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WO2025175564A1 - Méthode de traitement du cancer dépendant de l'autophagie avec un agent de dégradation de pikfyve - Google Patents

Méthode de traitement du cancer dépendant de l'autophagie avec un agent de dégradation de pikfyve

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Publication number
WO2025175564A1
WO2025175564A1 PCT/CN2024/078381 CN2024078381W WO2025175564A1 WO 2025175564 A1 WO2025175564 A1 WO 2025175564A1 CN 2024078381 W CN2024078381 W CN 2024078381W WO 2025175564 A1 WO2025175564 A1 WO 2025175564A1
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WO
WIPO (PCT)
Prior art keywords
subject
pikfyve
mutation
kras
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/078381
Other languages
English (en)
Inventor
Zhen Wang
Chengun LI
Ke Ding
Caleb CHENG
Yuanyuan QIAO
Costas LYSSIOTIS
Arul M. Chinnaiyan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
University of Michigan System
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
University of Michigan System
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS, University of Michigan System filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to PCT/CN2024/078381 priority Critical patent/WO2025175564A1/fr
Publication of WO2025175564A1 publication Critical patent/WO2025175564A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • This disclosure provides methods for treating autophagy dependent cancers.
  • methods for treating neuroendocrine prostate cancer (NEPC) , pancreatic ductal adenocarcinoma (PDAC) , pancreatic neuroendocrine tumors (PNETs) , and pancreatic neuroendocrine carcinomas (NECs) comprising administering a therapeutic agent, e.g., PIK5-12D or LCG-33, that inhibits PIKfyve.
  • a therapeutic agent e.g., PIK5-12D or LCG-33
  • Autophagy is an evolutionarily conserved, ordered pathway of degradation of intracellular materials required to sustain cellular homeostasis. Klionsky et al., Embo j. 2021; 40 (19) : e108863. Autophagy is often exacerbated under stress conditions like nutrient deprivation, protein aggregation, organelle senescence, and hypoxia that commonly occur in different types of cancers, thereby creating a potential therapeutic vulnerability to autophagy inhibitors in certain contexts. Poillet-Perez et al., Nature. 2018; 563 (7732) : 569-73; Nguyen et al., Oncogene. 2014; 33 (36) : 4521-30; Yang et al., Genes Dev. 2011; 25 (7) : 717-29; Russell et al., Embo j. 2022; 41 (13) : e110031; Levy et al., Nat Rev Cancer. 2017; 17 (9) : 528-42.
  • a simplified overview of the autophagy pathway involves formation of double-membraned autophagosomes that encapsulate cytoplasmic material targeted for degradation, followed by fusion of autophagosomes with lysosomes, which contain enzymes that degrade the encapsulated contents so that nutrients and metabolites can be recycled back into the cytoplasm.
  • TRPML1 a key player in lysosomal trafficking, is a cation channel on the lysosomal membrane that releases Ca2 + from the lumen into the cytosol in response to trafficking cues, such as changes in levels of the phosphoinositide PI (3, 5) P2, Dong et al., Nature Communications. 2010; 1, to increase lysosome proteolytic activity and clearance of lysosomal storage.
  • trafficking cues such as changes in levels of the phosphoinositide PI (3, 5) P2, Dong et al., Nature Communications. 2010; 1, to increase lysosome proteolytic activity and clearance of lysosomal storage.
  • PIKfyve FYVE finger-containing phosphatidylinositol-3-phosphate 5-kinase
  • PIKfyve is a lipid kinase located on endosomal membranes and is the sole enzyme responsible for phosphorylating PI3P to generate PI (3, 5) P2.
  • Direct inhibition of PIKfyve results in lysosome enlargement and inhibition of autophagic flux, Choy et al., J Cell Sci. 2018; 131 (10) .; Gayle et al., Blood.
  • the present disclosure provides methods of treating prostate cancer or pancreatic cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of PIK5-12D
  • the present disclosure provides methods of treating prostate cancer or pancreatic cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of PIK5-12D or LCG-33 in combination with a therapeutically effective amount or a KRAS-MAPK inhibitor.
  • the prostate cancer is NEPC.
  • the pancreatic cancer is PDAC, PNETs, or NECs.
  • the prostate cancer or pancreatic cancer is characterized as having a KRAS mutation and/or a Trp53 mutation.
  • the present disclosure provides a method of treating a subject having NEPC, PDAC, PNETs, or NECs the method comprising:
  • the present disclosure provides a method, comprising administering a therapeutically effective amount of PIK5-12D or LCG-33 to a subject in need thereof, wherein:
  • the subject has NEPC, PDAC, PNETs, or NECs;
  • the PDAC, PNETs, or NECs is characterized as having a KRAS mutation and/or a Trp53 mutation.
