WO2015065505A1 - Utilisation d'inhibiteurs de cyp27a1, de statine ou d'antagonistes du lxr, seuls ou en association avec un traitement classique du cancer du sein - Google Patents

Utilisation d'inhibiteurs de cyp27a1, de statine ou d'antagonistes du lxr, seuls ou en association avec un traitement classique du cancer du sein Download PDF

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Publication number
WO2015065505A1
WO2015065505A1 PCT/US2014/010179 US2014010179W WO2015065505A1 WO 2015065505 A1 WO2015065505 A1 WO 2015065505A1 US 2014010179 W US2014010179 W US 2014010179W WO 2015065505 A1 WO2015065505 A1 WO 2015065505A1
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cancer
drug
cyp27a1
subject
cholesterol
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PCT/US2014/010179
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English (en)
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Donald P. Mcdonnell
Erik R. NELSON
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Duke University
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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • the present invention relates to methods of preventing and treating subjects suffering from estrogen dependent cancer or metastatic cancer, such as metastatic breast cancer, by administering a drug that lowers 27-hydroxy cholesterol (27HC) levels in the subject alone or in combination with a conventional cancer therapy.
  • Obesity and metabolic syndrome are established risk factors for estrogen receptor (ER) positive breast cancer in postmenopausal women. This has been attributed to increases in circulating insulin and insulin-like growth factors, local production of estrogens in adipose tissue, and the influence of adipokines and inflammatory cytokines on tumors and their microenvironment.
  • Hypercholesterolemia a comorbidity of obesity, is a risk factor for ER positive breast cancers and is associated with a decreased response of tumors to endocrine therapies.
  • the present disclosure is directed to a method for preventing or treating a subject suffering from or at risk of suffering from an estrogen dependent cancer.
  • the method comprises administering to the subject a drug, wherein the drug lowers 27-hydroxy cholesterol (27HC) levels in the subject.
  • the drug may be administered alone or in combination with an endocrine therapy.
  • the estrogen dependent cancer may be breast cancer, ovarian cancer or endometrial cancer.
  • the subject may be suffering from estrogen receptor positive breast cancer.
  • the drug may include a CYP27A1 inhibitor, a statin, a cholesterol uptake inhibitor, or a combination thereof.
  • the CYP27A1 inhibitor may include GI268267X, GW273297X, cyclosporin A, an inhibitory RNA, or a retinoic acid receptor antagonist.
  • the inhibitory RNA may target
  • the statin may include Atorvastatin, Simvastatin, Lovastatin, Pitavastatin,
  • the drug may inhibit the conversion of cholesterol to 27HC.
  • the cholesterol uptake inhibitor may include eztimibe.
  • the drug may be administered in combination with an endocrine therapy.
  • the endocrine therapy may include at least one of a selective estrogen receptor modulator (SERM), an aromatase inhibitor, a HER2 intervention drug, or combinations thereof.
  • SERM selective estrogen receptor modulator
  • the SERM may include tamoxifen, raloxifene, toremifene, lasofoxifene, pipendoxifene, apeledoxifene, or ospemifene, the aromatase inhibitor comprises anastrozole, letrozole, exemestane, formestane, fadrozole, aminoglutethimide, or testolactone, and the HER2 intervention drug comprises Herceptin (trastuzumab), pertuzumab, or lapatinib.
  • the drug may be administered as a neoadjuvant therapy or post-surgery.
  • the subject may have high levels of cholesterol in the blood.
  • the subject may have normal levels of cholesterol in the blood.
  • a therapeutically effective amount of the drug may be administered.
  • the present disclosure is directed to a method of preventing or treating a subject suffering from or at risk of suffering from a metastatic cancer.
  • the method comprises administering a drug that inhibits the activation of liver X receptor (LXR) in the subject.
  • LXR liver X receptor
  • the drug may be administered alone or in combination with a conventional cancer therapy.
  • the drug may inhibit activation of LXR by lowering the 27- hydroxy cholesterol (27HC) levels in the subject.
  • the drug may include at least one of a CYP27A1 inhibitor, a statin, a LXR antagonist, or combinations thereof.
  • the CYP27A1 inhibitor may include GI268267X, GW273297X, cyclosporin A, an inhibitory RNA, or a retinoic acid receptor antagonist, the statin comprises atorvastatin, and the LXR antagonist comprises GSK2033.
  • the inhibitory RNA may target CYP27A1.
  • the conventional cancer therapy may include at least one of endocrine therapy, surgery, radiation therapy, bone-directed therapy, chemotherapy, targeted therapy, or
  • the conventional cancer therapy may include endocrine therapy.
  • the endocrine therapy may include at least one of a selective estrogen receptor modulator (SERM), an aromatase inhibitor, a HER2 intervention drug, or combinations thereof.
  • SERM may include tamoxifen, raloxifene, toremifene, lasofoxifene, pipendoxifene, apeledoxifene, or ospemifene
  • the aromatase inhibitor comprises anastrozole, letrozole, exemestane, formestane, fadrozole, aminoglutethimide, or testolactone
  • the HER2 intervention drug comprises Herceptin (trastuzumab), pertuzumab, or lapatinib.
  • the metastatic cancer may include metastatic breast cancer, metastatic colon, metastatic melanoma, metastatic lung cancer, or metastatic pancreatic cancer.
