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WO2024163039A1 - Traitement du cancer à l'aide d'inhibiteurs de pi3k en combinaison avec des antibiotiques ou des régimes alimentaires purifiés - Google Patents

Traitement du cancer à l'aide d'inhibiteurs de pi3k en combinaison avec des antibiotiques ou des régimes alimentaires purifiés Download PDF

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WO2024163039A1
WO2024163039A1 PCT/US2023/081396 US2023081396W WO2024163039A1 WO 2024163039 A1 WO2024163039 A1 WO 2024163039A1 US 2023081396 W US2023081396 W US 2023081396W WO 2024163039 A1 WO2024163039 A1 WO 2024163039A1
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cancer
antibiotics
days
pi3k inhibitor
diet
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Joshua Rabinowitz
Asael ROICHMAN
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Princeton University
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Princeton University
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • 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
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • This invention relates generally to methods for cancer treatment using PI3K inhibitors in combination with one or more antibiotics or purified diets.
  • PI3K phosphatidylinositol 3-kinase
  • PI3K inhibitors show poor and variable responses against solid tumors in the clinic, often due to drug resistance and low drug tolerance. That said, one PI3K inhibitor, BYL-719 (alpelisib), was approved for the treatment of hormone receptorpositive (HER2) tumors, but even in combination with hormone receptor blockade, a majority of patients progressed within 12 months, and many patients experienced side effects including cutaneous reactions and hyperglycemia. A major challenge is finding ways to sensitize tumors to PI3K inhibitors and improve drug tolerability.
  • the disclosure provides a method of treating a cancer.
  • the method comprises administering to a subject in need thereof (i) a therapeutically effective amount of a phosphoinositide 3-kinase (PI3K) inhibitor, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of one or more antibiotics or a purified diet.
  • PI3K phosphoinositide 3-kinase
  • the one or more antibiotics comprise ampicillin, neomycin, metronidazole, vancomycin, amoxicillin, piperacillin, ticarcillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a combination thereof.
  • the one or more antibiotics comprise ampicillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • the one or more antibiotics comprise (a) ampicillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (b) any one of neomycin, metronidazole, vancomycin, amoxicillin, piperacillin, ticarcillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a combination thereof.
  • the one or more antibiotics are administered at one or more doses of from about 5 mg/kg to about 500 mg/kg of body weight of the subject.
  • the purified diet comprises a ketogenic diet, a control purified diet, or a combination thereof.
  • the ketogenic diet comprises 20 wt%, 10 wt%, 5 wt%, or less of proteins.
  • the ketogenic diet comprises about 5 wt% of proteins, about 93 wt% of fat, and about 2 wt% of carbohydrates.
  • control purified diet comprises from about 5 wt% to about 40 wt% of proteins. In some embodiments, the control purified diet comprises about 20 wt% of proteins, about 12 wt% of fat, and about 68 wt% of carbohydrates. In some embodiments, the purified diet is administered at one or more doses of from about 10,000 mg/kg to about 500,000 mg/kg of body weight of the subject.
  • the PI3K inhibitor comprises a PI3K-alpha inhibitor. In some embodiments, the PI3K inhibitor comprises a pan-PI3K inhibitor. In some embodiments, the PI3K inhibitor comprises BYL-719, BKM-120, or a combination thereof.
  • the PI3K inhibitor is administered at one or more doses of from about 1 mg/kg to about 200 mg/kg of body weight of the subject.
  • the PI3K inhibitor is administered to the subject before or after the one or more antibiotics or the purified diet. In some embodiments, the PI3K inhibitor is administered to the subject concurrently with the one or more antibiotics or the purified diet.
  • the PI3K inhibitor, the one or more antibiotics, or the purified diet are administered at least every 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, or 4 weeks.
  • the PI3K inhibitor or the one or more antibiotics are administered to the subject intratumorally, intravenously, subcutaneously, intraosseously, orally, transdermally, sublingually, in sustained release, in controlled release, in delayed release, or as a suppository.
  • the PI3K inhibitor is contained in the same composition with the one or more antibiotics or the purified diet.
  • the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin’s lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt’s lymphoma, Waldenstrom’s macroglobulinemia (WM), Burkitt’s lymphoma, multiple myeloma, and myelofibrosis.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic leukemia
  • NHL diffuse large B cell lymphoma
  • FL follicular lymphoma
  • MCL mantle cell lymphoma
  • Hodgkin’s lymphoma B cell acute lymphoblastic leukemia
  • B-ALL B cell acute
  • the cancer is a solid tumor selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, glioma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, colon cancer, primary central nervous system lymphoma, and brain cancer.
