WO2021236498A1 - Traitement de cancers à variant kras avec des inhibiteurs d'absorption de la sérotonine - Google Patents

Traitement de cancers à variant kras avec des inhibiteurs d'absorption de la sérotonine Download PDF

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WO2021236498A1
WO2021236498A1 PCT/US2021/032715 US2021032715W WO2021236498A1 WO 2021236498 A1 WO2021236498 A1 WO 2021236498A1 US 2021032715 W US2021032715 W US 2021032715W WO 2021236498 A1 WO2021236498 A1 WO 2021236498A1
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serotonin uptake
uptake inhibitor
cancer
halide
sibutramine
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Joann SWEASY
Z Ping LIN
Elena Ratner
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Yale University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to methods and compositions for treating a cancer that has a variant in the KRAS gene.
  • Ovarian cancer is a cancer that forms in or on an ovary. Ovarian cancer is diagnosed in an estimated 22,240 women in the United States each year. According to the American Cancer Society, ovarian cancer is the fifth leading cause of cancer-related death of women.
  • a single base mutation in the 3’ untranslated region (3’-UTR) of the KRAS gene has been associated with increased risk of ovarian cancer.
  • the prevalence of this variant is 5.8% among global populations (2).
  • the KRAS variant is an inherited, germline variant that may serve as a genetic marker of increased risk of epithelial ovarian cancer (EOC), with a presence in over 25% of patients with this disease (3,4), although it is controversial as to whether the variant predicts risk (5).
  • EOC epithelial ovarian cancer
  • the KRAS variant is suggested to be associated with hereditary breast and ovarian cancer (HBOC) (6) in which 61% of HBOC patients harbor the KRAS variant (3), where it may represent a new genetic marker of ovarian risk for patients from HBOC families.
  • HBOC hereditary breast and ovarian cancer
  • the KRAS variant impacts responses to various cancer therapies.
  • the KRAS variant impacts responses to various cancer therapies.
  • Ovarian tumors with the KRAS variant are resistant to treatment with standard chemotherapies including cisplatin.
  • the standard chemotherapy regimen for treatment of EOC is carboplatin and paclitaxel, based upon prospective randomized clinical trials (7).
  • Tumor microRNA expression patterns have been associated with resistance to platinum-based chemotherapy in patients with EOC (21).
  • EOC tumors harboring the KRAS- variant were found to be significantly more resistant to treatment with platinum than those without the KRAS- variant (8).
  • a method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a serotonin uptake inhibitor, wherein the subject comprises rs61764370 variant of the KRAS gene.
  • the subject comprises rs61764370 variant of the KRAS gene in cancer cells.
  • the cancer is an ovarian cancer.
  • the ovarian cancer is a hereditary ovarian cancer.
  • the ovarian cancer is an epithelial ovarian cancer.
  • the cancer is a breast cancer.
  • the serotonin uptake inhibitor has a structure according to formula (I):
  • Ri is selected from H, a halide, and a C1-C3 perfluorocarbon
  • R2 and R3 are independently selected from H and a C1-C3 hydrocarbon, or R2 and R3 together form a 4-, 5-, or 6-membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon;
  • R4 is selected from H and a C1-C6 hydrocarbon optionally substituted with -OH or a halide;
  • R5 and R6 are independently selected from H and a C1-C3 hydrocarbon
  • R7 is absent or is selected from a halide and a C1-C3 perfluorocarbon.
  • a pharmaceutically acceptable salt of the compound is provided.
  • the serotonin uptake inhibitor has a structure according to formula (I) in which
  • Ri is selected from a halide and a C 1 -C 3 perfluorocarbon; R 2 and R 3 together form a 4-, 5-, or 6-membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon;
  • R 4 is a C 1 -C 6 hydrocarbon optionally substituted with -OH or a halide
  • R 5 and R 6 are independently selected from H and -CH3;
  • R 7 is absent or is a halide.
  • a pharmaceutically acceptable salt of the compound is provided.
  • the serotonin uptake inhibitor has a structure according to formula (I) in which
  • Ri is a halide
  • R 2 and R 3 together form a 4-, 5-, or 6-membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon;
  • R 4 is a C 3 -C 6 hydrocarbon optionally substituted with -OH or a halide
  • R 5 and R 6 are independently selected from H and -CH3;
  • R 7 is absent.
  • a pharmaceutically acceptable salt of the compound is provided.
  • the serotonin uptake inhibitor has a structure according to formula (I) in which
  • Ri is -Cl
  • R 2 and R 3 together form a 4-membered carbocycle
  • R 4 is a selected from n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl;
  • R 5 and R 6 are independently selected from H and -CH3;
  • R 7 is absent.
  • a pharmaceutically acceptable salt of the compound is provided.
  • the compound of formula (I) is selected from sibutramine, desmethylsibutramine, and didesmethylsibutramine.
  • the serotonin uptake inhibitor is selected from fluoxetine, citalopram, escitalopram, sertraline, norsertraline, fluvoxamine, femoxetine, indalpine, alaproclate, cericlamine, ifoxetine, zimelidine, dapoxetine, etoperidone, desmethylcitalopram, didesmethylcitalopram, and seproxetine.
  • the serotonin uptake inhibitor is sibutramine.
  • the serotonin uptake inhibitor is (R)-sibutramine.
  • the serotonin uptake inhibitor is (S)- sibutramine. In a specific embodiment, the serotonin uptake inhibitor is desmethylsibutramine or didesmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (R)- desmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (S)- desmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (R)- didesmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (S)- didesmethylsibutramine.
  • the serotonin uptake inhibitor is more effective in killing a cancer cell comprising the rs61764370 variant of the KRAS gene than killing a corresponding cancer cell that does not comprise the rs61764370 variant of the KRAS gene.
  • the serotonin uptake inhibitor is more effective in inhibiting survival of a cancer cell comprising the rs61764370 variant of the KRAS gene than in inhibiting survival of a corresponding cancer cell that does not comprise the rs61764370 variant of the KRAS gene.
  • the administration of the serotonin uptake inhibitor results in inhibition of the growth of a tumor of the cancer.
  • the method further comprises administering one or more additional anti-cancer agents.
  • the serotonin uptake inhibitor and the additional anti-cancer agent are administered concurrently.
  • the serotonin uptake inhibitor and the additional anti-cancer agent are administered in one composition.
  • the serotonin uptake inhibitor and the additional anti cancer agent are administered sequentially.
  • the additional anti-cancer agent is a chemotherapeutic agent.
  • the chemotherapeutic agent is selected from paclitaxel, a PARP inhibitor, a platinum agent, and doxorubicin.
  • the method further comprises administering to the subject one or more additional anti-cancer treatments selected from a radiation therapy, an immunotherapy and a gene therapy.
  • the serotonin uptake inhibitor is administered orally.
  • the subject is a human.
  • composition comprising a serotonin uptake inhibitor and one or more additional anti-cancer agents.
  • the serotonin uptake inhibitor has a structure according to formula (I):
  • Ri is selected from H, a halide, and a C1-C3 perfluorocarbon
  • R2 and R3 are independently selected from H and a C1-C3 hydrocarbon, or R2 and R3 together form a 4-, 5-, or6-membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon;
  • R 4 is selected from H and a C 1 -C 6 hydrocarbon optionally substituted with -OH or a halide;
  • R5 and R 6 are independently selected from H and a C1-C3 hydrocarbon
  • R7 is absent or is selected from a halide and a C1-C3 perfluorocarbon.
