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WO2016065353A1 - Thérapie combinatoire à base de fénofibrate et de 2-désoxyglucose ou de 2-désoxymannose - Google Patents

Thérapie combinatoire à base de fénofibrate et de 2-désoxyglucose ou de 2-désoxymannose Download PDF

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Publication number
WO2016065353A1
WO2016065353A1 PCT/US2015/057333 US2015057333W WO2016065353A1 WO 2016065353 A1 WO2016065353 A1 WO 2016065353A1 US 2015057333 W US2015057333 W US 2015057333W WO 2016065353 A1 WO2016065353 A1 WO 2016065353A1
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Prior art keywords
cancer
deoxyglucose
deoxymannose
fenofibrate
administered
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Theodore J. Lampidis
Metin Kurtoglu
Huaping Liu
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University of Miami
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University of Miami
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/08—Deoxysugars; Unsaturated sugars; Osones
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms

Definitions

  • the present disclosure relates to combination therapy comprising fenofibrate and 2- deoxyglucose or 2-deoxymannose for use in treating cancer and other hyperproliferative diseases.
  • Fenofibrate (propan-2-yl 2- ⁇ 4-[(4-chlorophenyl)carbonyl]phenoxy ⁇ -2- methylpropanoate; abbreviated FF) is a drug that has been prescribed for decades to treat high cholesterol. The majority of the FF administered is metabolized in vivo to fenofibric acid via hydrolysis of the carboxyl ester moiety. FF is thought to lower cholesterol and triglycerides by activating peroxisome proliferator- activated receptor alpha (PPARa), which in turn activates lipoprotein lipase, thereby increasing lipolysis and eliminating triglyceride-rich particles from the blood. FF is typically administered orally in a dosage of 40 mg to 120 mg per day for this indication.
  • PPARa peroxisome proliferator- activated receptor alpha
  • Sugar analogs having a substitution of the hydroxyl group at the 2' position of the sugar molecule are widely used as medical imaging and diagnostic agents, e.g., to measure tissue uptake of glucose. Such sugar analogs cannot undergo further glycolysis.
  • Examples of 2-deoxyglucose compounds include 2-deoxy-D-glucose (C 6 H 12 O 5 ), fluorodeoxyglucose (C 6 H 11 FO 5 ), and 2-deoxy-2- chloroglucose (C 6 H 11 CIO 5 ), and examples of 2-deoxymannose compounds include 2-deoxy-2- fluoromannose (C 6 H 11 FO 5 ) and 2-deoxy-2-chloromannose (C 6 H 11 CIO 5 ).
  • the present disclosure is related to combination therapy comprising (1) fenofibrate (FF) and (2) 2-deoxyglucose or 2-deoxymannose.
  • a method of inhibiting cancer cell growth described herein comprises contacting a cancer cell with (1) FF and (2) 2- deoxyglucose or 2-deoxymannose in an amount effective to inhibit cancer cell growth.
  • the cancer cell is in vivo and the contacting step comprises administering FF and 2-deoxyglucose or 2-deoxymannose to a subject.
  • the disclosure provides a method of treating or preventing a neoplastic, hyperplastic, or hyperproliferative disorder in a subject in need thereof comprising administering a therapeutically effective amount of FF and 2- deoxyglucose or 2-deoxymannose to the subject.
  • FF and/or 2-deoxyglucose or 2-deoxymannose is administered orally, intravenously, intratumorally, topically, or intraperitoneally.
  • the FF is administered in a daily dosage of about 1 mg to about 100 mg and/or the 2-deoxyglucose or 2-deoxymannose is administered in a daily dosage of about 1 mg/kg to about 60 mg/kg.
  • the FF is administered in an amount effective to achieve a plasma FF concentration of about 10 ⁇ to about 50 ⁇ .
  • the FF is administered in an amount effective to achieve a plasma fenofibric acid concentration of less than about 10 ⁇ .
  • the 2-deoxyglucose or 2-deoxymannose is selected from the group consisting of 2-deoxy-D-glucose, 2-deoxy-2-fluoroglucose, 2-deoxy-2-fluoromannose, 2- deoxy-2-chloromannose, and combinations thereof.
  • the FF and/or the 2- deoxyglucose or 2-deoxymannose is administered in a sub-therapeutic amount.
  • the FF and 2-deoxyglucose or 2-deoxymannose are administered concurrently.
  • the FF is administered before the 2-deoxyglucose or 2-deoxymannose.
  • the 2-deoxyglucose or 2-deoxymannose is administered before the FF.
  • the amount of FF and 2- deoxyglucose or 2-deoxymannose is effective to induce apoptosis in cancer cells.
  • the administration of FF and 2-deoxyglucose or 2-deoxymannose results in a synergistic increase in cancer cell death.
  • the 2-deoxyglucose is administered in an amount effective to increase the cytotoxicity of the FF compared to FF administered alone and/or the FF is administered in an amount effective to increase the cytotoxicity of the 2-deoxyglucose or 2- deoxymannose compared to 2-deoxyglucose or 2-deoxymannose administered alone.
  • the administration of 2-deoxyglucose or 2-deoxymannose mitigates an insulin response.
