WO2019204154A1 - Compositions et méthodes pour le traitement du cancer du foie - Google Patents

Compositions et méthodes pour le traitement du cancer du foie Download PDF

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WO2019204154A1
WO2019204154A1 PCT/US2019/027244 US2019027244W WO2019204154A1 WO 2019204154 A1 WO2019204154 A1 WO 2019204154A1 US 2019027244 W US2019027244 W US 2019027244W WO 2019204154 A1 WO2019204154 A1 WO 2019204154A1
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day
cancer
inhibitor
pharmaceutical composition
tyrosine kinase
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PCT/US2019/027244
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English (en)
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Yushan ZHAO
Dezu MIAO
Shujie HOU
Jian XUE
Kai Liu
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Reyoung Corporation
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • Hepatocellular carcinoma is a primary malignancy of liver cancer.
  • HCC hypertension-associated fatty acid metabolism, diabetes, obesity, hereditary conditions (e.g., hemochromatosis), and metabolic disorders.
  • HCC accounts for 70%-85% of primary liver cancer cases in some countries.
  • El-Serag HB N Engl JMed., 365(12): 1118-27 (2011).
  • HCC is often asymptomatic in its early stages; thus, almost 85% of patients diagnosed with HCC are in intermediate or advanced stages, for which only limited treatment options are available.
  • the disclosure of the present invention meets this medical need by providing a pharmaceutical composition comprising a tyrosine kinase inhibitor, an antihistamine, and a pharmaceutically acceptable carrier.
  • the tyrosine kinase inhibitor comprises an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial cell growth factor receptor (VEGFR) inhibitor, a platelet-derived growth factor receptor
  • the tyrosine kinase inhibitor comprises one or more of imatinib, bafetinib, dasatinib, nilotinib, bosutinib, ponatinib, thiazol, thiadiazole, and their salts, derivatives, or analogs. In one embodiment the tyrosine kinase inhibitor comprises imatinib.
  • the antihistamine comprises one or more of perphenazine, sertralin, thioridazine, chlorpromazine, paroxetine, flupentixol, fluphenazine, hydroxyzine, promethazine, loratadine, cyproheptadine, and their salts, derivatives, or analogs.
  • the disclosure relates to methods of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor and an antihistamine.
  • the tyrosine kinase inhibitor comprises an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial cell growth factor receptor (VEGFR) inhibitor, a platelet-derived growth factor receptor
  • the tyrosine kinase inhibitor comprises one or more of imatinib, bafetinib, dasatinib, nilotinib, bosutinib, ponatinib, thiazol, thiadiazole, and their salts, derivatives, or analogs.
  • the tyrosine kinase inhibitor comprises imatinib.
  • the antihistamine comprises one or more of perphenazine, sertralin, thioridazine, chlorpromazine, paroxetine, flupentixol, fluphenazine, hydroxyzine, promethazine, loratadine,
  • the disclosure relates to methods of reducing proliferation of a cancer cell comprising contacting the cancer cell with a therapeutically effective amount of a tyrosine kinase inhibitor and an antihistamine.
  • the tyrosine kinase inhibitor comprises an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial cell growth factor receptor (VEGFR) inhibitor, a platelet-derived growth factor receptor (PDGFR) inhibitor, a c-KIT inhibitor, an FMS-like tyrosine kinase 3 (FLT-3) inhibitor, and a Breakpoint cluster region Abelson (BCR-ABL) inhibitor.
  • EGFR epidermal growth factor receptor
  • VEGFR vascular endothelial cell growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • BCR-ABL Breakpoint cluster region Abelson
  • the tyrosine kinase inhibitor comprises one or more of imatinib, bafetinib, dasatinib, nilotinib, bosutinib, ponatinib, thiazol, gefitinib, afatinib, thiadiazole, and their salts, derivatives, or analogs.
  • the tyrosine kinase inhibitor comprises imatinib.
  • the antihistamine comprises one or more of perphenazine, sertralin, thioridazine, chlorpromazine, paroxetine, flupentixol, fluphenazine, hydroxyzine, promethazine, loratadine, cyproheptadine, and their salts, derivatives, or analogs.
  • Figure 1A shows the inhibition rates of HepG2 cell growth in response to treatment of imatinib in absence or presence of cyproheptadine.
  • Figure 1B shows the inhibition rates of HepG2 cell growth in response to treatment of cyproheptadine in absence or presence of imatinib.
  • Figure 2 shows inhibition rates of Huh- 7 cell growth in response to treatment of imatinib in absence or presence of cyproheptadine.
  • Figure 3 shows inhibition rates of normal human L-02 cells in response to treatment of imatinib in absence or presence of cyproheptadine.
  • Figure 4 shows the tumor volumes in mice implanted with HepG2 cells.
  • Figure 5 shows the body weights of mice.
  • Figure 6 shows the survival rates mice.
  • Figure 7 shows the survival rates of mice after treatments with CMC-Na, combination of cyproheptadine (6 mg/kg/day) and imatinib, and sorafenib.
  • Figure 8 shows the body weights of mice after treatments with CMC-Na, combination of cyproheptadine (6 mg/kg/day) and imatinib, and sorafenib.
  • Figure 9A shows the surviving rates of A549 cells after treatment of gefitinib alone, or in combination of cyproheptadine or loratadine.
  • Figure 9B shows the surviving rates of A549 cells after treatment of afatinib alone, or in combination of cyproheptadine or loratadine.
  • compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding more than trace amount of other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention.
  • the term“inhibitor” refers to a substrate that blocks or suppresses the activity, function, or effect of a target.
  • the target is a compound, a protein, a gene, a cell, or an agent.
  • the target is a tyrosine kinase.
  • the inhibitor includes a compound that prevents binding of another molecule to an enzyme or molecular pump.
  • the inhibitor is a compound that causes downregulation of the enzyme.
  • An inhibitor can be a competing or non-competing inhibitor.
  • non-competing inhibitor refers to a type of inhibitor that binds to an enzyme or a target so that the enzyme or the target cannot bind to or act on another substrate.
  • tyrosine kinase inhibitor is a compound that can compete with ATP for the ATP binding site of a phospho tyrosine kinase and reduce tyrosine kinase phosphorylation.