  • a pharmaceutically acceptable salt of the compound is provided.
  • the serotonin uptake inhibitor of the pharmaceutical composition has a structure according to formula (I) in which:
  • Ri is selected from a halide and a C 1 -C 3 perfluorocarbon
  • R 2 and R 3 together form a 4-, 5-, or 6-membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon;
  • R 4 is a C 1 -C 6 hydrocarbon optionally substituted with -OH or a halide
  • R5 and R 6 are independently selected from H and -CH3;
  • R 7 is absent or is a halide.
  • a pharmaceutically acceptable salt of the compound is provided.
  • the serotonin uptake inhibitor of the pharmaceutical composition has a structure according to formula (I) in which:
  • Ri is a halide
  • R 2 and R 3 together form a 4-, 5-, or 6-membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon;
  • R 4 is a C 3 -C 6 hydrocarbon optionally substituted with -OH or a halide
  • R5 and R 6 are independently selected from H and -CH3; R7 is absent.
  • a pharmaceutically acceptable salt of the compound is provided.
  • the serotonin uptake inhibitor of the pharmaceutical composition has a structure according to formula (I) in which:
  • Ri is -Cl
  • R2 and R3 together form a 4-membered carbocycle
  • R4 is a selected from n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl;
  • R5 and R6 are independently selected from H and -CH 3 ;
  • R7 is absent.
  • a pharmaceutically acceptable salt of the compound is provided.
  • the compound of formula (I) is selected from
  • a pharmaceutically acceptable salt of the compound is provided.
  • the serotonin uptake inhibitor is selected from fluoxetine, citalopram, escitalopram, sertraline, norsertraline, fluvoxamine, femoxetine, indalpine, alaproclate, cericlamine, ifoxetine, zimelidine, dapoxetine, etoperidone, desmethylcitalopram, didesmethylcitalopram, and seproxetine.
  • the serotonin uptake inhibitor is sibutramine.
  • the serotonin uptake inhibitor is (R)- sibutramine.
  • the serotonin uptake inhibitor is (S)-sibutramine. In a specific embodiment, the serotonin uptake inhibitor is desmethylsibutramine or didesmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (R)- desmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (S)- desmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (R)- didesmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (S)- didesmethylsibutramine. In a specific embodiment, the additional anti-cancer agent is paclitaxel, a PARP inhibitor, a platinum agent, or doxorubicin.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
  • FIG. 1 is a diagram of the KRAS variant.
  • the KRAS-variant is a miRNA-binding site mutation in the 3’-UTR of the KRAS gene. The mutation interferes with binding of let-7 family of miRNAs. If let-7 doesn’t bind to the 3’UTR it is unable to inhibit KRAS expression.
  • FIG. 2 is a graph showing the effects of sibutramine in a clonogenic survival assay.
  • KRAS-variant ovarian cancer cells are more sensitive to sibutramine than non-KRAS variant isogenic control ovarian cancer cells (SKOV isogenic control).
  • FIGs. 3A and 3B are graphs showing the effects of sibutramine in a tumor xenograft study.
  • FIG. 3A shows tumor growth in response to sibutramine treatment in the athymic nude mice implanted with SKOV3 xenograft with wild type KRAS.
  • FIGs. 4A and 4B are images of the crystal structures of serotonin transporter (SERT) and 5'-3' Exoribonuclease 2 (XRN2), respectively.
  • FIGs. 5A-5C are schematics of the chemical structures of sibutramine (FIG. 5A) and its two metabolites, desmethylsibutramine (FIG. 5B) and didesmethylsibutramine (FIG. 5C).
  • FIGs. 6A-6B are graphs showing the inhibitory effects of fluoxetine (FE), sibutramine (SE), cisplatin (CisP) (FIG. 6A), and paclitaxel (P) (FIG. 6B) on the proliferation of MCF-7 cells, with cisplatin (CisP) and paclitaxel (P) used as the positive control.
  • FE fluoxetine
  • SE sibutramine
  • CisP cisplatin
  • P paclitaxel
  • FIGs. 7A-7B are graphs showing the inhibitory effects of fluoxetine (FE), sibutramine (SE), cisplatin (CisP) (FIG. 7A), and paclitaxel (P) (FIG. 7B) on the proliferation of ZR-75-1 cells, with cisplatin (CisP) and paclitaxel (P) used as the positive control.
  • FE fluoxetine
  • SE sibutramine
  • CisP cisplatin
  • P paclitaxel
  • patient refers to mammals, including, without limitation, human, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.) and experimental animal models (e.g., mouse, rabbit, rat).
  • veterinary animals e.g., cats, dogs, cows, horses, sheep, pigs, etc.
  • experimental animal models e.g., mouse, rabbit, rat.
  • the subject is a human.
  • the terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing, delaying, or reducing the incidence and/or likelihood of the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e.
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • an effective amount refers to an amount of a serotonin uptake inhibitor that is effective to treat a cancer in a subject.
  • pharmaceutically acceptable refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., a human).
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • carrier or “a pharmaceutically acceptable carrier” as used herein, refers to any clinically useful solvents, diluents, adjuvants, excipients, recipients, vehicles and the like for use in preparing admixtures of a pharmaceutical composition.
  • the invention provides a method of treating a cancer in a subject, in which a cell of the cancer comprises a variant in the KRAS gene. An effective amount of one or more serotonin uptake inhibitors is administered to the subject.
  • the invention provides a method of treating a cancer in a subject in need thereof.
  • An effective amount of a serotonin uptake inhibitor is administered to the subject.
  • the subject has the rs61764370 variant of the KRAS gene.
  • serotonin uptake inhibitor refers to any compound that is capable of directly or indirectly inhibiting the reupdate of serotonin.
  • a serotonin uptake inhibitor may inhibit the uptake of serotonin by blocking the action of the serotonin transporter.
  • Serotonin, or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter.
  • the serotonin uptake inhibitor also inhibits the uptake of other neurotransmitter(s) such as dopamine and norepinephrine.
  • the serotonin uptake inhibitor is a selective serotonin reuptake inhibitor or SSRI.
  • Serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein encoded by the SLC6A4 gene in human. SERT is a type of monoamine transporter protein that transports serotonin from the synaptic cleft to the presynaptic neuron.
  • the KRAS gene encodes a KRAS protein which is a p21 GTPase belonging to the small GTPase superfamily.
  • the KRAS protein functions as an on/off switch relaying the extracellular signals of receptor tyrosine kinases (i.e. EGFR) and initiating the cascade of signal transduction.
  • Activated KRAS phosphorylates and activates Raf, which in turn phosphorylates and activates MEK, which eventually promotes cellular survival.
  • the KRAS gene belongs to a class of genes known as oncogenes, which when mutated can cause normal cells to become cancerous.
  • a single amino acid substitution, or a single nucleotide substitution may be responsible for an activating mutation.
  • Abnormally active KRAS protein may direct cells to proliferate in an uncontrolled way. Mutations in the KRAS gene have been associated with various types of cancer.
  • the cancer is ovarian cancer. In various embodiments, the cancer is breast cancer. In various embodiments, the cancer is a glioma cancer. In various embodiments, the cancer is a prostate cancer. In various embodiments, the cancer is a lung cancer. In various embodiments, the cancer is a colorectal cancer. In various embodiments, the cancer is a head and neck cancer.