  • the present disclosure provides a method of identifying whether a subject having NEPC, PDAC, PNETs, or NECs as a candidate for treatment with PIK5-12D or LCG-33, the method comprising:
  • the present disclosure provides a method of predicting treatment outcome in a subject having NEPC, PDAC, PNETs, or NECs, the method comprising determining whether a KRAS mutation and/or a Trp53 mutation is present or absent in a biological sample taken from the subject, wherein:
  • FIG. 1 Pikfyve is essential for progression of precursor PanIN lesions to PDAC.
  • the KPC Pikfyve +/+ scores used as a reference are the same as those used in Fig. 1A.
  • the two cohorts were stained and analyzed in the same batch. (Multiple unpaired two-tailed t-test)
  • PIKfyve is essential for progression of precursor PanIN lesions to PDAC.
  • Fig. 3 Genetic or pharmacological perturbation of PIKfyve disrupts autophagic flux and induces vacuolization in PDAC cells.
  • Figure 4 PIKfyve inhibition obligates PDAC cells to stimulate a lipogenic transcriptional and metabolic program.
  • Fig. 6 Metabolic CRISPR screen nominates the de novo fatty acid synthesis pathway as synthetically critical upon PIKfyve inhibition.
  • ROC Receiver operator characteristic
  • Fig. 7 KRAS-MAPK perturbation downregulates lipogenic transcriptional program and induces autophagic flux in direct opposition to PIKfyve inhibition’s effects.
  • C Counts per million (CPM) from RNA-seq analysis on AsPC1 cells treated with MRTX1133 (100 nM) for 24 hours. Data plotted are biological triplicates from publicly available RNA-seq data 44 . (Unpaired two-tailed t-test)
  • PIKfyve a lipid kinase integral to lysosomal functioning
  • PDAC lipid kinase inhibitor
  • PIKfyve inhibition obligates PDAC to upregulate de novo lipid synthesis.
  • PIKfyve inhibition triggers a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, including genes such as FASN and ACACA.
  • the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels.
  • the present disclosure provides methods of treating prostate cancer or pancreatic cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of PIK5-12D or LCG-33.
  • the present disclosure provides methods of treating prostate cancer or pancreatic cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a PIKfyve inhibitor, e.g., PIK5-12D or LCG-33, in combination with a therapeutically effective amount of a KRAS-MAPK inhibitor.
  • a PIKfyve inhibitor e.g., PIK5-12D or LCG-33
  • KRAS-MAPK inhibitors include AMG510 (Sotorasib) , MRTX849 (Adagrasib) , and MRTX-1133.
  • the prostate cancer is NEPC.
  • the pancreatic cancer is PDAC, PNETs, or NECs.
  • the prostate cancer or pancreatic cancer is characterized as having a KRAS mutation and/or a Trp53 mutation.
  • one or more anticancer agents are administered to the subject in combination, i.e., co-administered, with PIK5-12D or LCG-33.
  • the anticancer agent is one or more of a chemotherapeutic agent, an immune checkpoint inhibitor, e.g., pembrolizumab, nivolumab, cemipilimab, atezolizumab, avelumab, durvalumab, ipilimumab, or radiation therapy.
  • anticancer agents are contemplated for use in the methods of the present disclosure. Indeed, the present disclosure contemplates, but is not limited to, administration of numerous anticancer agents such as: agents that induce apoptosis; polynucleotides (e.g., anti-sense, ribozymes, siRNA) ; polypeptides (e.g., enzymes and antibodies) ; biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated with anticancer drugs, toxins, defensins) , toxins; radionuclides; biological response modifiers (e.g., interferons (e.g., IFN- ⁇ ) and interleukins (e.g., IL-2) ) ; adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-
  • anticancer agents comprise agents that induce or stimulate apoptosis.
  • Agents that induce apoptosis include, but are not limited to, radiation (e.g., X-rays, gamma rays, UV) ; tumor necrosis factor (TNF) -related factors (e.g., TNF family receptor proteins, TNF family ligands, TRAIL, antibodies to TRAIL-R1 or TRAIL-R2) ; kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitor, vascular growth factor receptor (VGFR) kinase inhibitor, fibroblast growth factor receptor (FGFR) kinase inhibitor, platelet-derived growth factor receptor (PDGFR) kinase inhibitor, and Bcr-Abl kinase inhibitors (such as GLEEVEC) ) ; antisense molecules; antibodies (e.g., HERCEPTIN, RITUXAN, ZEVALIN,
  • compositions and methods of the present disclosure provide PIK5-12D or LCG-33 and at least one anti-hyperproliferative or antineoplastic agent selected from alkylating agents, antimetabolites, and natural products, e.g., herbs and other plant and/or animal derived compounds.