  • the 2-deoxyglucose or 2-deoxymannose is administered gradually, e.g., via a slow- release pump or in a modified release formulation.
  • the FF is administered in a formulation that prevents conversion of the FF to fenofibric acid.
  • the formulation is a liposomal formulation.
  • the present disclosure also provides a method of treating or preventing a neoplastic, hyperplastic, or hyperproliferative disorder in a subject in need thereof comprising administering a
  • the subject has multiple myeloma.
  • the present disclosure further provides a pharmaceutical composition comprising (1) FF and (2) 2-deoxyglucose or 2-deoxymannose.
  • the pharmaceutical composition comprises FF in a dosage amount of about 1 mg to about 100 mg and/or 2-deoxyglucose or 2- deoxymannose in a dosage amount of about 1 mg/kg to about 60 mg/kg.
  • kits comprising (1) FF and (2) 2-deoxyglucose or 2-deoxymannose and instructions for co-administering the FF and 2-deoxyglucose or 2-deoxymannose to a subject.
  • the kit or pharmaceutical composition comprises FF and/or 2-deoxyglucose or 2- deoxymannose in a formulation to be administered orally, intravenously, intratumorally, topically, or intraperitoneally.
  • the kit or pharmaceutical composition comprises FF in a formulation that prevents the conversion of FF to fenofibric acid (optionally, a liposomal formulation).
  • a kit or composition provides 2-deoxyglucose or 2- deoxymannose in a modified-release formulation, such as a formulation suitable for use in a slow-release pump.
  • combination therapy comprising FF and 2- deoxyglucose or 2-deoxymannose is administered to a subject having cancer.
  • the cancer is selected from the group consisting of bone cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, multiple myeloma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, prostate cancer, sarcoma, skin cancer, testicular cancer, throat cancer, thyroid cancer.
  • the cancer is bone cancer, breast cancer, multiple myeloma, or skin cancer.
  • Figure 1 depicts the cytotoxicity of fenofibrate (FF), 2-deoxy-D-glucose (2DG), and oligomycin (Olig), alone or in combination, in human osteosarcoma 143B cells.
  • the x-axis depicts the drug treatment.
  • the y-axis depicts the percentage of cells that are dead within the total cell population following treatment (Cell Death %).
  • Figure 2 depicts the cytotoxicity of FF, 2DG, and Olig, alone or in combination, in human breast cancer MCF7 cells.
  • the x-axis depicts the drug treatment.
  • the y-axis depicts the percentage of cells that are dead within the total cell population following treatment (Cell Death %).
  • Figure 3 depicts the cytotoxicity of FF, 2DG, and Olig, alone or in combination, in human breast cancer SKBR3 cells.
  • the x-axis depicts the drug treatment.
  • the y-axis depicts the percentage of cells that are dead within the total cell population following treatment (Cell Death %).
  • Figure 4 depicts the cytotoxicity of FF, 2DG, fluorodeoxyglucose (FDG), and Olig, alone or in combination, in human melanoma NM2C5 cells.
  • the x-axis depicts the drug treatment.
  • the y-axis depicts the percentage of cells that are dead within the total cell population following treatment (Cell Death %).
  • Figure 5A depicts ATP levels in human melanoma NM2C5 cells treated with FF, 2DG, and Olig, alone or in combination.
  • the x-axis depicts the drug treatment.
  • the y-axis depicts the ATP level expressed as a percentage of the ATP level in control cells (ATP %).
  • Figure 5B depicts ATP levels measured after 5 and 24 h of drug exposure. P value was
  • Figure 6 depicts the cytotoxicity of FF, 2DG, and FDG, alone or in combination, in human multiple myeloma cells.
  • the x-axis depicts the drug treatment.
  • the y-axis depicts the percentage of cells that are dead within the total cell population following treatment (Cell Death %).
  • Figure 7 shows apoptosis measured as cleaved caspase-3 (Casp3) in human melanoma NM2C5 cells treated with FF and 2DG, alone or in combination.
  • Figure 8 shows downregulation of pERK and the anti-apoptotic protein MCL-1 in human melanoma NM2C5 cells treated with FF, 2DG, and Olig, alone or in combination.
  • Figure 9 shows downregulation of the autophagy marker LC3BII in cells treated with FF and 2DG alone or in combination.
  • Figure 10 shows tumor volume in a mouse xenograft model of human melanoma cells treated with FF and 2DG, alone or in combination.
  • the 2DG was administered intraperitoneally (IP) or using a continuous release pump (PUMP).
  • IP intraperitoneally
  • PUMP continuous release pump
  • the x-axis depicts the treatment period in days.
  • the y-axis depicts tumor volume in cubic millimeters.
  • Figure 11 shows lactate levels in cells treated with FF or 2DG alone or in combination.
  • the x-axis depicts the treatment.
  • the y-axis depicts the Lactate %. Lactate levels in the medium were measured after 5 and 24 h of drug exposure. P value was *p ⁇ 0.05 and **p ⁇ 0.01 as compared to controls.