  • the metastatic cancer may include metastatic breast cancer.
  • therapeutically effective amount of the drug may be administered.
  • FIG. 1 shows that elevated 27HC promoted ER-dependent breast tumor growth.
  • C/D MMTV-PyMT mice were bred onto a
  • Figure 2 shows that hypercholesterolemia promoted tumor growth in a CYP27A1 dependent manner and can be attenuated by CYP27A1 inhibitors or statins.
  • A,B MMTV- PyMT mice were bred onto either a CYP27A1+/+ or -/- background and placed on a control diet (CD) or high cholesterol diet (HCD) at wean.
  • CD control diet
  • HCD high cholesterol diet
  • FIG. 1 shows that elevated 27HC increased metastasis to the lung.
  • FIG. 4 shows that 27HC was a SERM and LXR agonist.
  • A Microarray analysis of MCF7 breast cancer cells indicates that 27HC induces a shared set of genes with E2 and pathways associated with LXR activation.
  • B Heat map of genes with largest difference in regulation between 27HC and E2, with associated pathway analysis.
  • C Cluster 2 genes from
  • FIG. 5 shows that 27HC was a modulator of both ER and LXR target gene expression in cellular models of ERa+ breast cancer.
  • 27HC and synthetic LXR ligands T1317 and GW3965 induce ER target genes such as PS2 and LXR target genes such as ABCAl in MCF7, T47D, BT483 and BT474 cells.
  • ER target genes such as PS2 and LXR target genes such as ABCAl in MCF7, T47D, BT483 and BT474 cells.
  • Induction of ER target genes was ablated in the absence of ERa (siERa) or when ER activity was blocked with the antagonist ICI 182,780.
  • induction of LXR target genes was enhanced in absence or antagonism of ERa.
  • Time course and bar-graph representation of day 7 is indicated. Dose of 27HC and synthetic LXR ligands GW3965 and T0901317 (T1317) is in Log(M).
  • Figure 8 shows expression analysis of tumors from MMTV-PyMT mice treated with indicated ligands.
  • Figure 9 shows that CYP7B1 mRNA expression tracked with a better prognosis in patients with luminal A type breast cancer while CYP27A1 mRNA expression was not associated with relapse free survival in patients classified with any subtype of breast cancer.
  • FIG. 10 shows that CYP27A1 was highly expressed in macrophages within human benign and malignant mammary tissue.
  • A Benign tissue depicting large duct with negatively staining epithelial lining and macrophages in lumen.
  • B Benign tissue depicting weakly staining epithelium and strongly staining single stromal macrophage in center.
  • C Negatively staining tumor nests with aggregate of strongly positive macrophages in stroma.
  • D Negatively staining intraductal carcinoma with strongly positive macrophages in the lumen.
  • FIG. 12 shows that breast cancer cell intrinsic protein expression of CYP27A1 was associated with tumor grade. Supplemental data for Table 1. Representative breast cancer TMA cores demonstrate a wide range of CYP27A1 expression within cancer cells.
  • (A) negative staining, score 0.
  • (B) weak staining, score 1.
  • (C) moderate staining, score 2.
  • (D) strong staining, score 3.
  • Scale bars 80 ⁇ .
  • FIG 13 shows cholesterol and 27HC concentrations in MMTV-PyMT mice fed a high cholesterol diet (HCD). Supplemental data to Figure 2 A and B in text.
  • Statistics for (B) did not include CYP27A1-/- groups as no 27HC was detected. Values are mean +/- SEM and different letters denote statistical significance.
  • Figure 14 shows that CYP27A1 inhibitor GW273297X decreased plasma and intratumoral 27HC concentrations.
  • B Daily treatment ⁇ 3 mice on a HFD with the CYP27A1 inhibitor
  • Figure 15 shows that statin treatment effectively decreased total cholesterol and inhibited obesity driven tumor growth. Supporting data for Figure 2D.
  • p-values indicate difference probability that the slope ⁇ 0.
  • FIG 16 shows that a high fat diet failed to impact tumor growth in the MMTV- PyMT mouse model of mammary cancer, where circulating cholesterol levels were not altered by diet.
  • C Tumor latency was determined by age at which a palpable tumor was detected.
  • FIG. 17 shows that 27HC and GW3965 modulated expression of genes associated with EMT.
  • A 27HC and GW3965 modulate mRNA expression of genes associated with EMT.
  • c control, 2:27HC, G:GW3965.
  • B 27HC and GW3965 induce Snaill expression. Overlayed images of green (Snaill) and blue (dapi nuclear stain).
  • Figure 18 shows the chemical structures of small molecule inhibitors of CYP27A1.
  • the present disclosure provides a method of preventing or treating a subject suffering from or at risk of suffering from estrogen dependent cancer.
  • 27-hydroxycholesterol (27HC), an oxysterol produced in a stoichiometric manner from cholesterol, is an endogenous ligand for the ER and Liver X receptor (LXR).
  • 27HC impacts the growth and metastasis of breast tumors by increasing ER dependent growth and LXR-dependent metastasis in animal models of breast cancer.
  • the manipulation of the synthesis of 27HC may impact breast cancer pathophysiology.