  • the tyrosine kinase inhibitor comprises one or more of an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial cell growth factor receptor (VEGFR) inhibitor, a platelet-derived growth factor receptor (PDGFR) inhibitor, a c-KIT inhibitor, an FMS-like tyrosine kinase 3 (FLT-3) inhibitor, and a BCR- ABL inhibitor.
  • EGFR epidermal growth factor receptor
  • VEGFR vascular endothelial cell growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • FLT-3 FMS-like tyrosine kinase 3
  • BCR- ABL inhibitor BCR- ABL inhibitor.
  • the EGFR inhibitor includes one or more of gefitinib, erlotinib, canertinib, and their salts, derivatives, or analogs.
  • the VEGFR inhibitor includes one or more of vatalanib, semaxanib, sunitinib, and their salts, derivatives, or analogs.
  • the PDGFR inhibitor includes one or more of pazopanib, nilotinib, cediranib, and their salts, derivatives, or analogs.
  • the c-KIT inhibitor includes one or more of dasatinib, pazopanib, quzartinib, and their salts, derivatives, or analogs.
  • the FLT-3 inhibitor includes one or more of CEP701, sunitinib, PKC412, and their salts, derivatives, or analogs.
  • the BCR- ABL inhibitor includes one or more of imatinib, bafetinib, dasatinib, nilotinib, bosutinib, ponatinib, thiazol, thiadiazole, and their salts, derivatives, or analogs.
  • the BCR-ABL inhibitor is imatinib.
  • the EGFR inhibitor in one embodiment, comprises gefitinib and/or afatinib.
  • antihistamine is a compound that antagonizes histamine induced responses. Histamine is a biogenic amine that exerts its physiologic action by binding to receptors belonging to the superfamily of seven transmembrane G protein-coupled receptors (GPCRs). Monczor et al., Mol Pharmacol. 90:640-648 (2016). Histamine exerts its multiple biological actions via one of several receptors, including the Hl receptor (H1R), H2 receptor (H2R), H3 receptor (H3R), and more recently, H4 receptors (H4R).
  • H1R Hl receptor
  • H2R H2 receptor
  • H3R H3 receptor
  • H4R H4 receptors
  • the H1R signals through one or more of increased calcium signaling, cyclic guanosine monophosphate (cGMP) mediated signaling, nuclear factor kappaB (NFkappaB), increased phospholipase C (PLC) activity, increased phospholipase A2 and/or D activity, cyclic adenosine
  • cGMP cyclic guanosine monophosphate
  • NFkappaB nuclear factor kappaB
  • PLC phospholipase C
  • A2 and/or D activity cyclic adenosine
  • the antihistamine comprises one or more of perphenazine, sertralin, thioridazine, chlorpromazine, paroxetine, flupentixol, fluphenazine, hydroxyzine, promethazine, loratadine, cyproheptadine, and their salts, derivatives, or analogs.
  • the antihistamine is cyproheptadine.
  • Dosage or“dosage regiment” is defined herein as the amount needed for effectiveness of each of the various disease states. Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single dosage may be administered or several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage of a particular compound is provided as absolute weight.
  • the dosage of a particular compound is provided as mass ratio wherein the mass ratio is the fraction of a particular compound out of the total composition.
  • the dosage is provided as mg compound per kg total body weight of the subject to whom the composition is provided, and this dosage format is hereinafter designated mg/kg.
  • the dosage is provided in hourly, daily, weekly, or monthly dosage regimens.
  • the terms“patient,”“subject,”“individual,” and the like are used interchangeably herein and refer to any animal, or cells thereof, whether in vitro or in situ, amenable to the methods described herein.
  • the patient, subject, or individual is a mammal.
  • the mammal is a mouse, a rat, a guinea pig, a non-human primate, a dog, a cat, or a domesticated animal (e.g. , horse, cow, pig, goat, sheep).
  • the patient, subject, or individual is a human.
  • the term“cancer” is used herein to refer to conditions in which abnormal cells divide without control and can invade nearby tissues.
  • Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs.
  • Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.
  • Leukemia is a cancer that starts in blood-forming tissue, such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood.
  • Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system.
  • Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord.
  • the cancer is one or more of pancreatic cancer, renal cancer, small cell lung cancer, brain cancer, neural cancer, bone cancer, lymphoma, myeloma, colon cancer, uterine cancer, breast cancer, leukemia, liver cancer, prostate cancer, skin cancer, and melanoma.
  • the cancer is liver cancer.
  • the liver cancer is one or more of hepatocellular carcinoma, bile duct cancer, angiosarcoma, hemangiosarcoma, hepatoblastoma, hemangioma, hepatic adenoma, and focal nodular hyperplasia.
  • the term“treating” or“treatment” covers the treatment of a cancer described herein in a subject, such as a human, and includes (i) inhibiting a cancer, i.e., arresting its development; (ii) relieving a cancer or disorder, i.e., causing regression of the cancer; (iii) slowing progression of the cancer; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the cancer.
  • treatment of a cancer includes, but is not limited to, elimination of the cancer or the condition caused by the cancer, remission of the tumor, inhibition of the cancer, reduction, or elimination of at least one symptom of the tumor.
  • administering or“administration” of an agent to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function.
  • a route of administration is the path by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. Administration can be carried out by any suitable route, including parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via minicells, via antibody conjugation, via cell targeting peptides, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • Concurrently administering refers to administration of at least two agents to a patient over a period of time. Concurrent administration includes, without limitation, separate, sequential, and simultaneous administration.
  • the term“separate” administration refers to an administration of at least two active ingredients at the same time or substantially the same time by different routes.
  • sequential administration refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients.
  • composition refers to the administration of at least two ingredients by the same route and at the same time or at substantially the same time.
  • therapeutic means a treatment and/or prophylaxis.
  • a therapeutic effect is obtained by suppression, remission, or eradication of a disease state.
  • compositions can also be administered in combination with one or more additional therapeutic compounds.
  • the therapeutic compounds may be administered to a subject having one or more signs or symptoms of a disease or disorder.
  • analog refers to a compound in which one or more individual atoms or functional groups have been replaced, either with a different atom or a different functional, generally giving rise to a compound with similar properties.
  • the analog refers to a structure that is similar to another but differs in one or two components.