  • Figure 12A shows NM2C5 cells incubated with siRNA against either luciferase (SiLuciferase, as negative control) or Noxa (SiNoxa) for 24 h before addition of 40 ⁇ of FF, 2mM of 2DG or a combination of both as indicated. Following 72 h of treatment, cell death analysis was performed. P value was **p ⁇ 0.01 compared to FF combined with 2DG treatment in the control (SiLuciferase) group.
  • Figure 12B shows Western blot analysis of Noxa protein levels in NM2C5 cells treated as indicated. ⁇ -Actin was used as a loading control.
  • Figure 13A shows NM2C5 cells were treated with 1 mM of mannose (Mann), 20 uM of Z-VAD-FMK (zVAD) or 1 mM of glucose (Glue) in the presence of 40 ⁇ FF, 2 mM 2DG or combined, for 48 h followed by cell death analysis. P value was *p ⁇ 0.05 as compared to controls.
  • Figure 13B shows a Western blot of NM2C5 cells treated with 1 mM of Mann in the presence of 40 ⁇ of FF and 2 mM of 2DG for 24 h to detect the level of p-eIF2a protein.
  • Figure 13C shows a Western blot of NM2C5 cells treated with 1 mM of Glue in the presence of 40 ⁇ of FF and 2 mM of 2DG for 24 h to detect levels of p-AMPK and p-4EBPl proteins, ⁇ - Actin was used as a loading control.
  • the present disclosure relates to combination therapy comprising (1) fenofibrate (FF) and (2) 2-deoxyglucose or 2-deoxymannose.
  • FF fenofibrate
  • 2-deoxyglucose 2-deoxymannose
  • 2-deoxymannose are considered non-toxic and have been administered to human patients for non-cancer indications for years.
  • combination therapy comprising FF and 2-deoxyglucose or 2- deoxymannose is surprisingly effective at inhibiting growth of and killing a wide variety of cancer cell types, even when FF and 2-deoxyglucose or 2-deoxymannose are administered at doses that are not therapeutically effective when administered alone.
  • the synergistic cytotoxicity achieved using the combination of FF and 2-deoxyglucose or 2-deoxymannose according to the present disclosure allows for treatment of cancer and other hyperproliferative diseases using smaller doses of drug, thereby further minimizing potential side effects.
  • the following definitions may be useful in aiding the skilled practitioner in understanding the disclosure. Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art.
  • 2-deoxyglucose refers to a glucose molecule wherein the 2-hydroxyl group is substituted with hydrogen or another atom, e.g., a halogen atom.
  • 2-deoxyglucose compounds include 2-deoxy-D-glucose ((4R,5S,6R)-6-(hydroxymethyl)oxane-2,4,5-triol;
  • 2-deoxymannose refers to a mannose molecule wherein the 2-hydroxyl group is substituted with hydrogen or another atom, e.g., a halogen atom.
  • 2-deoxymannose compounds include 2-deoxy-2-fluoro-D-mannose and 2-deoxy-2-chloro-D- mannose.
  • co-administering and “combination therapy” mean that FF and 2- deoxyglucose or 2-deoxymannose are administered in a manner that permits the two compounds to exert physiological effects during an overlapping period of time.
  • combination therapy comprising FF and 2-deoxyglucose or 2-deoxymannose
  • the compounds may be administered in the same pharmaceutical composition or in separate compositions, via the same or different routes of administration.
  • the FF and 2-deoxyglucose or 2-deoxymannose may be coadministered concurrently, i.e., simultaneously, or at different times, as long as the compounds exert physiological effects during an overlapping period of time.
  • the FF and 2- deoxyglucose or 2-deoxymannose may both be administered to a subject within a time period of about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 24, or about 48 hours.
  • 2-deoxyglucose or 2-deoxymannose can be administered as a continuous intravenous infusion or in a slow-release oral formulation once or twice a day, and FF can be given orally or intravenously once or twice a day. If the FF and 2-deoxyglucose or 2- deoxymannose are not co-administered concurrently, either the FF or 2-deoxyglucose or 2- deoxymannose may be administered first.
  • a therapeutically effective amount refers to an amount of a single agent or combination therapy effective to achieve a desired biological, e.g., clinical, effect.
  • a therapeutically effective amount varies with the nature of the disease being treated, the length of time that activity is desired, and the age and the condition of the subject.
  • a therapeutically effective amount is an amount effective to inhibit growth of hyperproliferative cells, prevent cancer cell metastasis, and/or result in cancer cell death, e.g., via apoptosis or necrosis.
  • a “sub-therapeutic amount” refers to an amount of a single agent that does not achieve a desired biological, e.g., clinical, effect.
  • a sub-therapeutic amount of FF or 2-deoxyglucose or 2-deoxymannose may be an amount that does not cause a significant increase in cancer cell death compared to control (untreated) cells.
  • synergistic increase refers to an improvement in a therapeutic effect from administration of combination therapy comprising FF and 2-deoxyglucose or 2-deoxymannose compared to the sum of the therapeutic effects of FF and 2-deoxyglucose or 2-deoxymannose alone. For example, if a dosage of FF administered alone achieves X% cell death and a dosage of 2-deoxyglucose or 2-deoxymannose administered alone achieves Y% cell death, then a combination of those doses of FF and 2-deoxyglucose or 2-deoxymannose that achieves greater than (X+Y)% cell death is considered to have a synergistic increase in cell death.