  • Alkylating agents suitable for use in the present compositions and methods include, but are not limited to: 1) nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan (L-sarcolysin) ; and chlorambucil) ; 2) ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa) ; 3) alkyl sulfonates (e.g., busulfan) ; 4) nitrosoureas (e.g., carmustine (BCNU) ; lomustine (CCNU) ; semustine (methyl-CCNU) ; and streptozocin (streptozotocin) ) ; and 5) triazenes (e.g., dacarbazine (DTIC; dimethyltriazenoimid-azolecarboxamide) .
  • nitrogen mustards e.
  • antimetabolites suitable for use in the present compositions and methods include, but are not limited to: 1) folic acid analogs (e.g., methotrexate (amethopterin) ) ; 2) pyrimidine analogs (e.g., fluorouracil (5-fluorouracil; 5-FU) , floxuridine (fluorode-oxyuridine; FudR) , and cytarabine (cytosine arabinoside) ) ; and 3) purine analogs (e.g., mercaptopurine (6-mercaptopurine; 6-MP) , thioguanine (6-thioguanine; TG) , and pentostatin (2'-deoxycoformycin) ) .
  • folic acid analogs e.g., methotrexate (amethopterin)
  • pyrimidine analogs e.g., fluorouracil (5-fluorouracil; 5-FU) , floxuridine (flu
  • chemotherapeutic agents suitable for use in the compositions and methods of the present disclosure include, but are not limited to: 1) vinca alkaloids (e.g., vinblastine (VLB) , vincristine) ; 2) epipodophyllotoxins (e.g., etoposide and teniposide) ; 3) antibiotics (e.g., dactinomycin (actinomycin D) , daunorubicin (daunomycin; rubidomycin) , doxorubicin, bleomycin, plicamycin (mithramycin) , and mitomycin (mitomycin C) ) ; 4) enzymes (e.g., L-asparaginase) ; 5) biological response modifiers (e.g., interferon-alfa) ; 6) platinum coordinating complexes (e.g., cisplatin (cis-DDP) and carboplatin) ; 7) anthrofiben
  • any oncolytic agent that is routinely used in a cancer therapy context finds use in the compositions and methods of the present disclosure.
  • the U.S. Food and Drug Administration maintains a formulary of oncolytic agents approved for use in the United States.
  • International counterpart agencies to the U.S.F.D.A. maintain similar formularies.
  • Table 1 provides a list of exemplary antineoplastic agents approved for use in the U.S. Those skilled in the art will appreciate that the "product labels" required on all U.S. approved chemotherapeutics describe approved indications, dosing information, toxicity data, and the like, for the exemplary agents.
  • Anticancer agents further include compounds which have been identified to have anticancer activity. Examples include, but are not limited to, 3-AP, 12-O-tetradecanoylphorbol-13-acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT-751, ADI-PEG 20, AE-941, AG-013736, AGRO100, alanosine, AMG 706, antibody G250, antineoplastons, AP23573, apaziquone, APC8015, atiprimod, ATN-161, atrasenten, azacitidine, BB-10901, BCX-1777, bevacizumab, BG00001, bicalutamide, BMS 247550, bortezomib, bryostatin-1, buserelin, calcitriol, CCI-779, CDB-2914, cefixime, cetuximab, CG0070, cilengitide, clofarabine, combretastatin
  • anticancer agents and other therapeutic agents those skilled in the art are referred to any number of instructive manuals including, but not limited to, the Physician's Desk Reference and to Goodman and Gilman's "Pharmaceutical Basis of Therapeutics" tenth edition, Eds. Hardman et al., 2002.
  • the present disclosure provides methods for administering the PIK5-12D or LCG-33 with radiation therapy.
  • the disclosure is not limited by the types, amounts, or delivery and administration systems used to deliver the therapeutic dose of radiation to the subject.
  • the subject may receive photon radiotherapy, particle beam radiation therapy, other types of radiotherapies, and combinations thereof.
  • the radiation is delivered to the subject using a linear accelerator.
  • the radiation is delivered using a gamma knife.
  • the source of radiation can be external or internal to the subject.
  • External radiation therapy is most common and involves directing a beam of high-energy radiation to a tumor site through the skin using, for instance, a linear accelerator. While the beam of radiation is localized to the tumor site, it is nearly impossible to avoid exposure of normal, healthy tissue. However, external radiation is usually well tolerated by subjects.
  • Internal radiation therapy involves implanting a radiation-emitting source, such as beads, wires, pellets, capsules, particles, and the like, inside the body at or near the tumor site including the use of delivery systems that specifically target cancer cells, e.g., using particles attached to cancer cell binding ligands. Such implants can be removed following treatment, or left in the body inactive.
  • Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial irradiation, intracavity irradiation, radioimmunotherapy, and the like.
  • the subject may optionally receive radiosensitizers (e.g., metronidazole, misonidazole, intra-arterial Budr, intravenous iododeoxyuridine (IudR) , nitroimidazole, 5-substituted-4-nitroimidazoles, 2H-isoindolediones, [ [ (2-bromoethyl) -amino] methyl] -nitro-1H-imidazole-1-ethanol, nitroaniline derivatives, DNA-affinic hypoxia selective cytotoxins, halogenated DNA ligand, 1, 2, 4 benzotriazine oxides, 2-nitroimidazole derivatives, fluorine-containing nitroazole derivatives, benzamide, nicotinamide, acridine-intercalator, 5-thiotretrazole derivative, 3-nitro-1, 2, 4-triazole, 4, 5-dinitroimidazole derivative, hydroxylated texaphrins,
  • Radiotherapy any type of radiation can be administered to an subject, so long as the dose of radiation is tolerated by the subject without unacceptable negative side-effects.
  • Suitable types of radiotherapy include, for example, ionizing (electromagnetic) radiotherapy, e.g., X-rays or gamma rays, or particle beam radiation therapy, e.g., high linear energy radiation.
  • Ionizing radiation is defined as radiation comprising particles or photons that have sufficient energy to produce ionization, i.e., gain or loss of electrons (as described in, for example, U.S. 5,770,581 incorporated herein by reference in its entirety) .
  • the effects of radiation can be at least partially controlled by the clinician.
  • the dose of radiation is fractionated for maximal target cell exposure and reduced toxicity.
  • the total dose of radiation administered to s subject is about 0.01 Gray (Gy) to about 100 Gy.
  • about 10 Gy to about 65 Gy e.g., about 15 Gy, 20 Gy, 25 Gy, 30 Gy, 35 Gy, 40 Gy, 45 Gy, 50 Gy, 55 Gy, or 60 Gy
  • a complete dose of radiation can be administered over the course of one day
  • the total dose is ideally fractionated and administered over several days.
  • radiotherapy is administered over the course of at least about 3 days, e.g., at least 5, 7, 10, 14, 17, 21, 25, 28, 32, 35, 38, 42, 46, 52, or 56 days (about 1-8 weeks) .
  • a daily dose of radiation will comprise approximately 1-5 Gy (e.g., about 1 Gy, 1.5 Gy, 1.8 Gy, 2 Gy, 2.5 Gy, 2.8 Gy, 3 Gy, 3.2 Gy, 3.5 Gy, 3.8 Gy, 4 Gy, 4.2 Gy, or 4.5 Gy) , or 1-2 Gy (e.g., 1.5-2 Gy) .
  • the daily dose of radiation should be sufficient to induce destruction of the targeted cells.
  • radiation is not administered every day, thereby allowing the animal to rest and the effects of the therapy to be realized.
  • radiation desirably is administered on 5 consecutive days, and not administered on 2 days, for each week of treatment, thereby allowing 2 days of rest per week.
  • radiation can be administered 1 day/week, 2 days/week, 3 days/week, 4 days/week, 5 days/week, 6 days/week, or all 7 days/week, depending on the animal's responsiveness and any potential side effects.
  • Radiation therapy can be initiated at any time in the therapeutic period. In one embodiment, radiation is initiated in week 1 or week 2, and is administered for the remaining duration of the therapeutic period. For example, radiation is administered in weeks 1-6 or in weeks 2-6 of a therapeutic period comprising 6 weeks for treating, for instance, a solid tumor. Alternatively, radiation is administered in weeks 1-5 or weeks 2-5 of a therapeutic period comprising 5 weeks.
  • These exemplary radiotherapy administration schedules are not intended, however, to limit the present disclosure.
  • PIK5-12D or LCG-33 and one or more anticancer agents are administered to a subject under one or more of the following conditions: at different periodicities, at different durations, at different concentrations, by different administration routes, etc.
  • PIK5-12D or LCG-33 is administered prior to the anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks prior to the administration of anticancer agent.
  • PIK5-12D or LCG-33 is administered after the anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after the administration of the anticancer agent.
  • PIK5-12D or LCG-33 and the anticancer agent are administered concurrently but on different schedules, e.g., the compound is administered daily while the therapeutic or anticancer agent is administered once a week, once every two weeks, once every three weeks, or once every four weeks.
  • PIK5-12D or LCG-33 administered once a week while the anticancer agent is administered daily, once a week, once every two weeks, once every three weeks, or once every four weeks.