  • the effects of cholesterol on tumor pathology involved CYP27A1 dependent conversion to 27HC are shown herein to be attenuated by both CYP27A1 inhibitors and statins.
  • CYP27A1 expression increased with grade in breast tumors and that elevated expression of this enzyme was observed within tumor associated macrophages.
  • the disclosed methods may limit the presence of 27HC and likely increase the number of patients that respond to endocrine therapy and prolong relapse.
  • the present disclosure provides a method of preventing or treating a subject suffering from or at risk of suffering from metastatic cancer. Cholesterol via conversion to 27HC and subsequent activation of the LXRs promotes metastasis.
  • the present disclosure provides methods of preventing and/or treating metastatic cancer by inhibiting the activation of LXR using CYP27A1 inhibitors, statins, cholesterol uptake inhibitors, LXR antagonists, or combinations thereof.
  • the disclosed methods specifically target or prevent metastasis by limiting the presence of 27HC and/or limiting the activity of the LXR receptor and thus increase the time to relapse.
  • the present disclosure provides a method of using CYP27A inhibitors to reduce levels of 27HC in cells in vitro and in vivo as well as treat tumors.
  • CYP27A inhibitors were not previously used to treat animals or humans because it was believed that such an inhibitor would be toxic.
  • the CYP27A protein is involved in various processes and mutations in the CYP27A gene can cause hepatitis of infancy as well as cerebrotendinous xanthomatosis, a lipid storage disease.
  • each intervening number there between with the same degree of precision is explicitly contemplated.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • 27-hydroxycholesterol lowering drug refers to a drug or compound that lowers the levels of 27HC in a subject.
  • administering refers to providing, contacting, and/or delivery of the 27HC lowering drug by any appropriate route to achieve the desired effect.
  • agents may be administered to a subject in numerous ways including, but not limited to, orally, ocularly, nasally, intravenously, topically, as aerosols, suppository, etc. and may be used in combination.
  • Aromatase inhibitor refers to a compound that targets aromatase, which is an enzyme involved in the biosynthesis of estrogen. Aromatase inhibitors may block the production of estrogen or block the action of estrogen on receptors.
  • Breast cancer refers to a type of cancer that originates from and develops in the breast.
  • Metalstatic breast cancer refers to breast cancer that spreads outside the breast to the lymph nodes, bones, or other areas.
  • Cancer refers to the uncontrolled and unregulated growth of abnormal cells in the body. Cancerous cells are also called malignant cells. Cancer may invade nearby parts of the body and may also spread to more distant parts of the body through the lymphatic system or bloodstream. Cancers include Adrenocortical Carcinoma, Anal Cancer, Bladder Cancer, Brain Tumor, Breast Cancer, Carcinoid Tumor, Gastrointestinal, Carcinoma of
  • Lymphoma Central Nervous System (Primary) Lymphoma, Cutaneous T-Cell Lymphoma, Hodgkin's Disease Lymphoma, Non-Hodgkin's Disease Lymphoma, Malignant Mesothelioma, Melanoma, Merkel Cell Carcinoma, Metasatic Squamous Neck Cancer with Occult Primary, Multiple Myeloma and Other Plasma Cell Neoplasms, Mycosis Fungoides, Myelodysplasia Syndrome, Myeloproliferative Disorders, Nasopharyngeal Cancer, euroblastoma, Oral Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Pancreatic Cancer, Exocrine, Pancreatic Cancer, Islet Cell Carcinoma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pituitary Cancer, Plasma Cell Neoplasm, Prostate Cancer, Rhabdom
  • CYP27A1 refers to a gene encoding a cytochrome P450 oxidase, namely sterol 27-hydroxylase.
  • the CYP27A1 enzyme is located in many different tissues where it is found within the mitochondria. It is most prominently involved in the biosynthesis of bile acids.
  • the CYP27A1 enzyme participates in the degradation of cholesterol to bile acids in both the classic and acidic pathways. It is the initiating enzyme in the acidic pathway to bile acids, yielding oxysterols by introducing a hydroxyl group to the carbon at the 27 position in cholesterol.
  • CYP27A1 inhibitor refers to a drug or compound which interacts with a CYP27A1 enzyme and decreases CYP27A1 enzyme activity.
  • an effective dosage means a dosage of a drug effective for periods of time necessary, to achieve the desired therapeutic result.
  • An effective dosage may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the drug to elicit a desired response in the individual.
  • This term as used herein may also refer to an amount effective at bringing about a desired in vivo effect in an animal, mammal, or human, such as reducing and/or inhibiting the function of CYP27A and the like.
  • a therapeutically effective amount may be administered in one or more administrations (e.g.
  • the agent may be given as a preventative treatment or therapeutically at any stage of disease progression, before or after symptoms, and the like), applications or dosages and is not intended to be limited to a particular formulation, combination or administration route. It is within the scope of the present disclosure that the 27HC lowering drug may be administered at various times during the course of treatment of the subject. The times of administration and dosages used will depend on several factors, such as the goal of treatment (e.g., treating v. preventing), condition of the subject, etc. and can be readily determined by one skilled in the art.
  • Estrogen dependent cancer or “estrogen receptor positive cancer” as used interchangeably herein refers to a tumor that contains estrogen receptor (ER) positive cells, i.e., cells that have estrogen receptors, that respond to the presence of estrogen with increased proliferation.