  • a synergistic increase refers to a therapeutic effect resulting from combination therapy comprising FF and 2-deoxyglucose or 2-deoxymannose administered in sub-therapeutic amounts.
  • administered gradually refers to administration of a drug to a patient or release of a drug from a formulation in a manner that is slower compared to an intravenous or intraperitoneal bolus or immediate release formulation (i.e., a formulation wherein the drug is intended to be released immediately following administration to a subject).
  • a "modified release formulation” refers to a formulation wherein the drug release rate differs from an immediate release formulation. Modified release formulations include extended-release, delayed-release, and targeted-release formulations, and methods for their preparation are known in the art.
  • a method of inhibiting cancer cell growth comprises contacting a cancer cell with FF and 2-deoxyglucose or 2-deoxymannose in an amount effective to inhibit cancer cell growth.
  • the cancer cell is in vivo and the contacting step comprises administering FF and 2-deoxyglucose or 2-deoxymannose to a subject, e.g., a human patient.
  • a method of treating or preventing a neoplastic, hyperplastic or hyperproliferative disorder in a subject in need thereof is also provided and comprises administering a
  • FF and 2-deoxyglucose or 2-deoxymannose are therapeutically effective amounts of FF and 2-deoxyglucose or 2-deoxymannose to the subject.
  • the present disclosure also provides use of FF and 2-deoxyglucose or 2-deoxymannose for the preparation of a medicament, wherein the medicament comprises an amount of FF and 2- deoxyglucose or 2-deoxymannose that is effective for treating or preventing a neoplastic, hyperplastic or hyperproliferative disorder.
  • the administration of FF and 2-deoxyglucose or 2-deoxymannose results in a synergistic increase in cell (e.g., cancer or other hyperproliferative cell) death, i.e., compared to the effects of FF and 2-deoxyglucose or 2-deoxymannose administered alone.
  • the 2-deoxyglucose or 2-deoxymannose is administered in an amount effective to increase the cytotoxicity of the FF compared to FF administered alone.
  • the FF is administered in an amount effective to increase the cytotoxicity of the 2-deoxyglucose or 2- deoxymannose compared to 2-deoxyglucose or 2-deoxymannose administered alone.
  • both the 2-deoxyglucose or 2-deoxymannose and the FF are administered in an amount effective to increase the cytotoxicity of the other compound compared to the other compound administered alone.
  • one or more additional compounds may be administered to increase the efficacy of combination therapy comprising FF and 2-deoxyglucose or 2-deoxymannose.
  • additional compounds include, but are not limited to, butylated hydroxyanisole (BHA), any inhibitor of the anti-apoptotic protein MCL-1 or its upstream regulator ERK, and any inhibitor of protein kinase B (also known as Akt).
  • BHA butylated hydroxyanisole
  • Akt protein kinase B
  • inhibitors of Akt include Akt Inhibitor X ( ⁇ ) and curcumin.
  • the methods of the present disclosure comprise administering FF and/or
  • a sub-therapeutic dose of FF or 2- deoxyglucose or 2-deoxymannose has an anticancer effect comparable to a placebo.
  • a sub-therapeutic dose of FF or 2-deoxyglucose or 2-deoxymannose may achieve growth inhibition of cancer cells that is not significantly different than no treatment at all or may actually promote tumor growth.
  • the FF is administered in a sub-therapeutic amount.
  • the 2-deoxyglucose or 2-deoxymannose is administered in a subtherapeutic amount.
  • both the FF and 2-deoxyglucose or 2-deoxymannose are administered in a sub -therapeutic amount. According to the methods of the present disclosure, even when FF and/or 2-deoxyglucose or 2-deoxymannose is administered in a subtherapeutic amount, the combination of both compounds is still therapeutically effective.
  • the disease to be treated is cancer.
  • treatable cancers include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma
  • craniopharyngioma cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gyn
  • hemangiopericytoma hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangio sarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non- small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, medias
  • the methods of the present disclosure can be used to treat a cancer selected from the group consisting of bone cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, multiple myeloma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, prostate cancer, sarcoma, skin cancer, testicular cancer, throat cancer, and thyroid cancer.
  • the disease to be treated is bone cancer, breast cancer, multiple myeloma, or skin cancer.
  • treating a cancer does not require complete eradication of the cancer. Any beneficial physiologic response is contemplated, such as tumor shrinkage, tumor cell death, reduction or halting of metastasis, reduction in cancer cell markers, alleviation of symptoms and the like.
  • the disease to be treated is a benign hyperproliferative disorder including, but not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, benign prostate hyperplasia, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
  • benign soft tissue tumors including, but not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma
  • combination therapy described herein is administered to a subject in need thereof.
  • a particular administration regimen for a particular subject will depend, in part, upon the type and severity of the disease to be treated, the amount of combination therapy administered, the route(s) of administration, and the cause and extent of any side effects.