  • bladder cancer non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, glio
  • the subject is a mammal. In some embodiments, the subject is a human.
  • the method further comprises administering to the subject an additional therapeutic agent or therapy.
  • the additional therapeutic agent comprises a second PI3K inhibitor, a second antibiotic, a second purified diet, or a combination thereof.
  • PI3K inhibitor a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof in combination with one or more antibiotics or a purified diet in a method described herein.
  • this disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a PI3K inhibitor, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, and (b) one or more antibiotics or a purified diet.
  • the one or more antibiotics comprise ampicillin, neomycin, metronidazole, vancomycin, amoxicillin, piperacillin, ticarcillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a combination thereof.
  • the one or more antibiotics comprise ampicillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • the one or more antibiotics comprise (a) ampicillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (b) any one of neomycin, metronidazole, vancomycin, amoxicillin, piperacillin, ticarcillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a combination thereof.
  • the purified diet comprises a ketogenic diet, a control purified diet, or a combination thereof.
  • the ketogenic diet comprises 20 wt%, 10 wt%, 5 wt%, or less of proteins.
  • the ketogenic diet comprises about 5 wt% of proteins, about 93 wt% of fat, and about 2 wt% of carbohydrates.
  • the control purified diet comprises from about 5 wt% to about 40 wt% of proteins.
  • the control purified diet comprises about 20 wt% of proteins, about 12 wt% of fat, and about 68 wt% of carbohydrates.
  • the PI3K inhibitor comprises a PI3K-alpha inhibitor. In some embodiments, the PI3K inhibitor comprises a pan-PI3K inhibitor. In some embodiments, the PI3K inhibitor comprises BYL-719, BKM-120, or a combination thereof.
  • this disclosure further provides a kit comprising the pharmaceutical composition described herein.
  • Fig. 1 shows KPC tumors having similar responsiveness to PI3K inhibition on purified diets regardless of macronutrients composition.
  • CPD control purified diet
  • KD ketogenic diet
  • LP low protein
  • NP normal protein
  • Veh Vehicle.
  • Figs. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, and 21 show that diet source dictates response to PI3K inhibition.
  • Fig. 2A shows tumor volumes of K8484 KPC allografted tumors in mice fed chow, KD, or CPD and treated with the PI3K inhibitor BYL-719 or vehicle control. Statistics represent differences in tumor sizes on day 40 using two-way ANOVA with Sidak’s post hoc.
  • Fig. 2B shows survival curve of the same mice from Fig. 2A.
  • FIG. 2D shows serum glucose levels
  • Figs. 2E and 2F show serum BYL levels in response to BYL administration on day 17 of the experiment in Fig. 2A. Mice were fasted during the first 4h of the experiment, after which food was put back. Shaded area represents the dark cycle.
  • Figs. 2G, 2H, and 21 show the results of the principal component analysis of serum metabolome, fecal metabolome, and fecal microbiome at different timepoints after BYL administration for Fig. 2G or at the 8h time point for FIG. 2H and FIG. 21 on day 17.
  • n 5 for Figs. 2D, 2E, 2F, 2G, 2H, and 21. Values shown are mean ⁇ SEM. **, /? ⁇ 0.01, ***, ? ⁇ 0.001, ****,/? ⁇ 0.0001.
  • Fig. 3 shows that PI3K inhibition is still enhanced even when a purified diet is supplemented with high fiber.
  • Survival curve of K8484 KPC allografted tumors in mice fed CPD supplemented with high or low cellulose as insoluble fiber and inulin as soluble fiber and treated BYL-719 or vehicle control. Diets with low cellulose are plotted together as low fiber, and diets with high cellulose as high fiber, n 7-22. Values shown are mean ⁇ SEM.
  • Figs. 4A, 4B, 4C, and 4D show that gut microbiome ablation sensitizes tumors to PI3K inhibition.
  • Statistics represent differences in tumor sizes at endpoint using two-way ANOVA with Sidak’s post hoc. Figs.
  • Figs. 5A, 5B, 5C, and 5D show that ampicillin sensitizes tumors to PI3K inhibition.
  • Fig. 5B shows body weight of the mice from Fig. 5A.
  • Figs. 6A, 6B, 6C, and 6D show that purified diet and ampicillin sensitizes tumors to BKM- 120.
  • Fig. 6D shows body weights of mice from Fig. 6C. Values shown are mean ⁇ SEM. ***,£ ⁇ 0.001, ****,£> ⁇ 0.0001.
