Lapatinib the FDA-approved dose of lapatinib is 1,250 mg given orally once daily.
  • the dose of lapatinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of lapatinib.
  • the dose of lapatinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of lapatinib can be administered prior to, during, or after administration of lapatinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Sunitinib the FDA-approved dose of sunitinib is 1 ,250 mg given orally once daily.
  • the dose of sunitinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of sunitinib.
  • the dose of sunitinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of sunitinib can be administered prior to, during, or after administration of sunitinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Sorafenib the FDA-approved dose of sorafenib is 400 mg orally twice daily.
  • the dose of sorafenib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of sorafenib.
  • the dose of sorafenib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of sorafenib can be administered prior to, during, or after administration of sorafenib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Pazopanib the FDA-approved dose of pazopanib is 800 mg orally once daily (or 200 mg once daily for baseline moderate hepatic impairement). In the method of the present disclosure, the dose of pazopanib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of pazopanib.
  • the dose of pazopanib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of pazopanib can be administered prior to, during, or after administration of pazopanib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Axitinib the FDA-approved dose of axitinib is 5 mg orally twice daily.
  • the dose of axitinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of axitinib.
  • the dose of axitinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of axitinib can be administered prior to, during, or after administration of axitinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Tivozanib the European Union-approved dose of tivozanib is 1340 microgram once daily.
  • the dose of tivozanib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of tivozanib.
  • the dose of tivozanib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the European Union-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of tivozanib can be administered prior to, during, or after administration of tivozanib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Dovitinib the previous clinical trial study dose of dovitinib is 500 mg daily.
  • the dose of dovitinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of dovitinib.
  • the dose of dovitinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the previous clinical trial study dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of dovitinib can be administered prior to, during, or after administration of dovitinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Dasatinib the FDA-approved dose of dasatinib 100 mg once daily.
  • the dose of dasatinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of dasatinib.
  • the dose of dasatinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of dasatinib can be administered prior to, during, or after administration of dasatinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Bosutinib the FDA-approved dose of bosutinib is 500 mg once daily.
  • the dose of bosutinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of bosutinib.
  • the dose of bosutinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of bosutinib can be administered prior to, during, or after administration of bosutinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Imatinib the FDA-approved dose of imatinib is 100 - 800 mg once daily.
  • the dose of imatinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of imatinib.
  • the dose of imatinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of imatinib can be administered prior to, during, or after administration of imatinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Regorafenib the FDA-approved dose of regorafenib is 160 mg orally once daily.
  • the dose of regorafenib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of regorafenib.
  • the dose of regorafenib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of regorafenib can be administered prior to, during, or after administration of regorafenib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Cabozantinib the FDA-approved dose of cabozantinib is 60 mg orally once daily.
  • the dose of cabozantinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of cabozantinib.
  • the dose of cabozantinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of cabozantinib can be administered prior to, during, or after administration of cabozantinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Apatinib the previous clinical trial dose of apatinib is 500 mg once daily.
  • the dose of apatinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of apatinib.
  • the dose of apatinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the previous clinical dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of apatinib can be administered prior to, during, or after administration of apatinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Lenvatinib the FDA-approved dose of lenvatinib is 24 mg orally once daily.
  • the dose of lenvatinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of lenvatinib.
  • the dose of lenvatinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of lenvatinib can be administered prior to, during, or after administration of lenvatinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Nilotinib the FDA-approved dose of nilotinib is 300 mg orally twice daily.
  • the dose of nilotinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of nilotinib.
  • the dose of nilotinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of nilotinib can be administered prior to, during, or after administration of nilotinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Ranibizumab the FDA-approved dose of ranibizumab is 0.5 mg administered by intravitreal injection once a month.
  • the dose of ranibizumab can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of ranibizumab.
  • the dose of ranibizumab is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of ranibizumab can be administered prior to, during, or after administration of ranibizumab.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Everolimus the FDA-approved dose of everolimus is 10 mg once daily.
  • the dose of everolimus can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of everolimus.
  • the dose of everolimus is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of everolimus can be administered prior to, during, or after administration of everolimus.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Canertinib the previous clinical trial dose of canertinib is 30 to 60 mg/kg/day.