  • the amount of combination therapy administered to a subject e.g., a mammal, such as a human
  • the treatment period will depend on the particular condition and subject and may last one day to several days, weeks, months, or years.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) FF and (2) 2-deoxyglucose or 2-deoxymannose.
  • the pharmaceutical composition comprises FF in a dosage amount of about 1 mg to about 100 mg and/or 2-deoxyglucose or 2- deoxymannose is a dosage amount of about 1 mg/kg to about 60 mg/kg based on the weight of the tumor or subject.
  • the pharmaceutical composition is for use in the treatment of a neoplastic, hyperplastic, or hyperproliferative disease, such as cancer.
  • the present disclosure also provides use of a composition described herein for the preparation of a medicament, wherein the medicament comprises an amount of the composition that is effective for treating or preventing a neoplastic, hyperplastic or hyperproliferative disorder.
  • the pharmaceutical composition comprises a pharmaceutically acceptable carrier including, but not limited to, water, saline, phosphate buffered saline, and commercial buffers.
  • the composition is sterile.
  • Other excipients, including buffering agents, dispersing agents, and preservatives, are known in the art and may be included in the pharmaceutical composition. Further examples of components that may be employed in compositions are presented in Remington's Pharmaceutical Sciences, 16 th Ed. (1980) and 20 th Ed.
  • a composition may be in any suitable dosage form including, but not limited to, tablets, capsules, implants, depots, liquids, patches, pumps, lozenges, creams, ointments, lotions, aerosols, and eye drops.
  • kits comprising (1) FF and (2) 2-deoxyglucose or 2-deoxymannose and instructions for co-administration of a therapeutically effective amount of the FF and 2-deoxyglucose to a subject having cancer.
  • a kit or pharmaceutical composition of the present disclosure comprises FF and/or 2-deoxyglucose or 2-deoxymannose in a formulation to be administered orally, intravenously, intratumorally, topically or
  • Suitable methods of administering FF and 2-deoxyglucose or 2-deoxymannose, for example, in a pharmaceutical composition of the present disclosure, are well-known in the art.
  • FF and/or 2-deoxyglucose or 2-deoxymannose is introduced into tumor sites, applied or instilled into body cavities, absorbed through the skin or eye or mucous membranes, inhaled, ingested, and/or injected or otherwise introduced into circulation.
  • FF and/or 2- deoxyglucose or 2-deoxymannose can be administered orally or injected intravenously or intraperitoneally, resulting in systemic uptake, or administered locally by directly contacting tumor cells.
  • FF and/or 2-deoxyglucose or 2-deoxymannose through injection or infusion by intravenous, intratumoral, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intranasal, transdermal, enteral, topical, sublingual, urethral, vaginal, or rectal means; by controlled, delayed, gradual, sustained or otherwise modified release systems; or by implantation devices.
  • FF and/or 2-deoxyglucose or 2-deoxymannose is administered regionally via intratumoral administration, intraocular administration, intrathecal administration, intracerebral (intra-parenchymal) administration, intracerebroventricular administration, topical administration, subcutaneous administration, or intraarterial, intravenous, or intraperitoneal administration targeting the region of interest.
  • the combination therapy is administered locally via implantation of a matrix, membrane, pump, sponge, or another appropriate material loaded with FF and/or 2-deoxyglucose or 2-deoxymannose.
  • the device is, in one aspect, implanted into any suitable site (e.g., tissue, organ, or cavity), and delivery of the desired compound is, for example, via diffusion, timed-release bolus, gradual administration, or continuous administration.
  • the FF and/or 2-deoxyglucose or 2-deoxymannose may be administered orally, intravenously, intratumorally, topically or intraperitoneally.
  • the FF and 2-deoxyglucose or 2-deoxymannose are administered concurrently.
  • the 2-deoxyglucose or 2-deoxymannose is administered before the FF.
  • the FF is administered before the 2-deoxyglucose or 2- deoxymannose.
  • the methods of the present disclosure comprise administering, e.g., from about 1 mg/day to about 100 mg/day or more of FF and/or from about 1 mg/kg/day to about 60 mg/kg/day or more of 2-deoxyglucose or 2-deoxymannose, based on the weight of the tumor or subject, depending on the factors mentioned above.
  • the daily dosage of FF ranges from about 50 mg to about 100 mg, about 10 mg to about 40 mg, about 1 mg to about 20 mg, or about 20 mg to about 50 mg.
  • the daily dosage of 2-deoxyglucose or 2-deoxymannose ranges from about 1 mg/kg to about 25 mg/kg, about 10 mg/kg to about 40 mg/kg, about 5 mg/kg to about 20 mg/kg, or about 30 mg/kg to about 60 mg/kg.
  • the methods comprise administering FF in amount effective to achieve a plasma FF concentration of about 10 ⁇ to about 50 ⁇ and/or 2-deoxyglucose or 2- deoxymannose in an amount effective to achieve a plasma 2-deoxyglucose or 2-deoxymannose concentration of about 50 ⁇ g/mL to about 400 ⁇ g/mL.
  • the FF is administered in an amount effective to achieve a plasma FF concentration of about 10 ⁇ to about 30 ⁇ , for example, about 10 ⁇ to about 20 ⁇ , about 15 ⁇ to about 40 ⁇ , or about 25 ⁇ to about 50 ⁇ .