  • Estrogen dependent cancers may include breast cancer, ovarian cancer, or endometrial cancer.
  • Estrogen receptor positive breast cancer is a type of breast cancer that is sensitive to estrogen.
  • Estrogen-receptor downregulators refers to a drug or compound which binds and down-regulates the expression of an estrogen-receptor.
  • Estrogen receptor negative breast cancer or “Estrogen independent breast cancer” as used interchangeably herein refers to a tumor that does not contain estrogen receptor positive cells, i.e., cells that lack estrogen receptors, and does not depend on the presence of estrogen for ongoing proliferation.
  • HEPv2 intervention drug or "HER2 inhibitor” as used interchangeably herein refers to a compound that targets human Epidermal Growth Factor Receptor 2 (HER2).
  • HER2 is a member of the epidermal growth factor receptor family and is involved in the development and progression of certain aggressive types of breast cancer, such as estrogen dependent breast cancer.
  • a HER2 inhibitor may be a tyrosine kinase or a monoclonal antibody.
  • LXR antagonist refers to a drug of compound that binds to the LXR, which is a member of the nuclear receptor family of transcription factors. LXRs are regulators of cholesterol, fatty acid, and glucose homeostasis.
  • Metal cancer refers to a cancer that has spread from the part of the body where it started (the primary site) to other parts of the body.
  • Selective estrogen receptor modulators or “SERMs” as used interchangeably herein refers to a compound that interacts with an ER and whose relative agonist/antagonist activities are manifest in a cell selective manner. The prevention of estrogen binding to the estrogen receptor may lead to decreased proliferation of estrogen dependent cancer cells.
  • Statin refers to a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase.
  • Statins are also known as HMG-CoA reductase inhibitors.
  • any vertebrate means any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non- human primate (for example, a monkey, such as a cynomolgous or rhesus monkey, chimpanzee, etc.) and a human).
  • a mammal e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse
  • a non- human primate for example, a monkey, such as a cynomolgous or rhesus monkey, chimpanzee, etc.
  • the subject or subject may be a human or a non- human.
  • the subject may be a human subject at risk for developing or already suffering
  • Treatment are each used interchangeably herein to describe reversing, alleviating, or inhibiting the progress of a disease, or one or more symptoms of such disease, to which such term applies.
  • the term also refers to preventing a disease, and includes preventing the onset of a disease, or preventing the symptoms associated with a disease.
  • a treatment may be either performed in an acute or chronic way.
  • the term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease.
  • Such prevention or reduction of the severity of a disease prior to affliction refers to administration of the 27HC lowering drug to a subject that is not at the time of administration afflicted with the disease. "Preventing” also refers to preventing the recurrence of a disease or of one or more symptoms associated with such disease. "Treatment” and “therapeutically,” refer to the act of treating, as “treating” is defined above.
  • the present invention is directed to a method for preventing or treating a subject suffering from or at risk from suffering from an estrogen dependent cancer.
  • the method includes administering to the subject a drug that lowers 27HC levels in the subject.
  • the drug may be administered alone or in combination with an endocrine therapy.
  • the estrogen dependent cancer may be any cancer that needs the hormone estrogen to grow.
  • the estrogen dependent cancer may be a primary tumor, such as breast cancer, ovarian cancer or endometrial cancer.
  • the estrogen dependent cancer may be estrogen receptor positive breast cancer.
  • the present invention is directed to a method of preventing or treating a subject suffering from or is at risk from suffering metastatic cancer.
  • the method includes administering a drug that inhibits the activation of LXR in the subject.
  • the drug may be administered alone or in combination with a conventional cancer therapy.
  • a drug that inhibits the activation of LXR may include a 27HC lowering drug, such as a CYP27A1 inhibitor, a statin, or a cholesterol uptake inhibitor, a LXR antagonist, or combinations thereof.
  • the metastatic cancer may be any metastatic cancer.
  • the metastatic cancer may be metastatic breast cancer, metastatic colon cancer, metastatic melanoma, metastatic lung cancer or metastatic pancreatic cancer.
  • the metastatic breast cancer may be estrogen receptor positive breast cancer or estrogen receptor negative breast cancer.
  • Cholesterol subsequent to its conversion to 27HC by the enzyme CYP27A1 , can drive the progression of breast cancer in mouse models. There is a robust stoichiometric relationship between circulating cholesterol and 27HC.
  • a 27HC lowering drug lowers the levels of 27HC in a subject.
  • the 27HC lowering drug may be any drug that inhibits the conversion of cholesterol to 27HC, such as a CYP27A1 inhibitor or a statin, or inhibits cholesterol uptake.
  • the 27HC lowering drug can be administered to a patient in an amount of about 10 mg/day to about 500 mg/day, about 10 mg/day to about 200 mg/day (e.g., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg/day), 100 mg/day to about 200 mg/day, or about 200 mg/day to about 500 mg/day (e.g., 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650
  • Dosage regimens may be adjusted to provide the optimum desired response (e.g. , a therapeutic or prophylactic response). For example, a single bolus may be administered, 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. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein 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.
  • An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of the 27HC lowering drug is a dose of between 0.1 and 200 mg/kg, for example between 0.1 and 10 mg/kg.