  • derivatives refers to a compound that is formed from a similar, beginning compound by attaching another molecule or atom to the beginning compound. Further, derivatives, according to the invention, encompass one or more compounds formed from a precursor compound through addition of one or more atoms or molecules or through combining two or more precursor compounds.
  • pharmaceutically acceptable carrier refers to a carrier that is
  • compositions can also provide timed delayed release of the drug and targeted release of the drug to specific tissues.
  • Many types of delivery systems for targeted release of drugs are available and known to those of ordinary skill in the art, including controlled-release biodegradable polymers, polymeric microsphere carriers and liposomes, as well as the co-administration of cytoprotective agents with antineoplastics as described in Chonn and Cullis, Curr Opinion in Biotechnology, 6:698-708 (1995); Kemp et al., J. Clin. Oncol, 14:2101-2112 (1996); Kumanohoso et al., Cancer Chemother.
  • the liposomes can be further coated with polyethene glycol (PEG) to prolong their circulation time. Furthermore, targeted delivery of the drugs can be achieved by using minicells as described in WO 2005/079854.
  • PEG polyethene glycol
  • the minicells comprise a first arm that carries specificity for a bacterially derived minicell surface structure and a second arm that carries specificity for a mammalian cell surface receptor, to target drug-loaded minicells to specific mammalian cells and to cause endocytosis of the minicells by the mammalian cells.
  • the pharmaceutical composition is administered in a targeted release system.
  • cell targeting peptide refers to a peptide that is conventionally used in the art to recognize and bind specific cells and tissues as described in Mousavizadeh et al, Colloids and Surfaces B: Biointerfaces 158:507-517 (2017).
  • a person having ordinary skill in the art will know how to conjugate a small drug to a cell targeting peptide to achieve targeted delivery of the drug to specific cells and tissues.
  • antibody is used herein to refer to immunoglobulins conventionally used in the art to recognize and bind specific antigens and can be conjugated with small molecules for targeted delivery to specific cells and tissues as described in Tsuchikama et al, Protein Cell 9:33-46 (2016). A person having ordinary skill in the art will know how to conjugate small molecule drugs to antibodies.
  • PTKs Protein tyrosine kinases
  • RTKs receptor PTKs
  • NRTKs non-receptor PTKs
  • PTK activity usually leads to cell proliferation disorders, and is closely related to tumor invasion, metastasis and tumor angiogenesis. Overexpression of PTK genes cause abnormal PTK activity and activation of the signaling pathways that lead to cell proliferation and even tumor formation. Drake et al., Mol Cell Biol., 34: 1722-1732 (2014). Furthermore, genetic mutations in PTK genes often lead to constitutively activation of PTKs and unregulated cell growth. Prickett et al. , Nat Genet. , 41: 1127-1132 (2009).
  • the tyrosine kinase inhibitors (“TKIs”) can be used as anti tumor agents.
  • the TKIs inhibit the PTK-induced proliferation, differentiation, angiogenesis, metastasis, and/or cell death.
  • TKIs can be used to inhibit abnormal proliferation of cancer cells, reverse the cancer cell’s abnormal differentiation, and/or induce apoptosis in the cancer cell.
  • tyrosine kinase inhibitors (TKIs) compete with ATP for the ATP binding site of PTK and reduce tyrosine kinase phosphorylation.
  • Exemplary TKIs include but are not limited to EGFR inhibitors, VEGFR inhibitors, anaplastic lymphoma kinase (ALK) inhibitors, and Breakpoint cluster region Abelson (BCR-ABL) inhibitors. More than 20 TKIs have been approved by FDA for treatment of pancreatic cancer, renal cancer, small cell lung cancer, brain cancer, neural cancer, bone cancer, lymphoma, myeloma, colon cancer, uterine cancer, breast cancer, leukemia, liver cancer, prostate cancer, skin cancer, and melanoma. Arora et al., J
  • Imatinib is primarily used for treating chronic myeloid leukemia (CML) caused by constitutively active BCR-ABL tyrosine kinase due to chromosomal translocation.
  • CML chronic myeloid leukemia
  • TKIs Some features of TKIs, including high selectivity, high efficacy, low side effects, and ease of preparation, render them appealing as anti-cancer drugs.
  • TKIs have not tested effectively against diseases other than CML.
  • TKI fails to effectively treat solid tumors.
  • the incomplete elimination of tumor cell targets results in the development of drug-resistant cancer cells.
  • the median effective time for TKI therapy has been shown to be only 5 to 9 months.
  • imatinib was less effective in treating unresectable human hepatocellular carcinoma. Lin et al., Am J Clin Oncol., 3l(l):84— 8 (2008).
  • the present disclosure provides pharmaceutical compositions comprising a tyrosine kinase inhibitor, an antihistamine, and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions comprise imatinib, cyproheptadine, and a pharmaceutically acceptable carrier.
  • the TKI comprises one or more of an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial cell growth factor receptor (VEGFR) inhibitor, a platelet-derived growth factor receptor (PDGFR) inhibitor, a c-KIT inhibitor, an FMS-like tyrosine kinase 3 (FLT-3) inhibitor, and a BCR-ABL inhibitor.
  • EGFR epidermal growth factor receptor
  • VEGFR vascular endothelial cell growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • FLT-3 FMS-like tyrosine kinase 3
  • BCR-ABL inhibitor a BCR-ABL inhibitor.
  • the EGFR inhibitor includes one or more of afatinib, gefitinib, erlotinib, canertinib, and their salts, derivatives, or analogs.
  • the VEGFR inhibitor includes one or more of vatalanib, semaxanib, sunitinib, and their salts, derivatives, or analogs.
  • the PDGFR inhibitor includes one or more of pazopanib, nilotinib, cediranib, and their salts, derivatives, or analogs.
  • the c-KIT inhibitor includes one or more of dasatinib, pazopanib, quzartinib, and their salts, derivatives, or analogs.
  • the FLT-3 inhibitor includes one or more of CEP701, sunitinib, PKC412, and their salts, derivatives, or analogs.
  • the BCR- ABL inhibitor comprises one or more of imatinib, bafetinib, dasatinib, nilotinib, bosutinib, ponatinib, thiazol, thiadiazole, and their salts, derivatives, or analogs. In some embodiments, the BCR-ABL inhibitor is imatinib.
  • TKIs are contemplated herein, which includes their hydrates and co-crystals of such compounds and such salts.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, and combinations comprising one or more of the foregoing salts.