  • the 2-deoxyglucose or 2-deoxymannose is administered in an amount effective to achieve a plasma 2-deoxyglucose or 2-deoxymannose concentration of about 100 ⁇ g/mL to about 200 ⁇ g/mL, or about 250 ⁇ g/mL to about 400 ⁇ g/mL, or about 40 ⁇ g/mL to about 150 ⁇ g/mL.
  • a plasma 2-deoxyglucose or 2-deoxymannose concentration of about 100 ⁇ g/mL to about 200 ⁇ g/mL, or about 250 ⁇ g/mL to about 400 ⁇ g/mL, or about 40 ⁇ g/mL to about 150 ⁇ g/mL.
  • the administration of 2-deoxyglucose or 2-deoxymannose mitigates an insulin response.
  • Modified glucose molecules including 2-deoxyglucose or 2-deoxymannose can stimulate the release of insulin from the pancreas.
  • the insulin response leads to adsorption of 2- deoxyglucose or 2-deoxymannose by fat and muscle cells, thereby reducing the amount delivered to target cells.
  • the 2- deoxyglucose or 2-deoxymannose is administered gradually, for example, via a slow-release pump or in a modified-release formulation.
  • a slow-release pump such as a continuous-release osmotic pump, or modified-release formulation gradually administers drug over an extended period of time.
  • a kit or pharmaceutical composition comprises 2-deoxyglucose or 2-deoxymannose in a modified-release formulation.
  • the 2-deoxyglucose or 2- deoxymannose is administered at a rate slower than 50 ⁇ g/mL/hour, for example, about 40 ⁇ g/mL/hour, about 30 ⁇ g/mL/hour, or about 20 ⁇ g/mL/hour.
  • Such a gradual administration of 2- deoxyglucose or 2-deoxymannose mitigates, and may completely avoid, an insulin response that a single equivalent dose administered as a bolus can trigger (see U.S. Patent Application No. 12/994,265, incorporated herein by reference).
  • FF is administered in a formulation that prevents conversion of the FF to fenofibric acid. FF is typically rapidly and extensively (up to
  • a kit or pharmaceutical composition comprises FF in a formulation that prevents the conversion of FF to fenofibric acid.
  • the present disclosure thus also provides a method of treating or preventing a neoplastic, hyperplastic or hyperproliferative disorder in a subject in need thereof comprising administering a therapeutically effective amount of FF in a formulation that prevents conversion of the FF to fenofibric acid to the subject.
  • the subject has multiple myeloma.
  • FF is administered in an amount effective to achieve a plasma fenofibric acid concentration of less than about 10 ⁇ , for example, less than about 8 ⁇ , less than about 5 ⁇ , less than about 3 ⁇ , or less than about 1 ⁇ .
  • the methods and compositions of the present disclosure induce cytotoxic effects via the induction of apoptosis or necrosis.
  • the administration of FF and 2- deoxyglucose or 2-deoxymannose is effective to induce apoptosis in cancer cells.
  • Apoptotic cells may be identified by histological markers such as nuclear and cytoplasmic condensation and cellular fragmentation.
  • Necrotic cells may be identified by histological markers such as cellular and organelle swelling, chromatin flocculation, loss of nuclear basophilia, degraded cytoplasmic structure, impaired organelle function, increased membrane permeability, and cytolysis.
  • One mechanism for inducing apoptosis and/or necrosis involves the activation of initiator caspases (e.g., caspase-2, caspase-8, caspase-9, caspase-10), executioner caspases (e.g., caspase-3, caspase-6) and also pro-inflammatory caspases (e.g., caspase-1 and caspase-13).
  • initiator caspases e.g., caspase-2, caspase-8, caspase-9, caspase-10
  • executioner caspases e.g., caspase-3, caspase-6
  • pro-inflammatory caspases e.g., caspase-1 and caspase-13
  • Tdt-mediated dUTP nick-end labeling TUNEL
  • ISEL in situ end labeling
  • DNA laddering assays DNA fragmentation assays
  • FACS fluorescence- activated cell sorting
  • microscopy analysis cell staining (e.g., using trypan blue, propidium iodide,7-actinomycin D, Annexin V, Hoescht, fluorescein diacetate-green, DAPI, and/or other dyes known in the art) assays, and enzyme-linked immunosorbent assays (ELISA).
  • Apoptosis can also be promoted via a down-regulation of anti- apoptotic proteins such as MCL-1.
  • Tumor growth also can be analyzed to determine the antitumor activity of the combination therapy of the present disclosure.
  • Tumor mass, volume, and/or length can be assessed using methods known in the art such as calipers, ultrasound imaging, computed tomography (CT) imaging, magnetic resonance imaging (MRI), optical imaging (e.g., bioluminescence and/or fluorescence imaging), digital subtraction angiography (DSA), positron emission tomography (PET) imaging and/or other imaging analysis.
  • Tumor cell proliferation can also be analyzed using cellular assays that measure, e.g., DNA synthesis, metabolic activity, antigens associated with cell proliferation, and/or ATP.