  • the cancer is an ovarian cancer.
  • the ovarian cancer can be an epithelial ovarian cancer (EOC).
  • EOC epithelial ovarian cancer
  • Epithelial ovarian cancer starts on the surface of the ovaries, and may account for at least 80% of ovarian cancer cases.
  • the EOC can be a high-grade serous carcinoma (HGSC), an endometrioid carcinoma (EC), a clear cell carcinoma (CCC), a mucinous carcinoma (MC) or a low-grade serous (LGSC).
  • HGSC high-grade serous carcinoma
  • EC endometrioid carcinoma
  • CCC clear cell carcinoma
  • MC mucinous carcinoma
  • LGSC low-grade serous
  • the ovarian cancer can be a germ cell ovarian cancer that forms in the germ (egg) cells of the ovary.
  • the ovarian cancer can be a stromal ovarian cancer that arises from the connective tissue cells that hold the ovary together and produce hormones.
  • the ovarian cancer can be a mixed ovarian cancer.
  • the ovarian cancer can be a hereditary breast and ovarian cancer (HBOC).
  • HBOC is a condition where individuals develop breast and/or ovarian cancers due to inherited genetic abnormalities. HBOC may primarily be associated with mutations in the BRCA 1 or BRCA2 genes.
  • the variant in the KRAS gene is a mutation in the miRNA-binding site in the 3’ untranslated region (3’ UTR) of the KRAS gene.
  • MicroRNAs are a class of short noncoding RNAs (about 22 nucleotides) that are aberrantly expressed in virtually all cancer types, where they can function as a novel class of oncogenes or tumor suppressor genes (18-20).
  • the binding of miRNAs to their target mRNAs is critical for the regulation of mRNA levels and subsequent protein expression, and this regulation can be affected by mutations such as single-nucleotide polymorphisms (SNPs) in miRNA binding sites in the 3'UTR of genes.
  • SNPs single-nucleotide polymorphisms
  • the miRNA binding site is specific for a miRNA from the let-7 miRNA family.
  • the let-7 miRNA may be a let-7a, let-7b, let-7d or let-7g miRNA.
  • the let-7 family of miRNAs are global genetic regulators important in regulating cell proliferation, cell cycle, apoptosis, metabolism, and sternness.
  • the let-7 family of miRNAs have been shown to regulate KRAS.
  • Members of the let-7 family are known to be susceptible to degradation via the XRN-1 (5'-3' exoribonuclease 1) nuclease, both in human cells and in C. elegans.
  • tumors harboring the KRAS variant were found to have lower levels of let-7a, b, d, and g.
  • a mutation in the miRNA binding site in the KRAS gene may lead to defective binding of the let-7 family of miRNAs, resulting in upregulation of the KRAS gene, which may drive carcinogenesis.
  • the presence of the KRAS variant may also lead to downregulation of the let-7 family of miRNAs, likely via a degradative mechanism (1).
  • KRAS variant may impact responses of cancers to various cancer therapies.
  • tumors in epithelial ovarian cancer harboring the KRAS variant were found to be significantly more resistant to treatment with platinum than those without the KRAS variant (8).
  • the variant in the KRAS gene is rs61764370.
  • rs61764370 refers to a single-nucleotide polymorphism (SNP) of T>G at position chr12:25207290 (GRCh38 38.1/141) which is in the 3'UTR miRNA binding site of the KRAS gene.
  • SNP single-nucleotide polymorphism
  • the KRAS variant may be a miRNA-binding site mutation in the 3’-UTR of the KRAS gene as shown in FIG. 1.
  • the serotonin uptake inhibitor has a structure according to formula (I):
  • Ri is selected from H, a halide, and a C1-C3 perfluorocarbon
  • R2 and R3 are independently selected from H and a C1-C3 hydrocarbon, or R2 and R3 together form a 4-, 5-, or6-membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon;
  • R4 is selected from H and a C1-C6 hydrocarbon optionally substituted with -OH or a halide;
  • R5 and R6 are independently selected from H and a C1-C3 hydrocarbon
  • R 7 is absent or is selected from a halide and a C 1 -C 3 perfluorocarbon, or a pharmaceutically acceptable salt thereof.
  • the serotonin uptake inhibitor is sibutramine, fluoxetine, citalopram, escitalopram, sertraline, norsertraline, fluvoxamine, femoxetine, indalpine, alaproclate, cericlamine, ifoxetine, zimelidine, dapoxetine, etoperidone, desmethylcitalopram, didesmethylcitalopram, or seproxetine, or an analog, derivative or metabolite thereof.
  • the serotonin uptake inhibitor is sibutramine.
  • Sibutramine is a racemic mixture of R,S stereoisomers of the phenethylamine class of drugs and is subject to rapid first-pass metabolism in humans.
  • Sibutramine was developed to treat obesity and marketed under the name Meridia (for example see (16)).
  • Meridia for example see (16)
  • Sibutramine and its metabolites are known to inhibit uptake of dopamine, norepinephrine, and serotonin (16).
  • sibutramine desmethylsibutramine and didesmethylsibutramine are shown in FIGs. 5A-5C, respectively.
  • the present disclosure encompasses sibutramine, sibutramine metabolites, and their enantiomers, as well as analogs, derivatives, pharmaceutically acceptable salts, solvates, hydrates, clathrates, or prodrugs thereof.
  • Sibutramine was withdrawn for use as an anti-obesity drug due to a risk benefits analysis showing that subjects taking sibutramine lost only 5-10 pounds during the 3- 4 years they were enrolled on the SCOUT trial.
  • the inventors of the present disclosure have identified a surprising and unexpected activity of sibutramine in cancer treatment.
  • the serotonin uptake inhibitor administered is (R)- sibutramine. In another specific embodiment, the serotonin uptake inhibitor administered is (S)-sibutramine.
  • the serotonin uptake inhibitor administered is desmethylsibutramine or didesmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor administered is (R)-desmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor administered is (S)-desmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (R)-didesmethylsibutramine. In a specific embodiment, the serotonin uptake inhibitor is (S)-didesmethylsibutramine. [0062] In some embodiments, the serotonin uptake inhibitor is an analog of sibutramine that is brain-penetrable. Brain-penetrable compounds are capable of crossing the blood-brain barrier. Brain-penetrable analogs of sibutramine may be particularly useful in treating brain cancers (e.g., glioma) that harbor the KRAS variant.
  • brain cancers e.g., glioma
  • the serotonin uptake inhibitor is more effective in killing the cell of the cancer with the KRAS variant, e.g., rs61764370, than in killing a corresponding cell of a cancer that does not comprise the same variant in the KRAS gene.
  • the serotonin uptake inhibitor inhibits the growth of a tumor of the cancer.
  • a serotonin uptake inhibitor may exert anti-cancer activity through synthetic lethality with the KRAS mutation.
  • Synthetic lethality is based upon the premise that genetic mutations in cancers synergize with specific drugs to result in tumor kill.
  • BRCA1 and 2 mutations exhibit synthetic lethality with poly-ADP-ribose polymerase 1 (PARP1) inhibitors, resulting in FDA approval of the PARP inhibitor Olaparib for the treatment of BRCA1/2 mutant ovarian and breast cancer.
  • PARP1 poly-ADP-ribose polymerase 1
  • sibutramine may act to inhibit a target protein of the KRAS-MAPK pathway in a direct or indirect manner, thereby selectively inducing lethality of KRAS variant cancers.