  • the pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the TKIs.
  • non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like
  • alkaline earth metal salts such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.
  • Organic salts includes salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is 0-4, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N’-dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate, aspara
  • the tyrosine kinase inhibitors can also be conjugated to peptides and/or antibodies that recognize specific cell markers for targeted delivery to specific cells and tissue.
  • the tyrosine kinase inhibitor is conjugated to a cell targeting peptide or an antibody.
  • Histamine is a biogenic amine that exerts its physiologic action by binding to receptors belonging to the superfamily of seven transmembrane G protein-coupled receptors (GPCRs). Monczor et al., Mol Pharmacol. 90:640-648 (2016). Histamine exerts its multiple biological actions via one of several receptors including the Hi receptor (HiR), 3 ⁇ 4 receptor (H2R), H3 receptor (H3R), and 3 ⁇ 4 receptor (H4R).
  • Hi receptor Hi receptor
  • H2R 3 ⁇ 4 receptor
  • H3R H3 receptor
  • H4R 3 ⁇ 4 receptor
  • HiR signaling pathways are involved in calcium signaling, cyclic guanosine monophosphate (cGMP) mediated signaling, nuclear factor kappaB (NFkappaB) signaling, phospholipase C (PLC) activity, phospholipase A2 and/or D activities, cyclic adenosine monophosphate activity (cAMP) and/or nitric oxide synthase activities as described in U.S. Patent 9,808,444.
  • cGMP cyclic guanosine monophosphate
  • NFkappaB nuclear factor kappaB
  • PLC phospholipase C
  • cAMP cyclic adenosine monophosphate activity
  • nitric oxide synthase activities as described in U.S. Patent 9,808,444.
  • histamines can regulate a variety of cellular responses associated with these pathways or activities, e.g., cell proliferation, cell differentiation, apoptosis, cytoskeleton remodeling, vesicular trafficking, ion channel conductance, endocrine function, and neurotransmission.
  • an antihistamine is used to antagonize one or more of these histamine-associated pathways.
  • the antihistamine comprises one or more of perphenazine, sertralin, thioridazine, chlorpromazine, paroxetine, flupentixol, fluphenazine, hydroxyzine, promethazine, loratadine, cyproheptadine, and their salts, derivatives, or analogs.
  • the antihistamine is cyproheptadine.
  • the antihistamine is loratadine. [0053] Cyproheptadine was tested for its potential anti-cancer functions.
  • Cyproheptadine can inhibit expression of D cyclins and induce apoptosis. Mao et al, Blood, 112:760-769 (2008). Furthermore, cyproheptadine can function as a histone deacetylase inhibitor to exert antineoplastic activity. Paoluzzi et al., Br J Haematol., 146:656-659 (2009). Furthermore, cyproheptadine has been reported to activate p38 mitogen activated protein kinase (MAPK) and checkpoint kinase 2 (CHK2), resulting in cell cycle arrest. Feng et al., BMC Cancer, 15: 134 (2015).
  • MAPK mitogen activated protein kinase
  • CHK2 checkpoint kinase 2
  • Cyproheptadine was found to inhibit breast cancer cell growth. Takemoto et al. , J. Med. Chem., 59:3650-60 (2016). In addition, cyproheptadine may improve survival outcomes of sorafenib-treated advanced HCC patients. Feng et al, Jpn JClin Oncol., 45:336-342 (2015). Although these studies are promising, sorafenib remains currently the only systemic agent approved by FDA to treat HCC patients.
  • Inventors of the present disclosure surprisingly found that cyproheptadine can synergistically improve the anti-cancer properties of tyrosine kinase inhibitors.
  • the present disclosure provides novel pharmaceutical compositions or methods for treatment of liver cancers (e.g . , HCC).
  • the present disclosure provides a pharmaceutical composition which comprises a tyrosine kinase inhibitor, an antihistamine, and a pharmaceutically acceptable carrier.
  • the antihistamine comprises one or more of perphenazine, sertralin, thioridazine, chlorpromazine, paroxetine, flupentixol, fluphenazine, hydroxyzine, promethazine, cyproheptadine, and their salts, derivatives, or analogs.
  • the antihistamine is cyproheptadine, and its salts, derivatives, or analogs.
  • All forms of the antihistamines are contemplated herein, which include their hydrates, and co-crystals of such compounds and such salts.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, and combinations comprising one or more of the foregoing salts.
  • the pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the antihistamines.
  • non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.
  • Pharmaceutically acceptable organic salts includes salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
  • organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N’-dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate, asparaginate, glutamate, and the like; and combinations comprising one or more of the foregoing salts; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is 0-4, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine
  • the antihistamines can be conjugated to peptides and/or antibodies that recognize specific cell markers for targeted delivery to cells and tissues.
  • a person having ordinary skill in the art will know how to conjugate small molecule drugs to cell targeting peptides and antibodies.
  • the antihistamine is conjugated to a cell targeting peptide, or an antibody.
  • the disclosure provides that a combination of tyrosine kinase inhibitors and antihistamines can act synergistically to inhibit cancer cells.
  • a combination of the anti -histamine e.g ., cyproheptadine and loratadine
  • tyrosine kinase inhibitor e.g., imatinib
  • cancer cells e.g., HepG2 and Huh- 7
  • the combination treatment can also increase the survival rate of the mice suffering from liver cancer as compared to a single-agent treatment.
  • this disclosure provides compositions that enhance the clinical utility of tyrosine kinase inhibitors, including imatinib, and
  • antihistamines such as cyproheptadine or loratadine.
  • the disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition comprises, a tyrosine kinase inhibitor, an antihistamine, and a pharmaceutically acceptable carrier.
  • the dosages of the tyrosine kinase inhibitors can vary among patient.
  • the dosage to achieve the therapeutic effects of tyrosine kinase inhibitor in the pharmaceutical composition is from about 0.1 mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 75 mg/kg/day, from about 50 mg/kg/day to about 90 mg/kg/day, from about 1 mg/kg/day to about 50 mg/kg/day, from about 2 mg/kg/day to about 20 mg/kg/day, from about 2 mg/kg/day to about 15 mg/kg/day, or from about 4 mg/kg/day to about 10 mg/kg/day.