  • the method of the present disclosure reduces the size of a tumor at least about 5% (e.g., at least about 10%, at least about 15%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%).
  • the unexpected therapeutic efficacy of combination therapy comprising FF and 2-deoxyglucose or 2-deoxymannose may be associated with a suppression of protective cellular responses to stress, including autophagy and anti- apoptosis pathways.
  • FF is known to impair mitochondrial function
  • the combination of FF and 2-deoxyglucose is more toxic to cancer cells than 2-deoxyglucose and oligomycin (a more potent mitochondrial inhibitor) used together, indicating that the therapeutic efficacy of FF and 2-deoxyglucose or 2-deoxymannose is not merely due to the effect of FF on mitochondria.
  • studies involving other PPARa agonists indicate that the mechanism of action for the therapeutic efficacy of FF and 2-deoxyglucose or 2-deoxymannose is PPARa-independent.
  • NM2C5 human melanoma cells NM2C5 human melanoma cells, 143B human osteosarcoma cells, MCF-7 and SKBR3 human breast cancer cells, and human multiple myeloma cells were purchased from ATCC (Manassas, VA). All cell lines were cultured in low glucose (1 mg/mL) DMEM growth medium supplemented with 10% FBS and penicillin/streptomycin (Invitrogen, Grand Island, NY).
  • Drugs and antibodies 2-deoxy-D-glucose, mannose, D-(+)-Glucose, rapamycin, and fenofibrate were purchased (Sigma- Aldrich, St. Louis, MO).
  • Mouse anti-b-actin (A5441) primary antibody (Sigma- Aldrich), mouse anti-Noxa (OP180, Calbiochem), horseradish peroxidase-conjugated anti-rabbit (W4011) and anti-mouse (W4021) secondary antibody (Promega, Madison, WI) were also used.
  • Cytotoxicity assay Cells were seeded onto 24- well plates and cultured overnight. Melanoma, osteosarcoma, and breast cancer cells were incubated for 48 hours with growth medium or 0.1% DMSO as controls, or with FF (40 ⁇ ), 2-deoxy-D-glucose (2DG; 2 mM), 2- deoxy-2-fluoroglucose (FDG; 2 mM), oligomycin (0.1 ⁇ g/mL), or a combination of the foregoing. Multiple myeloma cells were incubated for 24 hours with control medium or with 20 ⁇ or 40 ⁇ FF, 1 mM or 2 mM 2DG, 2 mM FDG, or a combination of the foregoing.
  • HBSS Hanks Balanced Salt Solution
  • Vi-CELL® cell viability analyzer Beckman Coulter, Brea, CA
  • Fluorescent microscopy Cells were seeded onto 24- well plates and cultured for 18-22 h to approximately 60% confluence. After 24 h of drug exposure, cells were stained with DAPI (0.5 ug/ml) and visualized immediately with the Nikon Eclipse TE2000 microscope (Nikon, Melville, NY) to analyze changes in nuclear condensation and fragmentation. Microphotographs of the center of each well were taken at 60X magnification with the aid of imaging-capture software (NIS-Elements from Nikon, Melville, NY).
  • ATP quantification Intracellular ATP levels were measured with the CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI) according to the manufacturer's directions. Briefly, cells were seeded onto 96-well plates and cultured overnight to reach about 70% confluence. After 5 hours of drug exposure, cells were lysed in the same plate with the reagent included in the assay kit for 10 minutes. The mixtures were transferred onto opaque- walled 96-well plates, and luminescence produced from ATP-mediated chemical reaction was read by the luminescence module of the FLUOstar OPTIMA microplate reader (BMG
  • PVDF polyvinylidene fluoride
  • Oxygen consumption mitochondria respiration: Cells were grown in 75-cm 2 flasks until they were 70% to 80% confluent, and then were trypsinized. Cells (5 x 10 6 ) were resuspended in 1 mL of RPMI, which did not contain glucose or fetal bovine serum, and 2DG or oligomycin. Oxygen consumption was measured with a Clark electrode (Hansatech) for 10 minutes, and the rate was expressed as (nmol oxygen)/min/10 6 cells.
  • Lactate assay At 24h after seeding, grown cells were rinsed twice with PBS, fresh medium was added to the control and test cultures, at the indicated drug concentrations, and the cells were re-incubated in 5% C0 2 for 5 or 24 h. Then, 0.5 ml of medium was removed from each culture and deproteinated by adding 1 ml of perchloric acid at 8% w/v, vortexing for 30 s, then placing this mixture in 4 °C for 5 min, and centrifuging at 1,500 g for 10 min. The supernatent was centrifuged three times more.
  • lactic acid 0.025 ml of this supernatent was added to a reaction mixture containing 0.1 ml of lactic dehydrogenase (1,000 units/ml), 2 ml of glycine buffer (glycine, 0.6 mol/1, and hydrazine, pH 9.2), and 1.66 mg/ml NAD. Formation of NADH was measured with a Beckman DU 520 UV/VIS spectrophotometer at 340 nm, which directly corresponded to lactic acid levels as determined by a lactate standard curve. Readouts from control samples, normalized to cell number, were set at 100% and those from all the other samples were presented as percentages of controls. Samples were analyzed in triplicate.