  • compositions within the scope of this disclosure include all compositions wherein PIK5-12D or LCG-33 is contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • PIK5-12D or LCG-33 may be administered to subjects, e.g., human cancer patients, orally at a dose of 0.0025 to 100 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for disorders responsive to induction of apoptosis.
  • PIK5-12D or LCG-33 is orally administered to treat, ameliorate, or prevent prostate cancer or pancreatic cancer, e.g., NEPC, PDAC, PNETs, or NECs.
  • the dose is generally about one-half of the oral dose.
  • a suitable intramuscular dose would be about 0.0025 to about 25 mg/kg, or from about 0.01 to about 5 mg/kg.
  • the unit oral dose may comprise from about 0.01 to about 1000 mg, for example, about 0.1 to about 100 mg of PIK5-12D or LCG-33.
  • the unit dose may be administered one or more times daily as one or more tablets or capsules each containing from about 0.1 to about 10 mg, conveniently about 0.25 to 50 mg of PIK5-12D or LCG-33.
  • PIK5-12D or LCG-33 may be present at a concentration of about 0.01 to 100 mg per gram of carrier. In a one embodiment, PIK5-12D or LCG-33 is present at a concentration of about 0.07-1.0 mg/ml, for example, about 0.1-0.5 mg/ml, and in one embodiment, about 0.4 mg/ml.
  • the PIK5-12D or LCG-33 may be administered as part of a pharmaceutical formulation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of PIK5-12D or LCG-33 into preparations which can be used pharmaceutically.
  • the preparations particularly those preparations which can be administered orally or topically and which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of PIK5-12D or LCG-33, together with the excipient.
  • compositions comprising PIK5-12D or LCG-33 may be administered to any subject which may experience the beneficial effects of PIK5-12D or LCG-33.
  • subjects are mammals, e.g., humans, although the disclosure is not intended to be so limited.
  • Other subjects include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like) .
  • PIK5-12D or LCG-33 and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions of the present disclosure are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining PIK5-12D or LCG-33 with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are in one embodiment dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • the topical compositions of this disclosure are formulated in one embodiment as oils, creams, lotions, ointments and the like by choice of appropriate carriers.
  • suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin) , branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12 ) .
  • the carriers may be those in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762; each herein incorporated by reference in its entirety.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool.
  • a vegetable oil such as almond oil
  • a typical example of such an ointment is one which includes about 30%almond oil and about 70%white soft paraffin by weight.
  • Lotions may be conveniently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.
  • present disclosure provides methods of treating a subject having cancer, e.g., prostate cancer and pancreatic cancer, e.g., PDAC, PNETs, or NECs, comprising (a) determining whether a biomarker is present or absent in a biological sample taken from the subject; and (b) administering a therapeutically effective amount of PIK5-12D or LCG-33 and, optionally, one or more additional anticancer agents to the subject if the biomarker is present in the biological sample.
  • cancer e.g., prostate cancer and pancreatic cancer, e.g., PDAC, PNETs, or NECs
  • Biomarkers include, but are not limited to, KRAS mutations and/or Trp53 mutations.
  • the biomarker is a KRAS mutation, which is differentially present in a subject of one phenotypic status, e.g., a subject having PDAC, as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having cancer without PDAC.
  • the biomarker is Kras G12D .
  • the biomarker is Kras G12C .
  • the biomarker is a Trp53 mutation, which is differentially present in a subject of one phenotypic status, e.g., a subject having PDAC, as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having cancer without PDAC.
  • the biomarker is Trp53 R172H .
  • Biomarker standards can be predetermined, determined concurrently, or determined after a biological sample is obtained from the subject.
  • Biomarker standards for use with the methods described herein can, for example, include data from samples from subjects without cancer; data from samples from subjects with cancer, e.g., prostate cancer, that is not metastatic; and data from samples from subjects with cancer, e.g., prostate cancer and pancreatic cancer, that is metastatic. Comparisons can be made to establish predetermined threshold biomarker standards for different classes of subjects, e.g., diseased vs. undiseased subjects. The standards can be run in the same assay or can be known standards from a previous assay.
  • biomarker is differentially present between different phenotypic status groups if the mean or median expression or mutation levels of the biomarker is calculated to be different, i.e., higher or lower, between the groups.
  • biomarkers provide an indication that a subject, e.g., a cancer patient, belongs to one phenotypic status or another.
  • the determination of the expression level or mutation status of a biomarker in a subject can be performed using any of the many methods known in the art. Any method known in the art for quantitating specific proteins and/or detecting a KRAS mutation, a Trp53 mutation, or the expression or mutation levels of any other biomarker in a subject or a biological sample may be used in the methods of the disclosure. Examples include, but are not limited to, PCR (polymerase chain reaction) , or RT-PCR, flow cytometry, Northern blot, Western blot, ELISA (enzyme linked immunosorbent assay) , RIA (radioimmunoassay) , gene chip analysis of RNA expression, immunohistochemistry or immunofluorescence.