  • a serotonin uptake inhibitor may target one or more targets in the serotonin transporter (SERT) pathway or the miRNA processing pathway (e.g., enzymes or complex). Its target location(s) may be extracellular and/or intracellular. It may target the central nervous system (CNS) and/or other tissue types.
  • SERT serotonin transporter
  • miRNA processing pathway e.g., enzymes or complex.
  • CNS central nervous system
  • administering a serotonin uptake inhibitor to the subject for cancer treatment does not lead to weight loss.
  • administering a serotonin uptake inhibitor to the subject for cancer treatment does not lead to one or more of the following side effects: flu symptoms, runny or stuffy nose, sore throat, cough, fast or pounding heartbeats, high blood pressure, new or worsening shortness of breath, seizure (convulsions), fast or uneven heartbeats, dry mouth, upset stomach, loss of appetite, constipation, stomach pain, headache, back pain, joint pain, nervousness, dizziness, depression, trouble sleeping (insomnia), skin rash, and warmth, redness, or tingly feeling under the skin.
  • side effects flu symptoms, runny or stuffy nose, sore throat, cough, fast or pounding heartbeats, high blood pressure, new or worsening shortness of breath, seizure (convulsions), fast or uneven heartbeats, dry mouth, upset stomach, loss of appetite, constipation, stomach pain, headache, back pain, joint pain, nervousness, dizziness, depression, trouble sleeping (insomnia), skin rash, and
  • the method described herein further includes administering one or more anti-cancer agents.
  • Combination therapy of serotonin uptake inhibitors with other anti-cancer agents may exert synergistic or additive effects against the cancer.
  • the serotonin uptake inhibitor and the anti-cancer agent may be administered concurrently. In other embodiments, the serotonin uptake inhibitor and the anti-cancer agent may be administered sequentially, for example the serotonin uptake inhibitor is administered before the anti-cancer agent or the serotonin uptake inhibitor is administered after the anti-cancer agent.
  • the anti-cancer agent is a chemotherapeutic agent.
  • chemotherapeutic agent refers to any agent that has therapeutic usefulness in the treatment of cancer.
  • Chemotherapeutic agents as used herein encompass both chemical and biological agents. Such agents may function to inhibit a cellular activity upon which the cancer cell depends for continued survival.
  • chemotherapeutic agents include alkylating agents such as thiotepa, cyclophosphamide, and temozolomide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (e.g., mitomycin C), mycophenolic acid, No
  • the chemotherapeutic agent is paclitaxel, a PARP inhibitor, a platinum agent, or doxorubicin.
  • the chemotherapeutic agent used in the combination therapy is paclitaxel.
  • the chemotherapeutic agent used in the combination therapy is a PARP inhibitor or a platinum agent.
  • PARP inhibitors are a group of inhibitors of the enzyme poly (ADP-ribose) polymerase (PARP).
  • PARP enzyme poly
  • Exemplary PARP inhibitors that can be used in the methods described herein include olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib (BGB-290), Iniparib (BSI 201), CEP 9722, E7449, AG-14361, INO-1001, A-966492, PJ34 HCI, UPF 1069, AZD2461, ME0328, BGP-15 2HCI, Niraparib tosylate, NU1025, NVP-TNKS 656, NMS-P118, benzamide and picolinamide, and pharmaceutically acceptable salts, acids or derivatives thereof.
  • the PARP inhibitor is olaparib.
  • Platinum agents that can be used in the combination therapy described herein include, but are not limited to carboplatin, cis-platin, oxaliplatin, lobaplatin, enloplatin and miboplatin, and pharmaceutically acceptable salts, acids or derivatives thereof.
  • the platinum agent is carboplatin.
  • the platinum agent is cis-platin.
  • Additional chemotherapeutic agents that may be used in the combination therapy described herein include, but are not limited to, docetaxel, albumin bound paclitaxel, altretamine, bleomycin, capecitabine, cyclophosphamide, dactinomycin, etoposide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, pemetrexed, topotecan, vinblastine, vincristine and vinorelbine, and the like, and pharmaceutically acceptable salts, acids or derivatives thereof.
  • the anti-cancer agent is an anti-hormonal agent.
  • the anti-hormonal agent may be anti-estrogen or selective estrogen receptor modulator such as tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene; an aromatase inhibitor such as letrozole, anastrozole, and exemestane; a luteinizing-hormone-releasing hormone (LHRH) agonist such as goserelin, leuprolide and triptorelin; or an anti-androgen such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; or a pharmaceutically acceptable salt, acid or derivative thereof.
  • selective estrogen receptor modulator such as tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen,
  • the anti-cancer agent is a therapeutic antibody.
  • the therapeutic antibody may be 3F8, abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, drozitumab, duligotumab, dusigitumab, ecrom
  • the anti-cancer agent is an angiogenesis inhibitor.
  • the angiogenesis inhibitor may be axitinib, bevacizumab, cabozantinib, everolimus, lenalidomide, lenvatinib mesylate, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, thalidomide, vandetanib, or ziv-aflibercept, or a pharmaceutically acceptable salt, acid or derivative thereof.
  • the methods described herein also includes treating the subject with one or more of radiation therapy, immunotherapy, and gene therapy.
  • Radiation therapy that can be used in the methods described herein may include external beam radiation, intensity modulated radiation therapy (IMRT) and any form of radiosurgery including Gamma Knife, Cyberknife, Linac, and interstitial radiation (e.g. implanted radioactive seeds, GliaSite balloon).
  • IMRT intensity modulated radiation therapy
  • any form of radiosurgery including Gamma Knife, Cyberknife, Linac, and interstitial radiation (e.g. implanted radioactive seeds, GliaSite balloon).
  • immunotherapy improves the immune system’s ability to fight cancer.
  • immunotherapy involves the use of an immunotherapeutic agent which is an immune checkpoint inhibitor.
  • exemplary immune checkpoint inhibitors that may be used in the methods described herein include but are not limited to, anti-PD-1 agents, anti-PD-L1 agents, or anti-CTLA-4 agents.
  • Programmed Death-1 (PD-1) is an immunoinhibitory receptor expressed predominantly on previously activated T cells in vivo
  • PD-L1 is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that downregulate T cell activation and cytokine secretion upon binding to PD-1.
  • Cytotoxic T- Lymphocyte Antigen-4 is an immunoinhibitory receptor expressed exclusively on T cells in vivo, and binds to two ligands, CD80 and CD86 (also called B7-1 and B7-2, respectively).
  • the immune checkpoint inhibitors may be an anti-PD- 1 antibody such as pembrolizumab, nivolumab, and cemiplimab; an anti-PD-L1 antibody such as atezolizumab, avelumab and durvalumab, or an anti-CTLA-4 antibody such as ipilimumab.
  • gene therapy refers to the administration of nucleic acid (either native or modified) into a patient’s cells to treat cancer.
  • Gene therapies may be used to supply a functional copy of a mutated gene, inactivate a gene by targeting the gene’s DNA directly or targeting the mRNA transcript from the gene, or introduce a new gene into a target cell.