  • siRNA transfection Cells were seeded into 12 welled plates and cultured for 24 h to reach approximately 30% confluence using antibiotic-free media. Then, cells were transfected with either anti-Luc siRNA-1 (targeting luciferase) or Noxa siRNA (sc-37305, Santa Cruz Biotechnology, Inc.). Twenty-four hours after transfection, cells were treated for the indicated times and collected for immunoblotting or cytotoxicity analyses. The lowest concentrations of siRNAs were determined by dose response experiments which produced the most efficient knockdown with minimal toxicity.
  • mice were randomized into groups of 8 mice with comparable tumor size each and treated as follows: (1) 500 mg/kg of 2DG intraperitoneally every other day; (2) 100 mg/kg of FF by gavage every day; (3) ALZET® osmotic pumps (Durect Corporation, Cupertino, CA) filled with 2DG subcutaneously implanted in the mouse to deliver 41 ⁇ g/mL/hour of 2DG continuously; (4) combined FF and 2DG (intraperitonally or by pump); (5) saline injections or subcutaneously implanted pumps filled with saline (control).
  • ALZET® osmotic pumps Durect Corporation, Cupertino, CA
  • FF was formulated in 1% methylcellulose and 1% Tween-80, and 2DG was in PBS.
  • mice were anesthetized by 62 mg of ketamine hydrochloride and 5 mg of Xylazine/kg i.p. Following the manufacturer's instructions, a skin incision was made in the back of the mouse. The pump filled with saline or 2DG was inserted and the incision was closed with 2 or 3 wound clips. Tumor growth was evaluated at least once per week by measuring tumor dimension with a digital caliper, and tumor volume was calculated based on ellipsoid dimensions (width x length x 0.5) until the experiment ended within two months.
  • FF and 2DG induced cell death in the form of both necrosis (i.e., faintly stained nuclear "ghosts,” indistinct vacuolated cytoplasm which appear light due to ruptured plasma membranes) and apoptosis (i.e., cells in early stage of apoptosis show aggregated chromatin abutting the nuclear membrane and condensed, basophilic cytoplasm).
  • necrosis i.e., faintly stained nuclear "ghosts,” indistinct vacuolated cytoplasm which appear light due to ruptured plasma membranes
  • apoptosis i.e., cells in early stage of apoptosis show aggregated chromatin abutting the nuclear membrane and condensed, basophilic cytoplasm.
  • the morphological studies confirmed the absence of toxicity with either 2DG or FF alone, and synergistic increases in overall cell death at 24h when the two were combined.
  • oligomcyin when used in combination with 2DG, was not as effective as combination therapy comprising 2DG and FF ( Figures 1-4). Oligomycin is a more rapid and potent inhibitor of mitochondrial respiration than FF. Table 1 shows the rate of 0 2 consumption as a measure of mitochondrial respiration.
  • MCL-1 has been reported to correlate with survival in numerous cell types.
  • MCL-1 is the protein target of the pro-apoptotic BH3-only protein Noxa, and the combination of FF and 2DG resulted in increased Noxa.
  • cells treated with 2DG and FF were co-treated with siRNA specific to Noxa.
  • glucose metabolism which has been demonstrated by numerous PET scans to be a feature of most tumors and more recently shown to be driven by major oncogenes, presents a universal target that can be exploited by 2DG.
  • the methods and compositions of the present disclosure achieve therapeutic efficacy, even at sub-therapeutic doses of FF and 2-deoxyglucose or 2-deoxymannose, and provide an improved therapeutic option useful for treating cancer.

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Abstract

L'invention concerne une thérapie combinatoire comprenant (1) du fénofibrate et (2) du 2-désoxyglucose ou du 2-désoxymannose. L'invention concerne également des méthodes d'utilisation de la thérapie combinatoire dans le traitement de maladies hyperprolifératives, cancer compris, ainsi que des compositions pharmaceutiques comprenant (1) du fénofibrate et (2) du 2-désoxyglucose ou du 2-désoxymannose.
PCT/US2015/057333 2014-10-24 2015-10-26 Thérapie combinatoire à base de fénofibrate et de 2-désoxyglucose ou de 2-désoxymannose Ceased WO2016065353A1 (fr)

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US10792274B2 (en) 2016-11-04 2020-10-06 Emory University Dehydroacetic acid (DHAA) and derivative for uses in treating cancer
CN113271933B (zh) * 2018-11-12 2024-01-09 诺阿姆公司 抗癌组合物
WO2024102874A1 (fr) * 2022-11-10 2024-05-16 The Wistar Institute Of Anatomy And Biology Le fénofibrate améliore les thérapies par lymphocytes t

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Cited By (3)

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US10792274B2 (en) 2016-11-04 2020-10-06 Emory University Dehydroacetic acid (DHAA) and derivative for uses in treating cancer
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WO2024102874A1 (fr) * 2022-11-10 2024-05-16 The Wistar Institute Of Anatomy And Biology Le fénofibrate améliore les thérapies par lymphocytes t

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