  • the dose of canertinib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of canertinib.
  • the dose of canertinib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the previous clinical trial dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of canertinib can be administered prior to, during, or after administration of canertinib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Vatalanib the previous clinical trial dose of vatalanib is 250 mg to 1500.
  • the dose of vatalanib can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of vatalanib.
  • the dose of vatalanib is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the previous clinical trial dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of vatalanib can be administered prior to, during, or after administration of vatalanib.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Leflunomide the FDA-approved dose of leflunomide is 20 mg once daily.
  • the dose of leflunomide can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of leflunomide.
  • the dose of leflunomide is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of leflunomide can be administered prior to, during, or after administration of leflunomide.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Bevacizumab the FDA-approved dose of bevacizumab is 5-15 mg/kg IV every 2 weeks.
  • the dose of bevacizumab can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of bevacizumab.
  • the dose of bevacizumab is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of bevacizumab can be administered prior to, during, or after administration of bevacizumab.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Ramucirumab the FDA-approved dose of ramucirumab is 8 mg/kg IV every two weeks.
  • the dose of ramucirumab can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of ramucirumab.
  • the dose of ramucirumab is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of ramucirumab can be administered prior to, during, or after administration of ramucirumab.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • Aflibercept the FDA-approved dose of aflibercept is 2 mg IV every 4 weeks.
  • the dose of aflibercept can be significantly higher when it is used in combination of an agent that is capable of increasing the clearance (such as metabolism) of aflibercept.
  • the dose of aflibercept is about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 8 times, 9.5 times, 10 times, 1 1 times, 12 times, 13 times, 14 times, 15 times or more of the FDA-approved dose.
  • the agent that is capable of increasing the clearance (such as metabolism) of aflibercept can be administered prior to, during, or after administration of aflibercept.
  • the significantly higher dose as described herein is reduced by 75%, 50% and 25% for preterms, neonates and children, respectively.
  • the term "patient” refers to organisms to be treated by the methods of the present invention.
  • the patients are mammals (e.g. , murines, simians, equines, bovines, porcines, canines, felines, and the like), such as humans.
  • the term "patient” or "subject,” and variants thereof as used herein includes any subject that has, is suspected of having, or is at risk for having a disease or condition. Suitable subjects (or patients) include mammals, such as laboratory animals (e.g., mouse, rat, rabbit, guinea pig), farm animals, and domestic animals or pets (e.g., cat, dog).
  • a subject “at risk” may or may not have detectable disease and may or may not have displayed detectable disease prior to the diagnostic or treatment methods described herein.
  • “At risk” denotes that a subject has one or more so-called risk factors, which are measurable parameters that correlate with development of a condition described herein, which are described herein. A subject having one or more of these risk factors has a higher probability of developing a condition described herein than a subject without these risk factor(s).
  • the term "effective amount” refers to the amount of a compound (e.g. , a compound of the present invention) sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • a therapeutically effective amount refers to the level or amount of one or more agents needed to treat a condition, or reduce or prevent injury or damage, optionally without causing significant negative or adverse side effects.
  • a therapeutically effective amount includes an amount of a pharmaceutical formulation including for example one or more compounds sufficient to produce a desired therapeutic outcome (e.g., inhibiting the growth of abnormal skin cells).
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • treatment may refer to administering an agent, or carrying out a procedure for the purposes of obtaining an effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease, such as a cutaneous abnormality condition, or symptom thereof and/or may be therapeutic in terms of effecting a partial or complete cure for a disease and/or symptom of the disease.
  • the terms also refer to (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression or halting progression of the disease.
  • the terms “alleviate” and “alleviating” refer to reducing the severity of the condition, such as reducing the severity by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term "pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g. , such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
  • the term "pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g. , acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof.
  • salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • bases include, but are not limited to, alkali metal (e.g. , sodium) hydroxides, alkaline earth metal (e.g. , magnesium) hydroxides, ammonia, and compounds of formula NW ⁇ 4 + , wherein W is Ci-4 alkyl, and the like.