  • Exemplary gene therapies that may be used in the methods described herein include (1) tumor suppressor gene therapies that restore cell control through replacing tumor suppressor genes (e.g., p53 and IAWO ); (2) oncogene inhibition therapies that inactivate dominant oncogenes (e.g., EGFR and CLDN3) ⁇ (3) suicide gene therapies by an enzyme/prodrug system (e.g., herpes simplex virus-thymidine kinase (HVS-TK) system) or activating expression of a toxin (e.g., diphtheria toxin-A); (4) antiangiogenic gene therapy by delivering VEGFRs or angiogenesis inhibitors (e.g., angiostatin and endostatin); (5) immunopotentiation gene therapies by strengthening the immune response to tumor cells (e.g., chimeric antigen receptor T cell therapy), augmenting the expression of tumor antigens or the production of cytokines, interleukins (e.g., IL-21) and growth factors; (6) multi
  • any suitable route of administration may be employed for providing the subject with an effective dosage of the serotonin uptake inhibitor.
  • the serotonin uptake inhibitor may be administered by an oral, mucosal (e.g., nasal, sublingual, buccal, rectal, and vaginal), parenteral (e.g., intravenous, intramuscular, subcutaneous), or transdermal route, or a combination thereof.
  • the serotonin uptake inhibitor is administered orally.
  • the serotonin uptake inhibitor is administered to the subject in an amount from about 0.1 mg to about 60 mg.
  • the serotonin uptake inhibitor may be administered to the subject in an amount from about 0.1 mg to about 20 mg, from about 0.5 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 30 mg, from about 1 mg to about 40 mg, from about 2 mg to about 15 mg, from about 2 mg to about 30 mg, from about 2 mg to about 45 mg, from about 5 mg to about 20 mg, from about 5 mg to about 40 mg, from about 8 mg to about 30 mg, from about 8 mg to about 45 mg, from about 10 mg to about 30 mg, from about 10 mg to about 50 mg, from about 15 mg to about 30 mg, from about 15 mg to about 45 mg, from about 20 mg to about 40 mg, from about 20 mg to about 60 mg, from about 25 mg to about 50 mg, or from about 30 mg to about 60 mg.
  • the serotonin uptake inhibitor is administered to the subject in any one of the above-described amounts every 8 hours, every 12 hours, every 24 hours, every 36 hours, every 48 hours, or every 60 hours. In some embodiments, the serotonin uptake inhibitor is administered to the subject in any one of the above-described amounts once daily, twice daily or three times daily.
  • the serotonin uptake inhibitor is administered to the subject in subject in any one of the above-described amounts once daily.
  • the subject being treated is a human.
  • the subject may be an adult.
  • the subject may be a child.
  • Subjects with KRAS variant may be pre-selected by genetic testing specific for identifying the presence of the KRAS variant.
  • the invention provides a pharmaceutical composition comprising a serotonin uptake inhibitor and one or more anti-cancer agents.
  • the serotonin uptake inhibitor in the pharmaceutical composition has a structure according to formula (I):
  • Ri is selected from H, a halide, and a C1-C3 perfluorocarbon.
  • R2 and R3 are independently selected from H and a C1-C3 hydrocarbon, or R2 and R3 together form a 4-, 5-, or 6-membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon.
  • R 4 is selected from H and a C 1 -C 6 hydrocarbon optionally substituted with -OH or a halide.
  • R5 and R6 are independently selected from H and a C1-C3 hydrocarbon.
  • R7 is absent or is selected from a halide and a C1-C3 perfluorocarbon.
  • a pharmaceutically acceptable salt of the serotonin uptake inhibitor may be used.
  • Ri may be selected from a halide and a C1-C3 perfluorocarbon.
  • R2 and R3 may together form a 4-, 5-, or 6-membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon.
  • R4 may be a C1-C6 hydrocarbon optionally substituted with -OH or a halide.
  • R5 and R 6 may be independently selected from H and -CH3; R 7 may be absent, or may be a halide.
  • a pharmaceutically acceptable salt of the serotonin uptake inhibitor may be used.
  • Ri may be a halide.
  • R 2 and R 3 together may form a 4-, 5-, or 6- membered carbocycle optionally substituted with -OH, a halide, a C1-C3 perfluorocarbon, or a C1-C3 hydrocarbon.
  • R4 may be a C3-C6 hydrocarbon optionally substituted with -OH or a halide.
  • R5 and R6 may independently be selected from H and -CH3.
  • R7 may be absent.
  • a pharmaceutically acceptable salt of the serotonin uptake inhibitor may be used.
  • Ri may be -Cl.
  • R 2 and R 3 together may form a 4-membered carbocycle.
  • R 4 may be n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl.
  • R 5 and R 6 may be H or -CH3.
  • R7 may be absent.
  • a pharmaceutically acceptable salt of the serotonin uptake inhibitor may be used.
  • the compound of formula (I) may be sibutramine, desmethylsibutramine, or didesmethylsibutramine.
  • the serotonin uptake inhibitor in the pharmaceutical composition is sibutramine, fluoxetine, citalopram, escitalopram, sertraline, norsertraline, fluvoxamine, femoxetine, indalpine, alaproclate, cericlamine, ifoxetine, zimelidine, dapoxetine, etoperidone, desmethylcitalopram, didesmethylcitalopram, or seproxetine, or an analog, derivative or metabolite thereof.
  • the serotonin uptake inhibitor in the pharmaceutical composition is sibutramine.
  • the serotonin uptake inhibitor is (R)- sibutramine.
  • the serotonin uptake inhibitor is (S)-sibutramine.
  • the serotonin uptake inhibitor in the pharmaceutical composition is desmethylsibutramine or didesmethylsibutramine.
  • the serotonin uptake inhibitor is (R)-desmethylsibutramine.
  • the serotonin uptake inhibitor is (S)-desmethylsibutramine.
  • the serotonin uptake inhibitor is (R)- didesmethylsibutramine.
  • the serotonin uptake inhibitor is the serotonin uptake inhibitor is (S)- didesmethylsibutramine.
  • the anti-cancer agent in the pharmaceutical composition is a chemotherapeutic agent.
  • chemotherapeutic agents include alkylating agents such as thiotepa, cyclophosphamide, and temozolomide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marc
  • the chemotherapeutic agent is paclitaxel, a PARP inhibitor, a platinum agent, or doxorubicin.
  • the chemotherapeutic agent in the pharmaceutical composition is paclitaxel.
  • the chemotherapeutic agent in the pharmaceutical composition is a PARP inhibitor or a platinum agent.
  • the PARP inhibitor in the pharmaceutical composition is olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib (BGB-290),
  • Iniparib (BSI 201), CEP 9722, E7449, AG-14361, INO-1001, A-966492, PJ34 HCI, UPF 1069, AZD2461, ME0328, BGP-15 2HCI, Niraparib tosylate, NU1025, NVP-TNKS 656, NMS-P118, benzamide or picolinamide, or a pharmaceutically acceptable salt, acid or derivative thereof.
  • the PARP inhibitor is olaparib.
  • the platinum agent in the pharmaceutical composition is carboplatin, cis-platin, oxaliplatin, lobaplatin, enloplatin or miboplatin, or a pharmaceutically acceptable salt, acid or derivative thereof.
  • the platinum agent is carboplatin.
  • the platinum agent is cis-platin.
  • the chemotherapeutic agent in the pharmaceutical composition is docetaxel, albumin bound paclitaxel, altretamine, capecitabine, cyclophosphamide, dactinomycin, etoposide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, pemetrexed, topotecan, vinblastine, vincristine or vinorelbine, or a pharmaceutically acceptable salt, acid or derivative thereof.