  • Certain embodiments of the disclosure include methods wherein biomarker RNA expression (transcription) is determined. Other embodiments of the disclosure include methods wherein protein expression in the biological sample is determined.
  • a biological sample is obtained from the subject and the biological sample is assayed for determination of a biomarker expression or mutation status.
  • the present disclosure provides a method of treating a subject having NEPC, PDAC, PNETs, or NECs the method comprising:
  • the present disclosure provides a method, comprising administering a therapeutically effective amount of PIK5-12D or LCG-33 to a subject in need thereof, wherein:
  • the subject has NEPC, PDAC, PNETs, or NECs;
  • the PDAC, PNETs, or NECs is characterized as having a KRAS mutation and/or a Trp53 mutation.
  • the present disclosure provides a method of identifying whether a subject having NEPC, PDAC, PNETs, or NECs as a candidate for treatment with PIK5-12D or LCG-33, the method comprising:
  • the present disclosure provides a method of predicting treatment outcome in a subject having NEPC, PDAC, PNETs, or NECs, the method comprising determining whether a KRAS mutation and/or a Trp53 mutation is present or absent in a biological sample taken from the subject, wherein:
  • the KRAS mutation is Kras G12D .
  • the Trp53 mutation is Trp53 R172H .
  • the KRAS mutation is Kras G12C .
  • PKI5-12D refers to:
  • LCD-33 refers to:
  • anticancer agent refers to any therapeutic agent, e.g., chemotherapeutic compounds and/or molecular therapeutic compounds, antisense therapies, radiation therapies, or surgical interventions, used in the treatment of hyperproliferative diseases such as cancer, e.g., in mammals, e.g., in humans.
  • KRAS-MAPK inhibitor refers to a compound that inhibits KRAS and/or KRAS-mutant, e.g., G12C or G12D mutant, proteins.
  • KRAS-MAPK inhibitors are known in the art and include, but are not limited to, ARS-853, ARS-1620, AMG510 (Sotorasib) , MRTX849, (Adagrasib) , MRTX-EX185, MRTX-1133, ASP2453, RMC-6291, RMC-6236, RMC-036, RMC-037, BBO-8520, ERAS-3490, and JDQ443. See Tria et al., Cancers 15 (8) : 2375 (2023) ; https: //doi. org/10.3390/cancers15082375.
  • a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to result in amelioration of one or more symptoms of a disorder, or prevent advancement of a disorder, or cause regression of the disorder.
  • a therapeutically effective amount will refer to the amount of a therapeutic agent that decreases the rate of tumor growth, decreases tumor mass, decreases the number of metastases, increases time to tumor progression, or increases survival time by at least 1%, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
  • hyperproliferative disease refers to any condition in which a localized population of proliferating cells in an animal is not governed by the usual limitations of normal growth.
  • hyperproliferative disorders include tumors, neoplasms, lymphomas and the like.
  • a neoplasm is said to be benign if it does not undergo invasion or metastasis and malignant if it does either of these.
  • a "metastatic" cell means that the cell can invade and destroy neighboring body structures.
  • Hyperplasia is a form of cell proliferation involving an increase in cell number in a tissue or organ without significant alteration in structure or function.
  • Metaplasia is a form of controlled cell growth in which one type of fully differentiated cell substitutes for another type of differentiated cell.
  • neoplastic disease refers to any abnormal growth of cells being either benign (non-cancerous) or malignant (cancerous) .
  • normal cell refers to a cell that is not undergoing abnormal growth or division. Normal cells are non-cancerous and are not part of any hyperproliferative disease or disorder.
  • KRAS mutation refers to a mutated Kirsten rat sarcoma viral oncogene homologue (KRAS) oncogene. KRAS mutations are dominated by single-base missense mutations, 98%of which are found at codon 12 (G12) , codon 13 (G13) , or codon 61 (Q61) . See, e.g., Huang et al., Signal Transduction and Targeted Therapy 2021; 6: Article 386.
  • Trp53 mutation refers to a mutated transformation related protein 53 gene. This gene encodes tumor protein p53. Trp53 mutations have been shown to synergize with loss-of-function mutations in other tumor suppressor genes generally accelerating tumor development and progression. See, e.g., Hingorani et al., Cancer Cell 2002; 7 (5) 469-83.
  • treat, “treating, “ “treatment, “ and the like as used herein refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
  • the terms “treat, “ “treating, “ “treatment, “ and the like may include “prophylactic treatment, “ which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • the term “treat” and synonyms contemplate administering a therapeutically effective amount of PIK5-12D or LCG-33 to a subject in need of such treatment.
  • treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
  • the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
  • prevent refers to a decrease in the occurrence of pathological cells, e.g., hyperproliferative or neoplastic cells, in an subject.
  • the prevention may be complete, e.g., the total absence of pathological cells in a subject.
  • the prevention may also be partial, such that the occurrence of pathological cells in a subject is less than that which would have occurred without the present disclosure.
  • biological sample refers any tissue or fluid from a subject that is suitable for detecting a biomarker, e.g., KRAS mutation and/or a Trp53 mutation.
  • useful biological samples include, but are not limited to, biopsied tissues and/or cells, e.g., solid tumor, lymph gland, inflamed tissue, tissue and/or cells involved in a condition or disease, blood, plasma, serous fluid, cerebrospinal fluid, saliva, urine, lymph, cerebral spinal fluid, and the like.
  • Other suitable biological samples will be familiar to those of ordinary skill in the relevant arts.
  • a biological sample can be analyzed for genetic aberrations using any technique known in the art.
  • PIK5-12D or LCG-33 and one or more additional anticancer agents e.g., KRAS-MAPK inhibitors
  • the PIK5-12D or LCG-33 and one or more additional anticancer agents can be administered to the subject together, e.g., as part of a single pharmaceutical composition or formulation, or separately, e.g., as part of two or more separate pharmaceutical compositions or formulations.
  • PIK5-12D or LCG-33 and one or more additional anticancer agents administered to a subject at a different time, as well as administration concurrently, or in a substantially simultaneous manner.
  • Simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each of PIK5-12D or LCG-33 and the one or more additional anticancer agents or in multiple, single capsules, tablets, etc.
  • Sequential or substantially simultaneous administration of the PIK5-12D or LCG-33 and the one or more additional anticancer agents can be accomplished by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • PIK5-12D or LCG-33 and the one or more additional anticancer agents can be administered by the same route or by different routes.
  • an anticancer agent of the combination may be administered by intravenous injection while PIK5-12D or LCG-33 of the combination may be administered orally.
  • both PIK5-12D or LCG-33 and the one or more additional anticancer agents may be administered orally or both PIK5-12D or LCG-33 and the one or more additional anticancer agents may be administered by intravenous injection.
  • PIK5-12D or LCG-33 and one or more additional anticancer agents may also be administered in alternation.
  • PIK5-12D or LCG-33 and the one or more additional anticancer agents are administered to a subject separately, e.g., as part of two or more separate pharmaceutical compositions or formulations. The same principles apply when a PIK5-12D or LCG-33 and two or more anticancer agents are administered in combination to a subject.
  • PIK5-12D or LCG-33 is administered to a subject in combination with a KRAS-MAPK inhibitor.
  • Pikfve is dispensable for normal pancreas but is required for PDAC development
  • PDAC protein-derived neuropeptide
  • RNA-ISH with a probe targeting Pikfyve exon 6
  • Pikfyve expression was dramatically and consistently higher in lesion tissue compared to surrounding normal tissue in situ (Fig. 1A, B) .
  • PDAC may have an elevated utilization of PIKfyve-driven processes, relative to normal pancreatic tissue.
  • pancreata of a separate cohort of mice was evaluated and found that compared to pancreata of KC Pikfyve +/+ littermates, pancreata of KC Pikfyve f/+ and KC Pikfyve f/f mice weighed less and were closer in weight to pancreata of wild-type mice at 27 weeks of age (Fig. 1G, Fig. 2F) .
  • pancreata of KC mice with Pikfyve loss retained a higher degree of normal histological structures based on hematoxylin and eosin (H&E) staining or immunohistochemistry (IHC) staining for cytokeratin 19 (CK19) (Fig. 1H-I) . Consistent results were recapitulated at a later age of 40 weeks, as well as both on macroscopic and microscopic evaluations (Fig. 2G-H) .
  • pancreata from KPC Pikfyve +/+ mice displayed significantly and consistently lower degrees of PDAC burden based on histological evaluations employing H&E and IHC staining for CK19 (Fig. 1M-N) .
  • these data indicate that Pikfyve loss suppresses pancreatic cancer onset and progression in the KC and KPC models, respectively, while not affecting normal pancreatic tissue.
  • these studies with GEMMs suggest that PDAC has an elevated requirement for PIKfyve-driven processes.
  • PIKfyve perturbation suppresses autophagy and decreases PDAC cell proliferation
  • CRISPRi CRISPR interference
  • sgRNAs two independent single guide RNAs
  • PIKFYVE knockdown also increased the LC3A/B-II to LC3A/B-I ratio and increased p62 (SQSTM1) levels, suggesting an inhibition of autophagic flux (Fig. 4A) , consistent with data from previous reports 48, 50 .