  • the dosage of imatinib is from about 0.1 mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 75 mg/kg/day, from about 1 mg/kg/day to about 50 mg/kg/day, from about 2 mg/kg/day to about 20 mg/kg/day, from about 2 mg/kg/day to about 15 mg/kg/day, or from about 4 mg/kg/day to about 10 mg/kg/day.
  • the dosage of imatinib is at least 0.1 mg/kg/day, at least 0.2 mg/kg/day, at least 0.3 mg/kg/day, at least 0.4 mg/kg/day, at least 0.5 mg/kg/day, at least, at least 1 mg/kg/day, at least 2 mg/kg/day, at least 3 mg/kg/day, at least 4 mg/kg/day, at least 5 mg/kg/day, at least 6 mg/kg/day, at least 7 mg/kg/day, at least 8 mg/kg/day, at least 9 mg/kg/day, or at least 10 mg/kg/day.
  • the dosages of the antihistamines can vary among patients.
  • the dosage to achieve the therapeutic effects of antihistamines in the pharmaceutical composition is from about from about 0.01 mg/kg/day to about 10 mg/kg/day, from about 0.05 mg/kg/day to about 7.5 mg/kg/day, from about 1 mg/kg/day to about 7 mg/kg/day, from about 0.1 mg/kg/day to about 5.0 mg/kg/day, from about 0.1 mg/kg/day to about 2 mg/kg/day, from about 0.02 mg/kg/day to about 1.5 mg/kg/day, or from about 0.1 mg/kg/day to about 1.0 mg/kg/day.
  • the dosage of cyproheptadine is from about 0.01 mg/kg/day to about 10 mg/kg/day, from about 0.05 mg/kg/day to about 7.5 mg/kg/day, from about 1 mg/kg/day to about 7 mg/kg/day, from about 0.1 mg/kg/day to about 5.0 mg/kg/day, from about 0.1 mg/kg/day to about 2 mg/kg/day, from about 0.02 mg/kg/day to about 1.5 mg/kg/day, or from about 0.1 mg/kg/day to about 1.0 mg/kg/day.
  • the dosage of cyproheptadine is at least 0.1 mg/kg/day, at least 0.2 mg/kg/day, at least 0.3 mg/kg/day, at least 0.4 mg/kg/day, at least 0.5 mg/kg/day, at least 0.6 mg/kg/day, at least 0.7 mg/kg/day, at least 0.8 mg/kg/day, at least 0.9 mg/kg/day, or at least 1 mg/kg/day.
  • the dosage ratio of the tyrosine kinase inhibitor to the antihistamine is at least 2: 1, 5: 1, 10: 1, 20: 1, or 30: 1. In one embodiment, the dosage ratio of imatinib to cyproheptadine is at least 2: 1, 5: 1, 10: 1, 20: 1, or 30: 1.
  • the pharmaceutical composition further comprises one or more of sorafenib, sunitinib, brivanib, bevacizumab, ramucirumab, vatalanib, linifanib, TSU- 68, cediranib, erlotinib, nintedanib, regorafenib, cetuximab, lapatinib, cixutumumab, everolimus, sirolimus, and tivantinib.
  • a pharmaceutical composition is formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via minicells, via antibody conjugation, via cell targeting peptides, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via minicells, via antibody conjugation, via cell targeting peptides, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, or intrathecally administration to human beings.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.
  • the composition may be formulated as a sterile aqueous solution suitable for injection intravenously, subcutaneously, intraperitoneally, or intramuscularly.
  • compositions can be formulated orally in the form of tablets, capsules, cachets, gelcaps, solutions, or suspensions.
  • the tablets may be coated by methods well-known in the art.
  • Liquid preparations for oral administration may take the form of, but not limited to, solutions, syrups, or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • the composition further comprises one or more of binding agents, flavor agents, lubricating agents, flow agents, disintegration agents, delay agents, and organic solvents.
  • the binding agents comprise starch, modified starch, cellulose, modified cellulose, brewer’s yeast, sucrose, dextrose, whey, and dicalcium phosphate.
  • the lubricating agents comprise magnesium stearate, stearic acid, starch, modified starch, and modified cellulose.
  • the flow agents comprise silica dioxide, modified silica, fumed silica, and talc.
  • the disintegration agents comprise croscarmellose sodium, sodium starch glycolate, starch, and modified starch.
  • the delay agents comprise one or more of stearic acid, stearic acid salts, magnesium stearate, polyethylene glycols, starch, modified starch, and methacrylate polymers.
  • the organic solvents comprise propylene glycol, polyethylene glycols, ethanol, dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone, glycofurol, Solketal, glycerol formal, acetone, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, and ethyl lactate.
  • the concentration of the organic solvent is 0.1% to about 35% of the total volume of the composition. In some embodiments, the concentration of the organic solvent is 2% of the total volume of the composition.
  • the disclosure provides methods of treating a cancer in a subject, comprising, alternatively consisting essentially of, or yet consisting of administering to the subject an effective amount of a tyrosine kinase inhibitor and an effective amount of an antihistamine.
  • the subject is a human.
  • the subject is a mammal.
  • the subject is a non-mammal.
  • the mammal comprises a mouse, a rat, a guinea pig, a non-human primate, a dog, a cat, a horse, a cow, a pig, a goat, and/or a sheep.
  • the cancer is one or more of pancreatic cancer, renal cancer, small cell lung cancer, brain cancer, neural cancer, bone cancer, lymphoma, myeloma, colon cancer, uterine cancer, breast cancer, leukemia, liver cancer, prostate cancer, skin cancer, and melanoma.
  • the cancer is liver cancer.
  • the liver cancer is one or more of hepatocellular carcinoma, bile duct cancer, angiosarcoma, hemangiosarcoma,
  • hepatoblastoma hemangioma
  • hepatic adenoma hepatic adenoma
  • focal nodular hyperplasia hepatoblastoma, hemangioma, hepatic adenoma, and focal nodular hyperplasia.
  • the described TKI can be formulated as pharmaceutical compositions for any cancer described herein.
  • the TKI comprises one or more of an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial cell growth factor receptor (VEGFR) inhibitor, a platelet-derived growth factor receptor (PDGFR) inhibitor, a c-KIT inhibitor, an FMS-like tyrosine kinase 3 (FLT-3) inhibitor, and a BCR-ABL inhibitor.