  • alkali metal e.g. , sodium
  • alkaline earth metal e.g. , magnesium
  • W is Ci-4 alkyl
  • salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy ethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate,
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • the compound erlotinib has the chemical name N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)-4-quinazolinamine.
  • the compound gemcitabine has the chemical name 2',2'- difluoro-2'-deoxycytidine. The term also refers to a pharmaceutically acceptable salt thereof.
  • an "angiogenesis inhibitor” is a substance that inhibits the growth of new blood vessels (angiogenesis).
  • An angiogenesis inhibitor can reduce the production of pro- angiogenic factors, prevent them binding to their receptors or block their actions.
  • pro- angiogenic factors include, but are not limited to, angiogenin, vascular endothelial growth factor (VEFG), fibroblast growth factor (FGF), and transforming growth factor- ⁇ (TGF- ⁇ ), and those that stimulate endothelial cell proliferation, migration and invasion resulting in new vascular structures.
  • Such angiogenesis inhibitors include, but are not limited to, soluble VEGFR- 1 and NRP-1, Angiopoietin 2, TSP-1 and TSP-2, angiostatin and related molecules, endostatin, vasostatin, calreticulin, platelet factor-4, TIMP and CDAI, Meth-1 and Meth-2, IFN-a, - ⁇ and - ⁇ , CXCL10, IL-4, -12 and -18, prothrombin (kringle domain-2), antithrombin III fragment, prolactin, VEGI, SPARC, osteopontin, maspin, canstatin (a fragment of COL4A2), proliferin- related protein, bevacizumab (Avastin), itraconazole, carboxyamidotriazole, TNP-470 (an analog of fumagillin), CM101, IFN-a, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists
  • angiogenesis inhibitors are also described in US20080220075, US20050130903, US20070161570, US20140294768, US20030109671, US20170191137, US6919307, and US7157420, each of which is herein incorporated by references in its entirety for all purposes.
  • Tyrosine kinase inhibitors represent a class of therapeutic agents or drugs that target receptor and/or non-receptor tyrosine kinases in cells such as tumor cells.
  • the tyrosine kinase inhibitor is an antibody-based (e.g., anti-tyrosine kinase monoclonal antibody, etc.) or polynucleotide-based (e.g., tyrosine kinase antisense oligonucleotide, small interfering ribonucleic acid, etc.) form of targeted therapy.
  • the tyrosine kinase inhibitor is a small molecule that inhibits target tyrosine kinases by binding to the ATP-binding site of the enzyme.
  • small molecule tyrosine kinase inhibitors include, but are not limited to, gefitinib (Iressa®), sunitinib (Sutent®; SU11248), erlotinib (Tarceva®; OSI-1774), lapatinib (GW572016; GW2016), canertinib (CI 1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), imatinib (Gleevec®; ST1571), dasatinib (BMS-354825), leflunomide (SU10), vandetanib (Zactima®; ZD6474), pazopanib, axitinib,
  • tyrosine kinase inhibitors suitable for use in the present invention include quinazolines (e.g., PD 153035,4-(3- chloroanilino)quinazoline, etc.), pyridopyrimidines, pyrimidopyrimidines, pyrrolopyrimidines (e.g., CGP 59326, CGP 60261, CGP 62706, etc.), pyrazolopyrimidines, 4-(phenylamino)-7H- pyrrolo[2,3-d]pyrimidines, curcumin (diferuloyl methane), 4,5-bis(4-fluoroanilino)phthalimide, tyrphostines containing nitrothiophene moieties, quinoxalines (see, e.g., U.S.
  • quinazolines e.g., PD 153035,4-(3- chloroanilino)quinazoline, etc.
  • EGFR epidermal growth factor receptor
  • EGFR epidermal growth factor receptor
  • An exemplary EGFR is the human epidermal growth factor receptor (see Ullrich et al. (1984) Nature 309:418- 425; Genbank accession number NP-005219.2; complete cds AY588246.1). Binding of an EGF ligand activates the EGFR (e.g. resulting in activation of intracellular mitogenic signaling, autophosphorylation of EGFR).