  • PIKFYVE knockdown substantially slowed the growth of PDAC cells (Fig. 4B, Fig. 5) .
  • Lysosome inhibition by chloroquine treatment also decreased PDAC cell viability (Fig. 4B) .
  • PDAC is known to utilize autophagy and lysosomal processes to promote iron homeostasis and allow for mitochondrial respiration 24, 25, 56 ; therefore, we investigated whether PIKfyve inhibition decreased PDAC cell proliferation through a similar mechanism.
  • PIKfyve inhibition stabilized HIF1a upon eight hours of treatment, consistent with the effect of iron deprivation due to disrupting autophagy.
  • OCR basal oxygen consumption rate
  • PIKfyve inhibition did not decrease basal oxygen consumption rate (OCR) in 7940B or Panc 04.03 cells, contrasting the activity of chloroquine (CQ) and bafilomycin A1 (BAF) , the other autophagy and lysosomal inhibitors tested.
  • PIKfyve inhibition creates a synthetic lethality of de novo lipid synthesis in PDAC cells
  • a metabolism-focused CRISPR screen in MIA PaCa-2 cells treated with apilimod
  • Fig. 6A This screen accurately discriminated against core essential and non-essential genes, validating its biological relevance and consistency (Fig. 6B) .
  • Fig. 4C and Fig. 4D the most significantly depleted sgRNAs targeted genes core to the de novo fatty acid synthesis and elongation pathways, namely FASN, ACACA, SLC25A1, and HSD17B12.
  • ACOX1 which completes the first step of lipid beta-oxidation, was the target of some of the most significantly enriched sgRNAs in the screen (Fig. 4C) . Additionally, no cholesterol-specific genes were among the significant hits, suggesting that de novo fatty acid synthesis was a specific, functionally relevant synthetic essentiality of MIA PaCa-2 cells upon PIKfyve inhibition (Fig. 4E) .
  • Fig. 6C CRISPRi-mediated knockdown of FASN in MIA PaCa-2 cells and found that FASN knockdown with two independent sgRNAs (Fig. 6C) indeed sensitized cells to the PIKfyve degrader PIK5-33d (LCG) (Fig. 6D) .
  • ND646 is an inhibitor of ACC1 (protein name of ACACA) .
  • ACC1 protein name of ACACA
  • ND646 similarly sensitized PDAC cells to PIK5-33d (Fig. 6E) using MIA PaCa-2, PANC-1, and 7940B cell lines.
  • PIKfyve inhibition promotes the upregulation of de novo lipid synthesis in PDAC cells
  • PIKfyve inhibition obligates PDAC cells to maintain expression and function of the de novo fatty acid synthesis pathway
  • RNA-seq in 7940B cells we determined that eight-hour treatment of LCG-33 induced remarkably concordant gene expression changes, and the most upregulated pathways were related to cholesterol homeostasis, MTORC1 signaling, and fatty acid metabolism. Additionally, most of the top upregulated genes were targets of transcription factor sterol regulatory element binding transcription factor 1 (SREBP1) , a key regulator of lipogenesis 63 .
  • SREBP1 transcription factor sterol regulatory element binding transcription factor 1
  • KRAS-MAPK regulates de novo lipid biosynthesis in PDAC
  • KRAS is known to be a core driver of metabolic homeostasis in PDAC through MAPK signaling 10 ; thus, we determined whether KRAS-MAPK signaling drove FASN and ACACA expression.
  • KRAS-MAPK signaling drove FASN and ACACA expression.
  • iKras 9805 iKras 64
  • Kras OFF doxycycline withdrawal
  • MRTX1133 MRTX, KRAS G12D inhibitor
  • AMG510 AMG, KRAS G12C inhibitor
  • trametinib MEK inhibitor
  • NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105-109, doi: 10.1038/nature13148 (2014) .

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Abstract

L'invention concerne des méthodes de traitement de cancers dépendants de l'autophagie. En particulier, l'invention concerne des méthodes de traitement du cancer de la prostate neuroendocrinien (NEPC), d'un adénocarcinome canalaire pancréatique (PDAC), de tumeurs neuroendocrines pancréatiques (pNET), et de carcinomes neuroendocriniens pancréatiques (NEC) comprenant l'administration d'un agent thérapeutique, par exemple PIK5-12D ou LCG-33, qui inhibe PIKfyve.
PCT/CN2024/078381 2024-02-23 2024-02-23 Méthode de traitement du cancer dépendant de l'autophagie avec un agent de dégradation de pikfyve Pending WO2025175564A1 (fr)

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