  • EGFR epidermal growth factor receptor
  • VEGFR vascular endothelial cell growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • FLT-3 FMS-like tyrosine kinase 3
  • BCR-ABL inhibitor BCR-ABL inhibitor
  • the BCR-ABL inhibitor comprises one or more of imatinib, bafetinib, dasatinib, nilotinib, bosutinib, ponatinib, thiazol, thiadiazole, and their salts, derivatives, or analogs.
  • the effective amount of TKI is from about 0.1 mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 75 mg/kg/day, from about 1 mg/kg/day to about 50 mg/kg/day, from about 2 mg/kg/day to about 20 mg/kg/day, from about 2 mg/kg/day to about 15 mg/kg/day, from about 3 mg/kg/day to about 12 mg/kg/day, or from about 4 mg/kg/day to about 10 mg/kg/day.
  • the dosage of imatinib is at least 0.1 mg/kg/day, at least 0.2 mg/kg/day, at least 0.3 mg/kg/day, at least 0.4 mg/kg/day, at least 0.5 mg/kg/day, at least 1 mg/kg/day, at least 2 mg/kg/day, at least 3 mg/kg/day, at least 4 mg/kg/day, at least 5 mg/kg/day, at least 6 mg/kg/day, at least 7 mg/kg/day, at least 8 mg/kg/day, at least 9 mg/kg/day, or at least 10 mg/kg/day.
  • the described antihistamine (including its derivatives and analogs) can be formulated as pharmaceutical compositions for any cancer described herein.
  • the antihistamine comprises one or more of perphenazine, sertralin, thioridazine, chlorpromazine, paroxetine, flupentixol, fluphenazine, hydroxyzine, promethazine, cyproheptadine, and their salts, derivatives, or analogs.
  • the antihistamine is cyproheptadine.
  • the effective amount of antihistamine or cyproheptadine is from about 0.01 mg/kg/day to about 10 mg/kg/day, from about 0.05 mg/kg/day to about 7.5 mg/kg/day, from about 0.1 mg/kg/day to about 5.0 mg/kg/day, from about 0.1 mg/kg/day to about 2 mg/kg/day, from about 0.02 mg/kg/day to about 1.5 mg/kg/day, or from about 0.1 mg/kg/day to about 1.0 mg/kg/day.
  • the dosage of cyproheptadine is at least 0.1 mg/kg/day, at least 0.2 mg/kg/day, at least 0.3 mg/kg/day, at least 0.4 mg/kg/day, at least 0.5 mg/kg/day, at least 0.6 mg/kg/day, at least 0.7 mg/kg/day, at least 0.8 mg/kg/day, at least 0.9 mg/kg/day, or at least 1 mg/kg/day.
  • the tyrosine kinase inhibitors and/or antihistamines are administered parenterally, orally, intraperitoneally, intravenously, intraarterially,
  • transdermally sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via minicells, via antibody conjugation, via cell targeting peptides, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the method further comprises administering to the subject one or more of sorafenib, sunitinib, brivanib, bevacizumab, ramucirumab, vatalanib, linifanib, TSU-68, cediranib, erlotinib, nintedanib, regorafenib, cetuximab, lapatinib, cixutumumab, everolimus, sirolimus, and tivantinib.
  • the tyrosine kinase inhibitor and the antihistamine are administered separately, simultaneously, or sequentially.
  • Also provided in the disclosure is a method of inhibiting cancer cell growth by contacting the cancer cell with a TKI and an antihistamine.
  • Cancer cells often become resistant to the anti-proliferative effect of TKIs because the cancer cells may harbor mutations that allow them to escape the killing function of the TKI.
  • Applicant found that cyproheptadine can sensitize heptacellular carcinoma cells to the antiproliferative effect of imatinib on the heptacellular carcinoma cells HepG2 and Huh-7.
  • the combination treatment can be used to inhibit proliferation of cancer cells, especially those types that are resistant to conventional treatments.
  • the cancer cell targeted by the claimed method derives from liver cancer.
  • the liver cancer comprises one or more of hepatocellular carcinoma, bile duct cancer, angiosarcoma, hemangiosarcoma, hepatoblastoma, hemangioma, hepatic adenoma, and focal nodular hyperplasia.
  • the liver cancer is hepatocellular carcinoma.
  • the tyrosine kinase inhibitor is a BCR-ABL inhibitor.
  • the BCR-ABL inhibitor is imatinib.
  • the antihistamine is cyproheptadine.
  • the cancer cell is a mammal cancer cell.
  • the mammal is human.
  • the mammal comprises a mouse, a rat, a guinea pig, a non-human primate, a dog, a cat, a horse, a cow, a pig, a goat, and/or a sheep.
  • the method of reducing proliferation of a cancer cell further comprises contacting the cancer cell with an effective amount of sorafenib, sunitinib, brivanib, bevacizumab, ramucirumab, vatalanib, linifanib, TSU-68, cediranib, erlotinib, nintedanib, regorafenib, cetuximab, lapatinib, cixutumumab, everolimus, sirolimus, tivantinib, or a combination thereof.
  • the method of reducing proliferation of a cancer cell comprises contacting the cancer cell with the TKI and the antihistamine separately, simultaneously, or sequentially.
  • the cancer cell is contacted with imatinib and cyproheptadine separately, simultaneously, or sequentially.
  • the compounds disclosed herein can be administered in combination or alternation with a second biologically active agent to increase its effectiveness against the target disorder.
  • effective dosages of two or more agents are administered together, whereas during alternation therapy an effective dosage of each agent is administered serially.
  • the dosages will depend on absorption, inactivation, and elimination rates of the drug as well as other factors known to those with ordinary skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • a person with ordinary skill in the art would understand that a proper dosage for administration and know how to convert a proper dosage from one specie to another. For example, in view of a dosage for a mouse, the person with ordinary skill in the art would understand how to convert the dosage to an equivalent dosage for human.
  • compositions as described herein, are administered in effective amounts for treating the herein disclosed diseases.
  • the effective amount will depend upon the mode of administration, the particular condition being treated, and the desired outcome.
  • dosages determined by animal experiments can be converted an equivalent dosage for a different animal species or human. See, e.g., Nair et al., J. Basic Clin. Pharm. 7:27-31 (2016). For example, a dosage for an animal species can be converted to an equivalent dosage for human based on the conversion table in Nair et al., J. Basic Clin. Pharm. 7:27-31 (2016).