  • Intracellular domain of, a human, EGFR comprises a polypeptide sequence from amino acid adjacent to the transmembrane domain up to COOH-terminus of the EGFR. Intracellular domain comprises, inter alia, tyrosine kinase domain.
  • EGFR inhibitor refers to an agent which can inhibit the activity of EGFR, such as an agent that modify the activity of EGFR.
  • the agent is against EGFR at transcriptional level, translational level, post-translational level, and/or protein level.
  • the agent can specifically target EGFR, or target at least EGFR.
  • the agent can cause gene suppression and/or gene silencing of EGFR, e.g., knocking down or knocking out EGFR.
  • the agent can modify EGFR protein activity, such as modifying the EGFR binding activity to its ligand and/or its ability to induce downstream signaling pathways.
  • the agent is an antagonist or an antibody of the ligand of EGFR, for example, an antagonist or an antibody of epidermal growth factor (EGF), transforming growth factor a (TGFa), HB-EGF, amphiregulin, betacellulin, epigen, and/or epiregulin.
  • the agent can target to EGFR and/or the ligand and block ligand-receptor binding.
  • the agent can cause confirmation changes in the receptor and/or the ligand and reducing or inactivating EGFR mediated cell signaling.
  • the term "agent against the signaling pathway downstream of EGFR” refers to an agent that can modify the activity of the signaling pathway downstream of EGFR, such as one or more downstream targets of EGFR.
  • EGFR signaling pathway is described in Sechacharyulu et al. (Targeting the EGFR signaling pathway in cancer therapy, Expert Opin Ther Targets, 2012 January; 16(1): 15-31.), Oda et al. (A comprehensive pathway map of epidermal growth factor receptor signaling, Molecular Systems Biology 1 :2005.0010), and Development EGFR Signaling Pathway (Pathway Maps, Thomson Reuters, 2012), each of which is incorporated herein in its entirety for all purposes.
  • EGFR antibody refers to a polypeptide that specifically binds to EGFR.
  • Antibodies to EGFR include, but are not limited to IgG, IgM, IgA, and antibody fragments that retain EGFR binding capability, e.g., Fv, Fab, F(ab)2, single-chain antibodies, and the like; chimeric antibodies; etc.
  • Illustrative EGFR inhibitors include, but are not limited to, Cetuximab (Erbitux®, Imclone, Bristol-Myers Squibb), panitumumab (VECTIBIXTM), matuzumab, nimotuzumab, antibody 806, Sym004, and MM-151, either in their murine, chimeric or humanized versions including their immunologically effective fragments (Fab, Fv) and immunoconjugates, such as immunocytokines.
  • Fab, Fv immunologically effective fragments
  • Other antibodies (or other binding molecules) specific for the EGFR extracellular domain are known in the art and are contemplated for use herein (see, e.g., U.S. Pat. Nos.
  • the invention is not limited to these specific agents, and can include an agonist of such agents or agents having substantially similar biological activity as these agents.
  • the biological activity or biological action of a protein refers to any function(s) exhibited or performed by a naturally occurring form of the protein as measured or observed in vivo (i.e., in the natural physiological environment of the protein) or in vitro (i.e., under laboratory conditions).
  • Biological activities of EGFR include, but are not limited to, binding to EGF, receptor homo- or heterodimerization, tyrosine kinase activity, and downstream activities related to cellular homeostasis and development.
  • Anti-EGFR antibodies also include, but are not limited to hose described in PCT publication Nos.
  • Retinoids refer to a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth. Retinoids that can be used in the present invention include, but are not limited to tazarotene, retinoic acid, tretinoin, isotretinoin, adapalene, bexarotene, alitretinoin, vitamin A, retinol, retinoic acid, retinal, retinyl palmitate, retinyl acetate, ethyl 5-(2-(4,4- dimethylthiochroman-6-yl)ethynyl)thiophene-2-carboxylate, 6-(2-4,4- dimethylthiochroman- 6- yl)-ethynyl)-3-pyridylmethanol, and 2-(2-(4,4- dimethylthiochroman-6-yl)-ethyl)-ethy
  • a retinoid can be natural or synthetic.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • TGF trap refers to a molecule capable of inhibiting the interaction between a TGF and a TGF receptor.