  • This disclosure relates to an unexpected discovery that antibiotics or purified diets significantly enhance phosphoinositide 3 -kinase (PI3K) inhibition efficacy for cancer. Accordingly, this disclosure provides a novel method for treating a cancer using PI3K inhibitors in combination with antibiotics or purified diets.
  • PI3K phosphoinositide 3 -kinase
  • the method may include administering to a subject in need thereof (i) a therapeutically effective amount of a PI3K inhibitor, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of one or more antibiotics or a purified diet.
  • the PI3K inhibitor may be any PI3K inhibitor known in the art.
  • the term “PI3K inhibitor” refers to a nucleic acid, peptide, compound, or small organic molecule that binds to and inhibits at least one activity of PI3K.
  • the PI3K proteins can be divided into three classes, class 1 PI3Ks, class 2 PI3Ks, and class 3 PI3Ks.
  • Class 1 PI3Ks exist as heterodimers consisting of one of four p 110-catalytic subunits (p 110-alpha, p 110-beta, p 110-delta, and p 110-gamma) and one of two families of regulatory subunits.
  • a PI3K inhibitor may target the class 1 PI3K inhibitors.
  • a PI3K inhibitor displays selectivity for one or more isoforms of the class 1 PI3K inhibitors (/. ⁇ ?., selectivity for pl 10-alpha, pl 10-beta, pl 10-delta, and pl lO-gamma or one or more of pl lO-alpha, pl lO-beta, pl lO-delta, and pl lO-gamma).
  • a PI3K inhibitor that does not display isoform selectivity is considered a “pan-PI3K inhibitor.”
  • a PI3K inhibitor may compete for binding with ATP to the PI3K catalytic domain.
  • a selective PI3K inhibitor refers to an agent that exhibits a 50% inhibitory concentration with respect to PI3K that is at least 10-fold, at least 20-fold, at least 30- fold, at least 50-fold, at least 100-fold, at least 1000- fold, or more, lower than the inhibitor’s IC50 with respect to mTOR and/or other proteins in the pathway.
  • PI3K inhibitor may inhibit PI3K with an IC50 (concentration that inhibits 50% of the activity) of about 200 nM or less, about 100 nm or less, about 60 nM or less, about 25 nM, about 10 nM, about 5 nM, about 1 nM, about 100 uM, about 50 pM, about 25 pM, about 10 pM, about 1 pM, or less.
  • a PI3K inhibitor may inhibit PI3K with an IC50 from about 2 nM to about 100 nm, from about 2 nM to about 50 nM, or from about 2 nM to about 15 nM.
  • a PI3K inhibitor may be a PI3K-alpha inhibitor, a PI3K-gamma inhibitor, a PI3K-delta inhibitor, and a PI3K-gamma/delta inhibitor.
  • the PI3K inhibitor may include a PI3K-alpha inhibitor.
  • the PI3K inhibitor may include a pan-PI3K inhibitor.
  • non-limiting examples of PI3K inhibitors suitable for use in the disclosed methods may include Serabelisib, BEZ235, LY294002, GDC-0941, BYL719, GSK2636771, TGX-221, AS25242, CAL-101, IPI-145, MK-2206, GSK690693, GDC-0068, A- 674563, CCT128930, AZD8055, INK128, rapamycin, PF-04691502, everolimus, BI-D1870, H89, PF-4708671, FMK, AT7867, NU7441, PI-103, NU7026, PIK-75, ZSTK474, PP-121, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a combination thereof.
  • the PI3K inhibitor may include BYL-719, BKM-120, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a combination thereof.
  • PI3K inhibitors are described, for example, in U.S. Pat. Nos. 8,193,182 and 8,569,323, and U.S. Patent Application Publication Nos. 2012/0184568 Al, 2013/0344061 Al, and 2013/0267521 Al, the disclosures of which are incorporated by reference herein.
  • PI3K inhibitors may exist in various forms, such as stereoisomers, racemates, derivatives, prodrugs, analogs, or pharmaceutically acceptable salts, that are also suitable for use in the disclosed methods.
  • “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space, i.e., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold-Prelog R-S system.
  • the stereochemistry at each chiral carbon can be specified by either (R) or (S).
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S).
  • Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related to mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. “R” and “S” represent the configuration of substituents around one or more chiral carbon atoms. Thus, “R*” and “S*” denote the relative configurations of substituents around one or more chiral carbon atoms. The symbol in a structural formula represents the presence of a chiral carbon center.