  • the therapeutically or prophylactically effective amount of the 27HC lowering drug may be between 1 and 200 mg/kg, 10 and 200 mg/kg, 20 and 200 mg/kg, 50 and 200 mg/kg, 75 and 200 mg/kg, 100 and 200 mg/kg, 150 and 200 mg/kg, 50 and 100 mg/kg, 5 and 10 mg/kg, or 1 and 10 mg/kg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated.
  • the 27HC lowering drug dose may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the 27HC lowering drug to elicit a desired response in the individual.
  • the dose is also one in which toxic or detrimental effects, if any, of the 27HC lowering drug are outweighed by the therapeutically beneficial effects. It is to be further understood that for any particular subject, specific dosage regimens 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, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of the 27HC lowering drug is 0.1-20 mg/kg, more preferably 0.5-10 mg/kg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens 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, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • a CYP27A1 inhibitor may be used to treat the subject in the methods described above.
  • the CYP27A1 inhibitor may be a small molecule, such as GI268267X (Lyons et al. (2001) Lipids 36:701-711; see Figure 18 for chemical structure), GW273297X (Lyons et al. (2001) Lipids 36:701-711; see Figure 18 for chemical structure), or cyclosporin A
  • Cyclosporin A may down-regulate CYP27A1.
  • the CYP27A1 inhibitor may be an inhibitory RNA, such as a dsRNA, a siRNA, a piRNA, an antisense RNA, a RNAse external guide sequence, a miRNA, a ribozyme, or a shRNA comprising a sequence complementary to a portion of an RNA sequence encoding CYP27A, such mouse CYP27A (GenBank Accession No. NM_024264.4) or human CYP27A (GenBank Accession No. NM_000784.3).
  • the CYP27A1 inhibitor may be a retinoic acid receptor (RAR) antagonist.
  • the RAR antagonist may down-regulate CYP27A1.
  • the RAR antagonist may include BMS 453 (4-[(lE)- 2-(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl)ethenyl]-benzoic acid), BMS 195614 (4- [[[5,6-Dihydro-5,5-dimethyl-8-(3-quinolinyl)-2-naphthalenyl]carbonyl]amino]benzoic acid), BMS 493 (4-[(lE)-2-[5,6-Dihydro-5,5-dimethyl-8-(2-phenylethynyl)-2- naphthalenyl]ethenyl]benzoic acid), CD 2665 (4-[6-[(2-Methoxyethoxy)methoxy]-7-t ricyclo[3.3.
  • a statin may be used to treat the subject in the methods described above.
  • Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which is involved in the production of cholesterol in the liver.
  • a statin may include atorvastatin, simvastatin, lovastatin, pitavastatin, fluvastatin, mevastatin, pravastatin, and rosuvastatin
  • Cholesterol uptake inhibitors also known as cholesterol absorption inhibitors may be used to treat the subject in the methods described above. Cholesterol uptake inhibitors prevent the uptake of cholesterol from the small intestine into the circulatory system.
  • a cholesterol uptake inhibitor may include eztimibe ((3i?,45)-l-(4-fluorophenyl)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one).
  • a LXR antagonist may be used to treat the subject in the methods described above.
  • a LXR antagonist may reduce cholesterol levels in serum and liver.
  • the LXR antagonist may include GSK2033 (2,4,6-trimethyl-N-((3 * -(methylsulfonyl)biphenyl-4-yl)methyl)-N-((5- (trifluoromethyl)furan-2-yl)methyl)benzenesulfonamide).
  • Conventional cancer therapies may include surgery, radiation therapy, bone-directed therapy, chemotherapy, hormone therapy, and targeted therapy.
  • Examples of surgery include lumpectomy, quadrantectomy, mastectomy, such as simple mastectomy, skin-sparing
  • mastectomy modified radical mastectomy, prophylactic mastectomy, and radical mastectomy, prophylactic ovary removal, cryotherapy, and lymph node surgery, such as axillary lymph node dissection and sentinel lymph node biopsy.
  • radiation therapy include external beam radiation, such as accelerated breast irradiation and 3D-conformal radiotherapy, and
  • brachytherapy interstitial brachytherapy, intracavitary brachytherapy, and intraoperative radiation.
  • bone-directed therapy include bisphosphonates and denosumab.
  • chemotherapy include anthracyclines, such as doxorubicin
  • paclitaxel Taxol, Abraxane
  • docetaxel Taxotere
  • thiotepa Thioplex
  • vincristine Oncovin, Vincasar PES, Vincrex
  • vinorelbine Vifenolbine
  • trastuzumab Herceptin
  • lapatinib Tykerb
  • bevacizumab Avastin
  • pertuzumab Perjeta
  • everolimus Afinitor
  • Endocrine therapy also known as hormonal therapy, hormone therapy, and hormone treatment, is a treatment that adds, blocks, or removes hormones.
  • hormones may be given to adjust low hormone levels.
  • Synthetic hormones or other drugs may be given to block the body's natural hormones to slow or stop the growth of certain cancers (such as prostate and breast cancer).
  • Endocrine therapy may also include surgery to remove the gland that makes a certain hormones.