  • TGFp neutralizing antibodies include, but are not limited to, TGFp neutralizing antibodies, soluble TGFP receptors, anti-TGFp antibodies, anti-TGFp receptor antibodies, TGFp antagonists, such as fresohmumab (a pan-TGFp antibody), disitertide (a peptidic TGFpi inhibitor specifically designed to block the interaction with its receptor), IMCTR1 (LY3022859, a monoclonal antibody against TGFpRII), etc.
  • the term may also refer to a molecule that interrupt TGFP signaling pathway at transcription level, such as antisense oligonucleotides delivered directly intravenously or engineered into immune cells to prevent TGFP synthesis (e.g., trabedersen [AP12009], an antisense oligonucleotide targeting TGFP2) and Lucanix® [belagenpumatucel-L] (aTGFp2 antisense gene-modified allogeneic cancer cell vaccine).
  • antisense oligonucleotides delivered directly intravenously or engineered into immune cells to prevent TGFP synthesis e.g., trabedersen [AP12009], an antisense oligonucleotide targeting TGFP2
  • Lucanix® belagenpumatucel-L]
  • the term may also refer to a molecule that interrupt TGFP signaling pathway at intracellular level, such as TGFP receptor kinase inhibitors to prevent signal transduction (e.g., galunisertib [LY2157299], a small molecule inhibitor of TGFPRI, which is to date the most advanced TGFP signaling inhibitor under clinical development) (Smith et al, 2012; Katz et al, 2013).
  • TGFP receptor kinase inhibitors to prevent signal transduction
  • the term may also refer to any molecule that interrupts downstream signaling in the TGFP signaling pathway.
  • the TGFP signaling pathway is described in Neuzillet et al. (Pharmacology & Therapeutics 147 (2015) 22-31).
  • Transforming growth factor beta 1 or TGF- pi is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis.
  • TGF-pi is encoded by the TGFB1 gene.
  • TGF-P is a multifunctional set of peptides that controls proliferation, differentiation, and other functions in many cell types. TGF-P acts synergistically with TGFA in inducing transformation. It also acts as a negative autocrine growth factor. Dysregulation of TGF-P activation and signaling may result in apoptosis.
  • TGF-P 1 TGF-P 1
  • TGF-P2 TGF-P3
  • TGF-P3 all function through the same receptor signaling systems.
  • TGF-pi plays an important role in controlling the immune system, and shows different activities on different types of cell, or cells at different developmental stages. Most immune cells (or leukocytes) secrete TGF- ⁇ .
  • PDGF trap refers to a molecule capable of inhibiting the interaction between a PDGF and a PDGF receptor.
  • molecules include, but are not limited to, PDGF neutralizing antibodies, soluble PDGF receptors, anti-PDGF antibodies, anti-PDGF receptor antibodies, PDGF antagonists, etc.
  • the term may also refer to a molecule that interrupt PDGF signaling pathway at transcription level, such as antisense oligonucleotides delivered directly intravenously or engineered into immune cells to prevent PDGF synthesis.
  • the term may also refer to a molecule that interrupt PDGF signaling pathway at intracellular level, such as PDGF receptor kinase inhibitors to prevent signal.
  • the term may also refer to any molecule that interrupts downstream signaling in the PDGF signaling pathway.
  • the PDGF signaling pathway is described in Heldin (Cell Communication and Signaling 2013, 11 :97).
  • Platelet-derived growth factor (PDGF) plays a critical role in the regulation of mesenchymal cell migration and proliferation. Aberrant expression of PDGF and its receptor is often associated with a variety of disorders including atherosclerosis, fibroproliferative diseases of lungs, kidneys and joints, and neoplasia. PDGF may exert its function in white matter participating either in regeneration of damaged axons or in glial scar formation.
  • PDGF-BB and its receptor expressed on microvessel endothelial cells might be involved in angiogenesis after stroke.
  • PDGF plays a significant role in blood vessel formation (angiogenesis), the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled angiogenesis is a characteristic of cancer. PDGF contributes to cancer development and progression by both autocrine and paracrine signaling mechanisms.