  • the anti-cancer agent in the pharmaceutical composition is an anti-hormonal agent.
  • the anti-hormonal agent may be anti-estrogen or selective estrogen receptor modulator such as tamoxifen, raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene; an aromatase inhibitor such as letrozole, anastrozole, and exemestane; a luteinizing-hormone- releasing hormone (LHRH) agonist such as goserelin, leuprolide and triptorelin; or an anti androgen such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; or a pharmaceutically acceptable salt, acid or derivative thereof.
  • selective estrogen receptor modulator such as tamoxifen, raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene,
  • the anti-cancer agent in the pharmaceutical composition is a therapeutic antibody.
  • the therapeutic antibody may be 3F8, abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, drozitumab, duligotumab, dusigitumab,
  • the anti-cancer agent in the pharmaceutical composition is an angiogenesis inhibitor.
  • the angiogenesis inhibitor may be axitinib, bevacizumab, cabozantinib, everolimus, lenalidomide, lenvatinib mesylate, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, thalidomide, vandetanib, or ziv-aflibercept, or a pharmaceutically acceptable salt, acid or derivative thereof.
  • the pharmaceutical composition of the present disclosure may be prepared in a suitable dosage form, including, but not limited to, tablets, capsules (e.g., soft elastic gelatin capsules), caplets, troches, lozenges, dispersions, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters, solutions, elixirs, cachets, aerosols (e.g., nasal sprays or inhalers), gels, and patches.
  • a suitable dosage form including, but not limited to, tablets, capsules (e.g., soft elastic gelatin capsules), caplets, troches, lozenges, dispersions, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emul
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • the carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions.
  • the carrier can be a solid dosage form carrier, including but not limited to one or more of a binder (for compressed pills), a glidant, an encapsulating agent, a flavorant, and a colorant. Suitable pharmaceutical carriers described in “Remington’s Pharmaceutical Sciences” by E.W. Martin are also contemplated by the present disclosure.
  • the pharmaceutical composition is formulated into an oral dosage form.
  • Suitable oral dosage forms include but are not limited to dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups) and the like.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations.
  • carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations.
  • KRAS-variant ovarian cancer cells were screened against the Enzo FDA and NCI Oncology libraries at the Yale Center for Molecular Discovery. As predicted, cells harboring the KRAS-variant were significantly more resistant to platinum drugs than isogenic controls not having this variant. However, KRAS-variant ovarian cancer cells were highly sensitive to sibutramine, a drug previously approved by the FDA to promote weight loss.
  • a follow-up clonogenic survival assay was performed wherein the SKOV3 ovarian cancer cells and isogenic cells harboring the KRAS-variant (22-3 cells) were incubated with an increasing concentration of sibutramine (0- 200mM) and measured for percent survival at the end of the experiment.
  • the clonogenic survival assay was conducted by plating SKOV3 and 22-3 cells at various densities, treating with various concentrations of sibutramine, removing the sibutramine after 2 days, and replacing with cell growth medium. Colonies were then allowed to form for 12-14 days, stained with crystal violet, and counted. The results are shown in FIG. 2. The data provide strong evidence that 22-3 cells harboring the KRAS-variant exhibit significantly greater sensitivity to sibutramine than parental isogenic controls.
  • sibutramine The effects of sibutramine were also examined in a tumor xenograft study.
  • 5 x 10 6 cells were implanted subcutaneously into athymic nude mice, allowed to grow to 100mm 3 , and treated intraperitoneally with 30 mg/kg of sibutramine daily for 6 weeks. Tumor size and body weight of mice were measured.
  • Sibutramine treatment had no effect on the growth of the SKOV3 xenograft with wild type KRAS (FIG. 3A).
  • sibutramine treatment resulted in considerable suppression of tumor growth of the 22-3 xenograft harboring the KRAS-variant (FIG. 3B).
  • EXAMPLE 2 Evaluation of sibutramine alone and in combination with platinum and PARP inhibitor therapies in KRAS-variant ovarian cancer cells and xenografts in mice
  • Sibutramine is tested for synergistic, additive, or antagonistic effects for the combination of either carboplatin, paclitaxel, or olaparib and sibutramine, based on the median effect principle (MEP) of Chou and Talaly (10, 11). These experiments are first performed in multi-well plates in which both the anti-neoplastic drug concentrations and sibutramine concentrations are varied to provide the data set needed to query for synergism. Cell responses to the drugs are measured by quantifying cell proliferation in a microplate format, using the Cytation 3 Imaging Reader (BioTek, Inc.), which can perform live cell, automated fluorescence microscopy in 96- and 384-well microplates.
  • MEP median effect principle
  • the imaging compartment is temperature- and CC regulated for live cell imaging.
  • the Cytation 3 has built-in spot recognition software for automatic cell counting, using a process referred to as cell segmentation (28, 29).
  • the viable nuclear dye, Hoechst 33342 (H33342) is used in these experiments (30).
  • This approach facilitates accurate cell enumeration by the Cytation 3 spot recognition algorithms, especially at high cell densities (28, 29).
  • This approach is chosen because it can be readily applied to a wide range of diverse cell lines, without the requirement for extensive optimization initially for each cell line, and does not rely on cellular metabolism as with other types of assays including cell titer glo and MTT.
  • Cell numbers can be measured in a robust and highly reproducible manner, at multiple time-points and cell seeding densities for the SKOV and SKOV 22-3 cells and a variety of other cell lines.
  • Clonogenic assays are then performed with combinations in which synergism is observed. The most successful therapeutic combinations for studies are then evaluated in vivo.
  • a second isogenic pair of ovarian cancer cell lines IGROV1-KRAS-variant and IGROV1-wild type (WT) having or not having the KRAS variant, respectively, are utilized.
  • Methods of CRISPR-based single base editing are used to “mutate” the single point mutation in the KRAS 3’UTR (G) of IGROV1 cells back to the wild-type base (T) to generate an isogenic cell line not harboring the KRAS variant.
  • Clonal cells that are confirmed to have the wild-type base are used as controls in experiments to determine if sibutramine preferentially kills KRAS variant IGROV1 cells, using methods described for SKOV cells. After confirming KRAS variant IGROV1 cells are sensitive to sibutramine, experiments are performed to determine if specific drug combinations (i.e. , carboplatin, paclitaxel, or olaparib and sibutramine) act in a synergistic manner, using the IGROV1 KRAS variant cells and the isogenic controls. In the event that CRISPR-based methods are unsuccessful to engineer the “WT” 3’UTR in IGROV1 cells, zinc finger technology is utilized.
  • the effect of single agent sibutramine treatment is further examined in SKOV3 and IGROV1 cells.
  • the dose of sibutramine is varied using the SKOV and SKOV22-3 cells carrying the KRAS variant to determine the minimum effective dose.
  • the cell lines are luciferized using well-established methods (for example see Drapkin (12)). Once stable cell lines express the fluorescent marker, the clonogenic survival assays are performed to confirm that the KRAS variant cells exhibit significantly greater cytotoxicity to sibutramine versus isogenic controls lacking the KRAS variant. An orthotopic model is then employed to assess sibutramine efficacy.
  • Tumor bioluminescence among the various groups is compared using analysis of variance (ANOVA) as described (12,14) to determine if sibutramine induces significantly greater tumor growth delay in KRAS variant versus isogenic control xenografts. Tumor growth is monitored for up to 150 days unless mice exhibit symptoms of being moribund or have weight gain in excess of 30% of body weight due to tumor growth.