  • the dose of the TKI is from about 0.1 mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 75 mg/kg/day, from about 1 mg/kg/day to about 50 mg/kg/day, from about 2 mg/kg/day to about 20 mg/kg/day, from about 2 mg/kg/day to about 15 mg/kg/day, from about 3 mg/kg/day to about 12 mg/kg/day, or from about 4 mg/kg/day to about 10 mg/kg/day.
  • the dosage of the tyrosine kinase is at least 0.1 mg/kg/day, at least 0.2 mg/kg/day, at least 0.3 mg/kg/day, at least 0.4 mg/kg/day, at least 0.5 mg/kg/day, at least, at least 1 mg/kg/day, at least 2 mg/kg/day, at least 3 mg/kg/day, at least 4 mg/kg/day, at least 5 mg/kg/day, at least 6 mg/kg/day, at least 7 mg/kg/day, at least 8 mg/kg/day, at least 9 mg/kg/day, or at least 10 mg/kg/day.
  • the dose of the antihistamine is from about 0.01 mg/kg/day to about 10 mg/kg/day, from about 0.05 mg/kg/day to about 7.5 mg/kg/day, from about 0.1 mg/kg/day to about 5.0 mg/kg/day, from about 0.1 mg/kg/day to about 2 mg/kg/day, from about 0.02 mg/kg/day to about 1.5 mg/kg/day, or from about 0.1 mg/kg/day to about 1.0 mg/kg/day.
  • the dosage of the antihistamine is at least 0.1 mg/kg/day, at least 0.2 mg/kg/day, at least 0.3 mg/kg/day, at least 0.4 mg/kg/day, at least 0.5 mg/kg/day, at least 0.6 mg/kg/day, at least 0.7 mg/kg/day, at least 0.8 mg/kg/day, at least 0.9 mg/kg/day, or at least 1 mg/kg/day.
  • an effective amount of a pharmaceutical composition, TKI, and/or antihistamine is administered every 1 hour to every 24 hours, for example, every 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours.
  • the pharmaceutical composition, TKI, and/or antihistamine is administered every 1 day to every 21 days, for example, every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days.
  • an amount of the pharmaceutical composition is administered every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks.
  • compositions of the invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active ingredients without causing clinically unacceptable adverse effects.
  • the pharmaceutical compositions can be administered to a subject parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via minicells, via antibody conjugation, via cell targeting peptides, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • Modes of administration include oral, rectal, topical, nasal, intradermal, or parenteral routes.
  • parenteral includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous or intramuscular routes are not particularly suitable for long-term therapy and prophylaxis. Oral administration is used in prophylactic treatment because of the convenience to the patient as well as the dosing schedule.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s, or fixed 25 oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, inert gases, and the like. Lower doses will result from other forms of administration, such as intravenous administration. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
  • Delivery systems that targets specific tissues is used for effective treatment of solid cancers such as liver cancer to reduce toxic side effects on unintended tissues.
  • Many types of delivery systems for targeted release of drugs are available and known to those of ordinary skill in the art, including controlled-release biodegradable polymers, polymeric microsphere carriers and liposomes, as well as the co-administration of cytoprotective agents with antineoplastics as described in Chonn and Cullis, Curr. Opinion in Biotechnology, 6:698-708 (1995); Kemp et al., J. Clin. Oncol., 14:2101-2112 (1996); Kumanohoso et al., Cancer Chemother. Pharmacol, 40: 112-116 (1997); Schiller et al., J. Clin.
  • the liposomes can be further coated with polyethene glycol (PEG) to prolong their circulation time.
  • PEG polyethene glycol
  • minicells as described in WO 2005/079854.
  • the minicells comprises a first arm that carries specificity for a bacterially derived minicell surface structure and a second arm that carries specificity for a mammalian cell surface receptor, to target drug-loaded minicells to specific mammalian cells and to cause endocytosis of the minicells by the mammalian cells.
  • the pharmaceutical composition is administered in a targeted release system.
  • TKI is conjugated to a cell targeting peptide or an antibody.
  • antihistamine is conjugated to a cell targeting peptide or an antibody.
  • compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, or lozenges, each containing a predetermined amount of the active agent(s).
  • Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as a syrup, elixir, or emulsion.
  • Other delivery systems can include time-release, delayed-release, or sustained- release delivery systems. Such systems can avoid repeated administrations of the pharmaceutical composition of this invention, increasing convenience to the subject and the physician.
  • Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer-based systems such as poly (lactide- glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109. Delivery systems also include non-polymer systems that are lipids, including sterols such as cholesterol, cholesterol esters, and fatty acids or neutral fats such as mono-, di-, and tri-glycerides;
  • hydrogel release systems ; sylastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.
  • the pharmaceutical composition is administered in a time- release, delayed-release, or sustained-release delivery system.
  • the time- release, delayed-release, or sustained-release delivery system comprising the pharmaceutical composition of the invention is inserted directly into the tumor.
  • the pharmaceutical preparations of the invention are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions.
  • Such preparations may routinely contain salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents.
  • the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention.
  • Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like.
  • pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium, or calcium salts.
  • this invention relates to a kit of parts for treatment of a cancer in a subject, the kit comprising a TKI and an antihistamine.
  • the cancer is one or more of pancreatic cancer, renal cancer, small cell lung cancer, brain cancer, neural cancer, bone cancer, lymphoma, myeloma, colon cancer, uterine cancer, breast cancer, leukemia, liver cancer, prostate cancer, skin cancer, and melanoma.
  • the cancer is liver cancer.
  • the liver cancer is one or more of hepatocellular carcinoma, bile duct cancer, angiosarcoma, hemangiosarcoma, hepatoblastoma, hemangioma, hepatic adenoma, and focal nodular hyperplasia.
  • the TKI comprises, alternatively consists essentially of, or yet consists of one or more of one or more of one or more of an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial cell growth factor receptor (VEGFR) inhibitor, a platelet- derived growth factor receptor (PDGFR) inhibitor, a c-KIT inhibitor, an FMS-like tyrosine kinase 3 (FLT-3) inhibitor, and a BCR-ABL inhibitor.
  • the EGFR inhibitor includes one or more of gefitinib, erlotinib, canertinib, and their salts, derivatives, or analogs.