  • Cytochromes P450 refers to a group of hemoproteins of the superfamily containing heme as a cofactor. They are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems.
  • P450 is derived from the spectrophotometric peak at the wavelength of the absorption maximum of the enzyme (450 nm) when it is in the reduced state and complexed with carbon monoxide.
  • Cytochromes P450 proteins include, but are not limited to CYP1A1, CYP1A2, CYP1B1, CYP1D1P, CYPsyn: lA8P, CYP2A, CYP2ABFGST gene cluster, CYP2A6, CYP2A6v2, CYP2A7vl, CYP2A7v2, CYP2A7_vlaxA2a, CYP2A7P1, CYPsyn:2A18PN, CYP2A7PTX, CYP2A7PCX, CYP2A13, CYP2A18PC, CYP2B6, CYP2B7P1, CYP2B7P2X, CYP2B7P3X, CYP2C8, CYP2C gene cluster, CYP2C9, CYP2C18, CYP2C19, CYP2C23P, CYPsyn:2C62
  • CYPsyn:3A43-de4c6c CYP3A54P, CYPsyn:3A-sel, CYP3A55P, CYPsyn:3A-se2, CYP3A137P, CYPsyn:3A43- delb, CYP4A11, CYP4ABXZ gene cluster, CYP4A20X, CYP4A22, CYP4A26P, CYPsyn:4A-sel, CYP 4A27P, CYPsyn:4A-se3, CYP4A43P, CYPsyn:4A-se2, CYP4A44P, syn:4A-se4, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F9P, CYP4F10P, CYP4F11, CYP4F12, CYP4F22
  • a CYP450 used in methods of the present disclosure is a member of the CYPl, CYP2 or CYP3 family which is responsible for drug and steroid metabolism, such as CYPlAl, CYP1A2, CYPIBI, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S 1, CYP2U1, CYP2W1, CYP3A4, CYP3A5, CYP3A7, or CYP3A43.
  • VEGF inhibitor refers to an agent that is capable of inhibiting the activity of vascular endothelial growth factor (VEGF) signaling pathway.
  • the agent can neutralize, block, inhibt, abrogate, reduce or interfere with VEGF/VEGFR interaction.
  • the agent is against a vascular endothelial growth factor.
  • the agent is against a vascular endothelial growth factor receptor (VEGFR).
  • the agent is capable of inhibiting the interaction of a VEGF and a VEGFR directly and/or indirectly.
  • the inhibition is at transcriptional level, translational level, post-translational level, and/or protein level.
  • the agent can specifically target VEGF or VEGFR, or target at least VEGF or VEGFR.
  • the agent can cause gene suppression and/or gene silencing of VEGF or VEGFR, e.g., knocking down or knocking out VEGF or VEGFR.
  • the agent can modify VEGF or VEGFR protein activity, such as modifying its binding activity to its ligand/receptor, and/or its ability to induce downstream signaling pathways.
  • the agent is an antagonist or an antibody of VEGF or VEGFR, for example, an antagonist or an antibody of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGFR- 1 (Flt-1), VEGFR-2 (Flk-l/KDR), and/or VEGFR- 3 (Flt-4).
  • the agent is a hybrid antibody that binds to both a VEGF and a VEGFR.
  • the agent can target to VEGF and/or VEGFR and block ligand-receptor binding.
  • the agent can cause confirmation changes in the receptor and/or the ligand and reducing or inactivating VEGFR mediated cell signaling.
  • VEGF inhibitors include, but are not limited to, pazopanib, bevacizumab, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, and ziv-aflibercept.
  • VEGF inhibitors include anti-VEGF antibodies and antigen-binding fragments thereof, receptor molecules and derivatives which bind specifically to VEGF thereby sequestering its binding to one or more receptors, anti-VEGF receptor antibodies and VEGF receptor antagonists such as small molecule inhibitors of the VEGFR tyrosine kinases, and fusions proteins, e.g., VEGF-Trap (Regeneron), VEGF. sub. l21-gelonin (Peregrine).