  • ANOVA analysis of variance
  • This experiment consists of eight groups of 20 mice each: (1) mock treated control; (2) 7.5 mg/kg sibutramine- treated control; (3) 15 mg/kg sibutramine-treated control; (4) 30 mg/kg sibutramine-treated control; (5) mock-treated KRAS variant tumors; (6) 7.5 mg/kg sibutramine-treated KRAS variant tumors; (7) 15 mg/kg sibutramine-treated KRAS variant tumors; and (8) 30 mg/kg sibutramine-treated KRAS variant tumors. Twenty mice per experimental group have the power of 80% to detect a difference of 1.25 standard deviations between two groups at 5% significance level. Treatment is administered intraperitoneally as described in Example 1.
  • Tumors are also paraffin-embedded and sectioned for H&E staining and immunohistochemistry staining with anti-Ki-67 antibodies for impaired cell proliferation.
  • the minimum dose of sibutramine needed to impart tumor growth delay is determined from the studies.
  • mice Eight groups of 20 mice each are used in these experiments: (1) mock treated control; (2) sibutramine-treated control at a dose of 50% TGD; (3) sibutramine-treated control at a dose of 50% TGD plus either carboplatin, paclitaxel or olaparib; (4) control with either carboplatin, paclitaxel, or olaparib; groups 5-8 are with KRAS variant cells but with drugs as described for control tumors.
  • mice receive intraperitoneal injection once daily with sibutramine (50% tumor inhibitory dose/kg), olaparib (50 mg/kg), or intravenous injection of taxol (20 mg/kg) as described (15), or once intraperitoneal injection bi-weekly with carboplatin (25 mg/kg) for a 6-week period.
  • Tumor size and body weight, and analysis are performed as described in the experiments with sibutramine alone treatment.
  • the response of the tumors to the combination treatment is then determined.
  • the assays with xenografts as described in Example 1 are performed in the event that the ovarian orthotopic mouse model does not work well.
  • Adverse results for the mice with the combination studies are not anticipated, given that sibutramine is well-tolerated. However, if adverse effects are observed, the experiments with lower doses of the chemotherapy agents based on pilot studies are performed.
  • PDX patient-derived xenograft
  • Sibutramine is a racemic mixture (RS) containing two equal forms of the R and S enantiomers.
  • RS racemic mixture
  • both enantiomers of sibutramine are separated and their relative efficacy against the isogenic KRAS-variant 22-3 and SKOV parental ovarian cancer cells is determined as described in Example 2.
  • the ovarian orthotopic tumor assay is used with the same cells as described in Example 2 but with three different doses of the enantiomer that are determined in the cell survival assays. This constitutes a first step in target investigation.
  • the separation of the enantiomers of sibutramine, as well as its metabolites, is performed by chiral stationary phase chromatography as described in (17). The assignment of absolute conformations is known.
  • both metabolites of sibutramine i.e., desmethylsibutramine (M1) and didesmethylsibutramine (M2), are prepared to determine if these have any efficacy in the cellular and animal models described in Example 2.
  • the chemical structures of sibutramine, desmethylsibutramine and didesmethylsibutramine are shown in FIGs. 5A-5C, respectively.
  • the pure enantiomer metabolites of M1 and M2 are prepared via a racemic synthesis and a chiral separation is conducted. Alternatively, a chiral synthesis is conducted in the event that chiral separation cannot be satisfactorily achieved. Demonstration of differentiation of enantiomers helps determine the structure-activity relationship and allows for the development of more potent compounds for use in animal models and ultimately humans.
  • sibutramine is tested to see if it induces upregulation of the let-7 family of miRNAs, resulting in suppression of KRAS. It is hypothesized that sibutramine may target a protein or proteins that function to degrade let-7 miRNAs, resulting in their upregulation and suppression of expression of their target genes, including KRAS.
  • the levels of the mature let-7a, let-7b, let-7d, and let-7g along with mRNA levels of KRAS are quantified in SKOV WT and SKOV 22-3 KRAS variant ovarian cancer cells that are treated or not with the active compound of sibutramine using the miScript PCR system. This is performed as a function of time after treatment with sibutramine with a range of doses between 10-100 mM for 24 hours and harvested and analyzed at various intervals between 1-24 hours. Similar experiments are performed with the active R or S- metabolites purified and identified in Example 3. The basal levels of let-7 miRNAs may be lower in KRAS variant versus control cells, given previous results in lung tumor cells (2).
  • any increase in the levels of let-7 miRNAs and any decrease in KRAS mRNA, after treatment with sibutramine in KRAS variant versus control cells, might indicate that sibutramine (or its active compound) is targeting some aspect of miRNA processing.
  • the luciferase reporter constructs are used with and without the 3’UTR mutation, as described (2), to confirm that treatment with sibutramine results in upregulation (less degradation) of the let-7 miRNAs, resulting in suppression of KRAS expression.
  • let-7 miRNAs are overexpressed, one at a time, in KRAS variant and control ovarian cancer cell lines to determine if this leads to a greater change in resistance of KRAS variant versus control cells to sibutramine as well as downregulation of KRAS expression using the luc-reporters.
  • sibutramine might be targeting a transcription factor or otherwise preventing the miRNA processing machinery from degrading let-7 miRNAs.
  • concentrations of sibutramine and times of treatment or harvesting are varied based upon initial results.
  • Sibutramine-targeted genes are identified as follows. It has been suggested that KRAS gene expression is upregulated in KRAS variant cells. This was originally based on analysis of expression of a luciferase (luc) reporter linked to the 3’UTR of KRAS (2). Specifically, introduction of the luc reporter with the KRAS variant 3’UTR into A549 cells, which express let-7 miRNAs, resulted in a significant increase in the level of luc compared to a WT control. Upregulation of KRAS expression has also been detected by qRT- PCR in the endometria of women and in lung tissues harboring the KRAS variant versus controls (2, 37).
  • luc luciferase
  • fluoxetine Prozac
  • SSRI selective serotonin reuptake inhibitor
  • PDAC pancreatic ductal adenocarcinoma
  • Fluoxetine also reduces proliferation of pancreatic cancer cells by reducing intracellular 5-HT (serotonin) concentrations (41), via inhibition of the serotonin transporter SERT. Because 5-HT can bind to Rac and reduce GTP hydrolysis so as to prolong its activation, inhibition of transport into cells could result in reduced levels of 5-HT, less Rac activation, and fewer proliferation signals (41), especially in cells overexpressing KRAS protein.
  • sibutramine is a weak SSRI
  • an additional experiment can be performed to determine if SERT is expressed in the KRAS variant and isogenic control cell lines (including at least SKOV 3 and SKOV22-3), using quantitative western blotting.
  • SERT may be predominantly expressed in KRAS variant versus isogenic controls, or SERT may be expressed in both cell types.
  • a determination as to whether sibutramine and related compounds inhibit 5-HT uptake is made using the neurotransmitter transport uptake assay, which is adaptable to other types of cell lines (Molecular Devices). Specifically, this assay monitors transport using fluorescent dyes with the fluorescence detected using a plate reader. Decreased intracellular fluorescence may be observed in the presence of sibutramine if sibutramine acts to inhibit SERT in KRAS variant cells.