  • hormone therapy examples include selective estrogen receptor modulators
  • SERMs such as tamoxifen, raloxifene, toremifene, lasofoxifene, pipendoxifene, adoxifene, and ospemifene
  • aromatase inhibitors such anastrozole, letrozole, exemestane, formestane, fadrozole, aminoglutethimide, and testolactone
  • a HER2 intervention drug such as a HER2 inhibitor, such as Herceptin (trastuzumab), pertuzumab, and lapatinib
  • estrogen-receptor downregulators such as fulvestrant (ICI 182,780).
  • the methods described above are directed to treating a subject with drug that lowers 27HC levels.
  • the subject treated by the methods described above may be a subject or patient suffering from or at risk of suffering from an estrogen dependent cancer and/or metastatic cancer.
  • the subject may be diagnosed or identified as having or at risk of having estrogen dependent cancer using known methods and assays, such as a biopsy.
  • the subject may be treated with the 27HC lowering drug alone or in combination with a conventional cancer therapy, as described above.
  • the subject may be treated with the 27HC lowering drug as a neoadjuvant therapy or post-surgery.
  • the subject may have normal or high levels of cholesterol in the blood.
  • the subject may be a hypercholesterolemic patient or normocholesterolemic patient.
  • the subject may be identified or diagnosed as having normal or high levels of cholesterol by measuring total cholesterol, high density cholesterol, low density cholesterol, triglycerides, or combinations thereof.
  • DMEM/F12, DMEM, RPMI 1640 or RPMI 1640 supplemented with 8% fetal bovine serum, non-essential amino acids and sodium pyruvate.
  • cells were plated in the same media lacking phenol red and supplemented with 8% charcoal-stripped fetal bovine serum.
  • Microarray analysis was performed in R/Bioconductor using the Affy package.
  • Raw data was background corrected with RMA, Log2 transformed, and summarized by median polish.
  • RNA isolation quantitative real time PCR (QPCR) and proliferation assays were performed as previously described (Nelson et al, (2011) Endocrinology 152:4691).
  • Figures 5, 6, 8, 11, 13A, 14C, 15B and 17 1-way ANOVA followed by Student Newman-Keuls multiple comparison post-hoc test, or Kruskal-Wallis followed by Dunn's multiple comparison test.
  • Figure 15 linear regression was performed and slope compared to null hypothesis of 0. Graphpad Prism was used for analysis unless otherwise stated.
  • Statistical approaches for Table 1, Table 2 and Figure 12E have been described under CYP27A1 IHC Analysis.
  • MCF 7 Xenografts Athymic nude mice were ovariectomized and either implanted with a timed-release E2 pellet (0.72 mg E2/60 days), placebo (no hormone) pellet, or treated with 27HC (40mg/kg/day). Seven days post-surgery, MCF7 tumors were orthotopically grafted into the axial mammary fat pad. When E2 tumors reached a size of 0.2cm 3 , this group was randomized into vehicle treated or ICI 182,780 treated (weekly injection of 5mg/mouse). After 40 days, the 27HC treated mice were randomized into continued 27HC, no hormone withdrawal or 27HC + ICI 182,780 groups.
  • Tamoxifen resistant MCF7 Xenograft Tamoxifen resistant tumors were previously established by serial transfer in mice treated with tamoxifen (Conner et al. (2001) Cancer Res 61 :2917; Wardell et al., (2013) Clin Cancer Res 19:2420). Experimental mice were
  • ovariectomized and either implanted with a timed-release E2 pellet (0.72 mg E2/60 days), timed- release tamoxifen pellet (5 mg/60 days) or treated with either 27HC (40mg/kg/day) or vehicle (no hormone).
  • a timed-release E2 pellet (0.72 mg E2/60 days
  • timed- release tamoxifen pellet (5 mg/60 days) or treated with either 27HC (40mg/kg/day) or vehicle (no hormone).
  • 27HC 40mg/kg/day
  • vehicle no hormone
  • E2 but not vehicle treatment, supported the growth of ER-positive MCF7 cell derived tumors propagated as xenografts ( Figure 1 A, Figure 7).
  • 27HC also supported the growth of these tumors and this activity was inhibited by cotreatment with ICI 182,780 or upon cessation of 27HC supplementation.
  • the microarray analysis described above identified a potential association between 27HC exposure and the development of tamoxifen resistance.
  • TamR clinically relevant in vivo model of tamoxifen resistance
  • CYP7B 1 +/+ and CYP7B 1 -/- mice were maintained on a mixed 129/C57BL/6 background.
  • CYP7B1-/- were bred with MMTV-PyMT+ mice on an FVB background.
  • Resulting heterozygous (CYP7Bl+/-;PyMT+) progeny were crossed with either CYP7B1+/+ or CYP7B1-/- mice to create homozygous wildtype or knockout mice expressing PyMT.
  • These mice were again crossed with their respective CYP7B1 line to create breeding PyMT+ males of the appropriate genotype.
  • the males of this generation were bred with their respective CYP7B1 line to generate the PyMT+ females used in experiments.
  • mice were ovariectomized. Mice were monitored for first palpable tumors, the growth of which was then recorded through time.