  • VEGF inhibitors also include antagonist variants of VEGF, antisense molecules directed to VEGF, RNA aptamers specific to VEGF, and ribozymes against VEGF or VEGF receptors.
  • VEGF inhibitors act by interfering with the binding of VEGF to a cellular receptor, by incapacitating or killing cells which have been activated by VEGF, or by interfering with vascular endothelial cell activation after VEGF binding to a cellular receptor.
  • VEGF inhibitors are anti-VEGF antagonistic antibodies capable of inhibiting one or more of the biological activities of VEGF, for example, its mitogenic, angiogenic or vascular permeability activity.
  • Anti-VEGF antagonistic antibodies include, but not limited to, antibodies A4.6.1, rhuMab VEGF (bevacizumab), Y0317 (ranibizumab), G6, B20, 2C3, and others as described in, for example, W098/45331, US2003/0190317, U.S. Pat. Nos. 6,582,959 and 6,703,020; W098/45332; WO 96/30046; WO94/10202; WO2005/044853; EP 0666868B1 ; and Popkov et al, Journal of Immunological Methods 288: 149-164 (2004), each of which is incorporated herein by reference in its entirety.
  • compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

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Abstract

L'invention concerne des méthodes thérapeutiques, des kits et des compositions pharmaceutiques pour le traitement du cancer utilisant une association de (i) un premier agent anticancéreux, et (ii) un agent qui accroît la vitesse de clairance (tel que le métabolisme) du premier agent anticancéreux, et (iii) éventuellement un second agent anticancéreux. L'invention concerne également des méthodes thérapeutiques, des kits et des compositions pharmaceutiques pour le traitement d'anomalies cutanées, comprenant l'administration d'un inhibiteur d'angiogenèse et d'un agent capable d'améliorer l'efficacité de l'inhibiteur d'angiogenèse à un patient en ayant besoin. Dans certains modes de réalisation, un dosage pulsé de l'inhibiteur d'angiogenèse et/ou de l'agent capable d'améliorer l'efficacité de l'inhibiteur d'angiogenèse est utilisé. L'invention concerne en outre des méthodes thérapeutiques et des compositions pharmaceutiques pour le traitement d'affections associées à une matrice extracellulaire (MEC) anormale. L'invention se base, au moins en partie, sur la découverte selon laquelle la modulation d'une MEC anormale comme observée dans la fibrose tissulaire et la desmoplasie à l'aide d'un premier agent capable de moduler la MEC anormale améliore l'administration et/ou l'efficacité d'un second agent dans l'amélioration d'une affection qui est associée à la MEC anormale. Des procédés d'identification d'agents capables de moduler la MEC anormale sont en outre décrits.
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US11382913B2 (en) * 2019-09-06 2022-07-12 Consejo Nacional De Investigaciones Cientificas Y Tecnicas Pharmaceutical composition for topical wound treatment
CN114341111A (zh) * 2019-09-06 2022-04-12 阿根廷国家科学技术研究委员会 用于局部伤口治疗的药物组合物
WO2021046290A1 (fr) * 2019-09-06 2021-03-11 Consejo Nacional De Investigaciones Cientificas Y Tecnicas Composition pharmaceutique pour le traitement topique de plaies
CN111558044A (zh) * 2020-06-01 2020-08-21 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） 一种包含舒尼替尼的药物组合物及其制剂和应用
WO2022251386A1 (fr) * 2021-05-25 2022-12-01 Louis Habash Modulation du niveau d'expression d'un gène codant pour une protéine cytochrome p450 par traitement d'un sujet humain avec un nitroxyde
WO2022247881A1 (fr) * 2021-05-28 2022-12-01 凯复(苏州)生物医药有限公司 Polythérapie pour le traitement d'une tumeur
CN113425707B (zh) * 2021-07-30 2022-12-30 青岛大学附属医院 壬二酸预防蒽环类抗肿瘤药物心肌毒性的应用
CN113425707A (zh) * 2021-07-30 2021-09-24 青岛大学附属医院 壬二酸预防蒽环类抗肿瘤药物心肌毒性的应用
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