  • SERT is not expressed in KRAS variant cell lines, it is important to note that 5-HT can also be produced in cells and that extracellular 5-HT in serum can bind to serotonin receptors on the cellular membrane to activate Ras signaling (see for example (42)). Therefore if SERT is not expressed the KRAS variant cells, a determination is made as to whether cell survival is dependent upon intracellular synthesis of 5-HT or transport of 5-HT into cells via receptors. To follow up on intracellular synthesis, expression of Tryptophan hydroxylase 1 (TPH1) in cells is assayed using qRT-PCR (41). Also assayed is whether TPH1 downregulation via an inducible shRNA system, such as TRIPZ, leads to decreased proliferation of the KRAS variant cells (42).
  • TPH1 Tryptophan hydroxylase 1
  • Assays are also performed to determine which receptors are present in the KRAS variant cells, and whether their downregulation results in decreased proliferation of the KRAS variant cells. If downregulation of either TPH1 or one or more 5-HT receptors results in decreased proliferation of KRAS variant versus control cells, treatment of the downregulated KRAS variant cells (either TPH1 or receptor(s)) with sibutramine would have no effect, and thus be informative of the target. For example, if downregulation of TPH 1 leads to preferential decreased proliferation of KRAS variant cells, treatment with sibutramine would not lead to further reductions in proliferation if TPH1 was a direct or indirect target of the drug. While TPH1 and/or receptors might not be the target given what is known about sibutramine, these experiments would be performed if SERT is not expressed in the cells.
  • Sibutramine is tested for its effect in cancer cells other than ovarian cancer.
  • Isogenic pairs of a glioma cancer cell line (U251), a prostate cancer cell line and a breast cancer cell line (MCF7) that have or do not have the KRAS variant are engineered similarly as described for IGROV1 cells.
  • the isogenic pairs are utilized in cell survival assays to determine if the KRAS variant cancer cells are more sensitive to sibutramine treatment.
  • Sibutramine in combination with other appropriate chemotherapies are also evaluated in the isogenic pairs of a glioma cancer cell line, a prostate cancer cell line and a breast cancer cell line that have or do not have the KRAS variant.
  • sibutramine in combination with an alkylator such as temozolomide is tested.
  • sibutramine in combination with cisplatin, PARP inhibitor, or paclitaxel, and additionally doxorubicin and/or gemcitabine is tested. The most successful therapeutic combinations for studies are then evaluated in vivo.
  • SERT serotonin transporter
  • XRN2 nuclease There are two possible targets of sibutramine: the serotonin transporter (SERT) and the XRN2 nuclease.
  • SERT serotonin transporter
  • XRN2 nuclease The crystal structures exist for both SERT (PDB: 5I6X) and XRN2 from C. elegans (PDB: 5FIR), as shown in FIGs. 4A and 4B, respectively.
  • the crystal structure of SERT is at 3.15 Angstroms and the crystal structure of XRN2 is at 2.84 Angstroms.
  • Predictive algorithms are run on the high-resolution structures to suggest the number and quality of potential binding sites and assess the extent to which the proteins can be targeted by a drug. Information of the binding sites is used to design or modify candidate compounds with improved efficacy.
  • MCF-7 cells and ZR-75-1 cells were cultured to the logarithmic growth phase with RPMI 1640 medium, digested with trypsin, and then centrifuged at 1000 rpm for 5 minutes to collect the cells. The supernatant was discarded and appropriate amount of medium was added to resuspend the cells. 90 pL of cell suspension was added to each well of a 96-well plate, with a final cell density of 1000-6000 cells/well.
  • the TO plate (i.e. , the control plate) was subject to a condition of 37°C, 5% CO2, and 95% humidity. On the next day, the chemiluminescence of the TO plate was read as the background value. 10 pL of solvent-containing medium was added to each well for CTG analysis: the CTG reagent was thawed and the cell plate was equilibrated to room temperature for 30 minutes; 50 pl_ of CTG solution was added to each well; the plate was incubated on an orbital shaker for 2 minutes to lyse the cells; the cell plate was allowed to sit at room temperature for 10 minutes to stabilize the luminescence signal; and EnVision (2104 Multilabel Reader, PerkinElmer) was used to read the luminescence value. On the same day, the drugs were added, and cisplatin was added as the positive control drug.
  • concentration drugs were prepared as 10xFE, 10xSE, 10xP, and 10xCisP according to Table 1.
  • 10 mI_ of 10x drug solution was added to the 90 mI_ of cell suspension in each well (a triplicate of wells were allocated for each drug concentration) for a final concentration of 1x, and totally 9 different concentrations were used.
  • the cells were cultured under a condition of 37°C and 5% CO2.
  • the chemiluminescence of the plate was read: the CTG (cell-titer glo) reagent was thawed and the cell plate was equilibrated to room temperature for 30 minutes; 50 mI_ CTG solution was added to each well; the plate was vibrated on an orbital shaker for 2 minutes to lyse the cells; the plate was allowed to sit at room temperature for 10 minutes to stabilize the luminescence signal; and EnVision (2104 Multilabel Reader, PerkinElmer) was used to read the luminescence value.
  • CTG cell-titer glo
  • the cell viability formula is as follows:
  • Vsample is the chemiluminescence of the drug treatment group
  • Vvehicle control is the average value for the solvent control group.
  • FIGs. 6A and 6B Graphs showing the inhibitory effects of fluoxetine (FE), sibutramine (SE), cisplatin (CisP), and paclitaxel (P) on the proliferation of MCF-7 cells, with cisplatin (CisP) and paclitaxel (P) used as the positive control, are displayed in FIGs. 6A and 6B. Inhibitory effects of FE, SE, CisP and P drugs on the proliferation of breast cancer cell line ZR-75-1
  • the cell viability formula is as follows:
  • Vsample is the chemiluminescence of the drug treatment group
  • Vvehicle control is the average value for the solvent control group.
  • FIGs. 7A-7B Graphs showing the inhibitory effects of fluoxetine (FE), sibutramine (SE), cisplatin (CisP), and paclitaxel (P) on the proliferation of ZR-75-1 cells, with cisplatin (CisP) and paclitaxel (P) used as the positive control are shown in FIGs. 7A-7B.
  • G.G. Glasspool, R., Glendon, G., Godwin, A.K., Goodman, M.T., Gore, M., Greene, M.H., Grip, M., Gronwald, J., Gschwantler Kaulich, D., Guenel, P., Guzman, S.R., Haeberle, L., Haiman, C.A., Hall, P., Halverson, S.L., Hamann, U., Hansen, T.V.O., Harter, P., Hartikainen, J.M., Healey, S., Hebon, Hein, A., Heitz, F., Henderson, B.E., Herzog, J., MA, T.H., Hogdall,
  • Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts.

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Abstract

L'invention concerne une méthode de traitement d'un cancer ayant un variant KRAS chez un sujet, dans laquelle une quantité efficace d'un ou de plusieurs inhibiteurs d'absorption de la sérotonine est administrée au sujet. Un exemple d'inhibiteur d'absorption de la sérotonine est la sibutramine. L'inhibiteur d'absorption de la sérotonine peut être administré seul ou en combinaison avec un ou plusieurs agents anticancéreux. L'invention concerne également une composition pharmaceutique comprenant un inhibiteur d'absorption de la sérotonine et un ou plusieurs agents anticancéreux.
PCT/US2021/032715 2020-05-18 2021-05-17 Traitement de cancers à variant kras avec des inhibiteurs d'absorption de la sérotonine WO2021236498A1 (fr)

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