  • mice on an FVB background were obtained from Jackson Labs and bred in house. At ⁇ 5 weeks of age mice were
  • mice were monitored for first palpable tumors. At detection, mice were given daily treatment with placebo, 27HC (40mg/kg) to elevate circulating 27HC, GW3965 (30mg/kg) or E2 (l( ⁇ g/kg). After 28 days of treatment, serum 27HC concentrations were increased by approximately 40 fold in 27HC treated mice. Resulting plasma concentrations after 28 days of treatment were approximately 4.5 ⁇ . This was similar to concentrations found in patients with mutations in the CYP7B1 gene, although higher levels are apparent in atherosclerotic lesions, (in the millimolar range). Plasma levels of 27HC were 40-50 folds higher in PyMT mice treated with 27HC compared to placebo. Mice were euthanized when their collective tumor burden reached 2cm 3 .
  • CYP7Bl /_ mice Figure 1C. Once palpable tumors formed they grew at a significantly increased rate in CYP7Bl /_ mice compared to CYP7B1 +/+ mice ( Figure ID). Treatment of CYP7Bl /_ mice with ICI 182,780 resulted in tumor growth rates similar to that in wildtype mice confirming the role of ER in this process. In a separate study, at the time of tumor detection, otherwise wildtype MMTV-PyMT+ mice were treated daily with placebo, 27HC, E2 or the synthetic LXR agonist GW3965. As shown in Figure IE, treatment with E2 or 27HC significantly increased the growth of tumors compared to vehicle, while GW3965 slightly retarded tumor growth when compared to placebo, a result that mirrors the responses observed in vitro.
  • An integrative database comprising 4022 patients from 22 publicly available datasets was assembled for querying.
  • the raw data was downloaded from GEO, normalized with RMA and batch corrected using the COMBAT algorithm within R.
  • Clinical data was also aggregated from GEO and duplicate patient samples were filtered out.
  • Each tumor was then classified into tumor subtypes using the PAM50, MODI, and MOD2 gene modules in Genefu (Haibe-Kains et al. (2012) R package version 1.8.0; Parker et al. (2009) J Clin Oncol 27:1160).
  • Gene expression was split by the median into Low and High classifications. Reported p-values were calculated using the log-rank method.
  • Tissue microarrays were used that included duplicate 1 mm cores of formalin fixed, paraffin embedded primary human breast carcinomas from two independent cohorts of patients, as previously described: a group of 59 interpretable tumors from Vienna, Austria (Heller et al. (2007) Breast Cancer Res Treat 103:283) and a group of 112 interpretable tumors from Buffalo, NY (Sood et al. (2007) Hum Pathol 38: 1628). For all tumors, grade and ER/PR/HER2 biomarker data were available.
  • luminal A positive for ER and progesterone receptor (PR), negative for HER2
  • luminal B positive for ER and negative for PR and/or positive for HER2
  • H2 negative for ER and PR, positive for HER2
  • triple negative (TN) negative for ER, PR and HER2.
  • CYP27A1 was found to be associated with ER negative as well as PR negative tumors (Table 1). As shown in Table 1, CYP27A1 expression was associated with higher grade, ER-negative and PR negative tumors. Frequencies are shown with absolute tallies in brackets. P-values were calculated by exact test demonstrating association (grade and HER2) or ordinal logistic regression to determine estimated odds ratio (ER, PR status).
  • mice were bred with either wildtype or CYP27A1 -/- mice on a C57BL/6 background using a similar strategy to the CYP7B1 mice described above.
  • CYP27A1+/+; PyMT+ and CYP27A1-/-; PyMT+ females were established.
  • mice were placed on either a control diet (TestDiet 5001) or a high cholesterol diet (2% cholesterol, 0.5% sodium cholate), ad libitum. The addition of cholate abrogates the bile acid synthesis deficit and thus poor cholesterol absorption in CYP27A1-/- mice).
  • mice were ovariectomized. Mice were monitored for first palpable tumors, the growth of which was then recorded through time.
  • HCD high cholesterol diet
  • mice Male apoE3 mice were placed on a CD or HFD for 8 weeks prior to blood draw and/or tumor graft.
  • females were ovariectomized between 6-8 weeks of age and placed on their respective diets for 8 weeks.
  • treatment with indicated ligands was initiated and E0771 cells orthotopically grafted into the mammary fat pad.
  • the CYP27A1 inhibitor GW273297X was administered daily (lOOmg/kg) subcutaneously.
  • Atorvastatin was administered by daily oral gavage (40mg/kg).
  • mice do not normally become hypercholesterolemic when fed only a high fat diet (HFD). Therefore, the APOE3 targeted replacement mouse model was used, in which the mouse Apoe gene has been replaced with the human APOE3 allele.
  • a HFD significantly increased both total cholesterol and 27HC in these mice.
  • the elevated 27HC can be decreased by treatment with a CYP27A1 inhibitor (GW273297X) ( Figure 14). E0771 tumors grew at an increased rate in HFD APOE3 mice compared to mice on a control diet; a response that was attenuated by treatment with GW273297X ( Figure 2C).
  • GW273297X CYP27A1 inhibitor
  • CYP27A1 IHC Analysis TMA sections were deparaffinized, treated with sub-boiling antigen retrieval buffer (citrate, pH 6) for 20 minutes, and then reacted with an anti-CYP27Al rabbit monoclonal antibody (abl26785 from Abeam) at 1 :500 for 2 hours.
  • the detection reaction utilized the rabbit Envision kit from Dako.