  • the VEGFR inhibitor includes one or more of vatalanib, semaxanib, sunitinib, and their salts, derivatives, or analogs.
  • the PDGFR inhibitor includes one or more of pazopanib, nilotinib, cediranib, and their salts, derivatives, or analogs.
  • the c-KIT inhibitor includes one or more of dasatinib, pazopanib, quzartinib, and their salts, derivatives, or analogs.
  • the FLT-3 inhibitor includes one or more of CEP701, sunitinib, PKC412, and their salts, derivatives, or analogs.
  • the BCR-ABL inhibitor includes one or more of imatinib, bafetinib, dasatinib, nilotinib, bosutinib, ponatinib, thiazol, thiadiazole, and their salts, derivatives, or analogs. In some embodiments, the BCR-ABL inhibitor is imatinib.
  • the antihistamine comprises, alternatively consists essentially of, or yet consists of one or more of perphenazine, sertralin, thioridazine, chlorpromazine, paroxetine, loratadine, flupentixol, fluphenazine, hydroxyzine,
  • the antihistamine is cyproheptadine.
  • the kit further comprises sorafenib, sunitinib, brivanib, bevacizumab, ramucirumab, vatalanib, bnifanib, TSU-68, cediranib, erlotinib, nintedanib, regorafenib, cetuximab, lapatinib, cixutumumab, everolimus, sirolimus, and tivantinib.
  • the kit further comprises instructions for treating the cancer.
  • the kit of parts comprises instructions for dosing and/or administration of the pharmaceutic composition of this invention.
  • Example 1 In vitro treatment of hepatocellular carcinoma cells.
  • HCC cell lines Hep G2 and Huh-7 were maintained in DMEM containing 10% (v/v) FBS.
  • Human normal liver cell line L-02 was maintained in RPMI1640 containing 10% (v/v) FBS.
  • MTT assay was performed and IC50 of the drugs was calculated by the Graphpad Prism 5 software.
  • Cyproheptadine lowered the IC50 of imatinib from 22.2 mM to 0.3728 pM, thereby synergistically increasing the inhibitory effect of imatinib on HepG2 cells ( Figure 1 A).
  • Imatinib lowered the IC50 of cyproheptadine from 36.50 pM to 9.55 pM, thereby synergistically increasing the inhibitory effect of
  • Example 2 Treatment of mice implanted with hepatocellular carcinoma cells.
  • HpeG2 cells (IO c IO 6 ) were injected subcutaneously into the flank of BALB/c nude mice. When tumors reached a volume of ⁇ 1 OOmnT. mice were randomly divided into 4 groups with 10 mice per group:
  • Group 1 is the control in which the mice were administered 0.5% CMC-Na;
  • mice were administered imatinib at a dose of 80 mg/kg/day;
  • mice were administered cyproheptadine at a dose of 6 mg/kg/day;
  • mice in Group 4 were administered the combination of cyproheptadine (6
  • cyproheptadine can both inhibit the growth of hepatocellular carcinoma cells in vivo.
  • mice in Group 4 that received the combination of imatinib and cyproheptadine exhibited the least reduction in body weights caused by tumor and/or drug toxicity ( Figure 5).
  • the mice in this group also exhibited the best daily activities among the groups (Data not shown).
  • the survival rate for Group 4 was 40%; whereas the survival rates of Group 2 and Group 3 mice were 10% ( Figure 6).
  • the average survival period for 50% of the mice in Group 4 is 186 days which is significantly longer than those of Group 2 (120 days) and Group 3 (164 days).
  • the combination of imatinib and cyproheptadine increased the survival rate of mice with implanted hepatocellular carcinoma cells.
  • Example 3 Treatment of hepatocellular carcinoma in orthotopic mouse model.
  • mice with subcutaneous transplant of HepG2 cells (10* 10 6 ) was removed and cut into about 2 mm 3 slices, which were implanted into the left lobe of the livers of mice. 18 days after the orthotopic implantation, the mice were randomly divided into three groups based on different treatments:
  • mice were administered with CMC-Na as negative control;
  • mice were administered with combination of cyproheptadine (6 mg/kg/day) and imatinib (80 mg/kg/day); and
  • mice were administered with sorafenib at a dose of 30 mg/kg/day as
  • mice in Group 2 were administered orally.
  • the survival rate and body weights of mice in each group were measured at 169 days after the orthotopic implantation.
  • the results showed that the average survival period for 50% of the mice in Group 2 was 141 days, which is significantly longer than Group 1 (71 days) and also longer than Group 3 (135 days).
  • the survival rate for the mice in Group 1 is 10% and the survival rate for the mice both in Group 2 and Group 3 is 40% (Figure 7).
  • the mice in Group 2 that received the combination of imatinib and cyproheptadine exhibited the best body weights ( Figure 8) as well as daily activities.
  • Example 4 In vitro treatment of non-small-cell lung carcinoma.
  • A549 cells a type of human carcinoma cells, were maintained in DMEM containing

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Abstract

L'invention concerne des compositions d'inhibiteurs de tyrosine kinase et d'antihistaminiques. L'invention concerne en outre des méthodes de traitement du cancer et en particulier d'un carcinome hépatocellulaire avec les compositions, et des procédés d'augmentation des propriétés anti-prolifération des inhibiteurs de tyrosine kinase et des antihistaminiques.
PCT/US2019/027244 2018-04-18 2019-04-12 Compositions et méthodes pour le traitement du cancer du foie WO2019204154A1 (fr)

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CN112190573A (zh) * 2020-11-17 2021-01-08 四川大学华西医院 一种治疗肝癌的联合用药物
CN115475253A (zh) * 2021-05-31 2022-12-16 东南大学 拉帕替尼-癌细胞干性抑制剂偶联物、制法、药物组合物和应用

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112190573A (zh) * 2020-11-17 2021-01-08 四川大学华西医院 一种治疗肝癌的联合用药物
CN115475253A (zh) * 2021-05-31 2022-12-16 东南大学 拉帕替尼-癌细胞干性抑制剂偶联物、制法、药物组合物和应用
CN115475253B (zh) * 2021-05-31 2023-09-29 东南大学 拉帕替尼-癌细胞干性抑制剂偶联物、制法、药物组合物和应用

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