  • Diaminobenzidine (DAB) was used as chromogen, with hematoxylin as counterstain.
  • the immunohistochemistry (IHC) experiments were performed on an automated immunostainer (Intellipath from Biocare). Paraffin-embedded cell blocks of HEPG2 cells and normal human liver tissue served as external positive controls.
  • a blocking peptide (ab 139504) was able to ablate the signal. All analysis including cell type identification and staining intensity was performed by a board certified pathologist. Macrophages were identified by morphology. Staining intensity in tumor cells was scored as 0 (absent), 0.5 (borderline), 1 (weak), 2 (moderate) or 3 (strong). For statistical analysis, the tumors were categorized as weak (0, 0.5, 1), and overexpressed (2,3). Ordinal logistic regression was used for binary outcomes and proportional odds regression was used for Grade. Score was modeled as a binary predictor with levels weak and overexpressed. For outcomes with low cell counts an exact test of association was used. Analyses were conducted in SAS version 9.3 (SAS Institute, Cary, NC) and the R environment for statistical computing (RCoreTeam (2012) A language and environment for statistical computing. R
  • IRFP Near-infrared fluorescent protein
  • pENTR2B Invitrogen
  • pENTR2B-iRFP construct To generate a lentivirus expressing IRFP, pENTR2B-IRFP was recombined with the destination vector, pLenti-CMV/TO Neo DEST (Addgene 17292) using LR reaction.
  • Stable IRFP expressing Metl cells were established by flow cytometry. Metl cells were stably expressing IRFP were pretreated in culture with vehicle, 27HC or GW3965 for 72hrs. They were then injected (iv) into syngeneic recipient mice. 28 days later, mice were sacrificed, lungs were canulated, re-inflated with PBS and imaged with an IVIS- Kenetic machine (Caliper Life Sciences).
  • 27HC and LXR agonists induce the expression of several genes implicated in epithelial-mesenchymal-transition (EMT) ( Figure 17). Furthermore, the treatment of breast cancer cell lines in vitro with 27HC, or a synthetic LXR agonist, results in them adopting a spindle like morphology, the degree of which tracks with increased expression of vimentin, Snaill and FAPa, established markers of EMT ( Figure 3C, Figure 17). To test the functional consequence of these observations, the metastatic potential of ER-negative Metl cells pretreated in vitro with 27HC was assess. 27HC increased their ability to metastasize to the lung (Figure 3D). Therefore, it is likely that 27HC, acting through LXR, increased lung metastasis secondary to effects on EMT.
  • EMT epithelial-mesenchymal-transition
  • mice with 27-hydroxycholesterol increased the metastasis of colon cancer. See Table 4.
  • Mice were treated with placebo or 27HC for 10 days prior to cell inoculation.

Abstract

L'invention concerne des méthodes permettant de prévenir et de traiter un cancer dépendant des œstrogènes ou un cancer métastatique en administrant au sujet un médicament qui réduit les taux de 27-hydroxycholestérol chez ledit sujet. Le médicament peut être administré seul ou en association avec un traitement antinéoplasique classique.
PCT/US2014/010179 2013-10-29 2014-01-03 Utilisation d'inhibiteurs de cyp27a1, de statine ou d'antagonistes du lxr, seuls ou en association avec un traitement classique du cancer du sein WO2015065505A1 (fr)

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CN114209838A (zh) * 2022-01-06 2022-03-22 领星生物科技（上海）有限公司 用于治疗kras突变的胆管癌的药物
EP3931349A4 (fr) * 2019-02-28 2023-02-08 The Rockefeller University Génotypage apoe dans le pronostic et le traitement du cancer
US11878956B2 (en) 2019-12-13 2024-01-23 Inspirna, Inc. Metal salts and uses thereof

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WO2004028546A1 (fr) * 2002-09-24 2004-04-08 Baker Medical Research Institute Flux sortant de cholestérol et son utilisation
US20070037755A1 (en) * 2002-07-30 2007-02-15 Schaffner Carl P Compositions of ezetimibe and methods for the treatment of cholesterol-associated benign and malignant tumors
US20120053196A1 (en) * 2008-05-16 2012-03-01 Jirstroem Karin Combination Treatment of Breast Cancer
US20130111615A1 (en) * 2005-08-23 2013-05-02 The Trustees Of The University Of Pennsylvania RNA Containing Modified Nucleosides and Methods of Use Thereof
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WO2004028546A1 (fr) * 2002-09-24 2004-04-08 Baker Medical Research Institute Flux sortant de cholestérol et son utilisation
US20130111615A1 (en) * 2005-08-23 2013-05-02 The Trustees Of The University Of Pennsylvania RNA Containing Modified Nucleosides and Methods of Use Thereof
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US20120053196A1 (en) * 2008-05-16 2012-03-01 Jirstroem Karin Combination Treatment of Breast Cancer

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3931349A4 (fr) * 2019-02-28 2023-02-08 The Rockefeller University Génotypage apoe dans le pronostic et le traitement du cancer
US11878956B2 (en) 2019-12-13 2024-01-23 Inspirna, Inc. Metal salts and uses thereof
CN114209838A (zh) * 2022-01-06 2022-03-22 领星生物科技（上海）有限公司 用于治疗kras突变的胆管癌的药物

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