  • Racemate or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity, i.e., they do not rotate the plane of polarized light.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • “R,” “S,” “St,” “R*,” “E,” “Z,” “cis,” and “trans” indicate configurations relative to the core molecule.
  • a “derivative,” as used herein, refers to a chemical substance related structurally to another, i.e., an “original” substance, which can be referred to as a “parent” compound.
  • a “derivative” can be made from the structurally related parent compound in one or more steps.
  • the phrase “closely related derivative” means a derivative whose molecular weight does not exceed the weight of the parent compound by more than 50%.
  • the general physical and chemical properties of a closely related derivative are also similar to the parent compound.
  • “Pharmaceutically active derivative” refers to any compound that, upon administration to the recipient, is capable of providing, directly or indirectly, the activity disclosed herein.
  • an “analog” refers to a small organic compound, a nucleotide, a protein, or a polypeptide that possesses similar or identical activity or function(s) as the compound, nucleotide, protein or polypeptide or compound having the desired activity of this disclosure, but need not necessarily include a sequence or structure that is similar or identical to the sequence or structure of the preferred embodiments.
  • prodrug refers to a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein.
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers the advantages of solubility, tissue compatibility, or delayed release in a mammalian organism see, e.g., Bundgaard, H., Design of Prodrugs (1985) (Elsevier, Amsterdam).
  • prodrug also refers to any covalently bonded carriers, which release the active compound in vivo when administered to a subject.
  • Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the active parent compound.
  • Prodrugs include, for example, compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively.
  • prodrugs include, but are not limited to, acetates, formates, and benzoate derivatives of alcohol, various ester derivatives of a carboxylic acid, or acetamide, formamide, and benzamide derivatives of an amine functional group in the active compound.
  • Various forms of prodrugs are well known in the art and are described in: (a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); (b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers, 1991); and (d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.
  • an “antibiotic” or “antibiotic agent” refers to a substance that has the capacity to inhibit or slow down the growth of or destroy bacteria and/or other microorganisms.
  • the antibiotic agent is a bacteriostatic antibiotic agent.
  • the antibiotic is a bacteriolytic antibiotic agent.
  • Non-limiting examples of antibiotic agents are set forth in the U.S. Patent Publication US 2006/0269485, which is herein incorporated by reference in its entirety.
  • the antibiotic agent is selected from the classes including betalactam antibiotics, aminoglycosides, ansa-type antibiotics, anthraquinones, antibiotic azoles, antibiotic glycopeptides, macrolides, antibiotic nucleosides, antibiotic peptides, antibiotic polyenes, antibiotic polyethers, quinolones, antibiotic steroids, sulfonamides, tetracycline, dicarboxylic acids, antibiotic metals, oxidizing agents, substances that release free radicals and/or active oxygen, cationic antimicrobial agents, quaternary ammonium compounds, biguanides, triguanides, bisbiguanides and analogs and polymers thereof and naturally occurring antibiotic compounds.
  • betalactam antibiotics aminoglycosides, ansa-type antibiotics, anthraquinones, antibiotic azoles, antibiotic glycopeptides, macrolides, antibiotic nucleosides, antibiotic peptides, antibiotic polyenes, antibiotic polyethers, quinolones, antibiotic steroids, s
  • Non-limiting examples of beta-lactam antibiotics may include 2-(3-alanyl)clavam, 2- hydroxymethylclavam, 8-epi-thienamycin, acetyl-thienamycin, amoxicillin, amoxicillin sodium, amoxicillin trihydrate, amoxicillin-potassium clavulanate combination, ampicillin, ampicillin sodium, ampicillin trihydrate, ampicillin-sulbactam, apalcillin, aspoxicillin, azidocillin, azlocillin, aztreonam, bacampicillin, biapenem, carbenicillin, carbenicillin disodium, carfecillin, carindacillin, carpetimycin, cefacetril, cefaclor, cefadroxil, cefalexin, cefaloridine, cefalotin, cefamandole, cefamandole, cefapirin, cefatrizine, cefatrizine propylene glycol, cefazedone,
  • antibiotics may include ampicillin, neomycin, metronidazole, vancomycin, amoxicillin, piperacillin, ticarcillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a combination thereof.
  • antibiotics may include ampicillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • antibiotics may include (a) ampicillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (b) any one of neomycin, metronidazole, vancomycin, amoxicillin, piperacillin, ticarcillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a combination thereof.
  • the purified diet may include a ketogenic diet, a control purified diet, or a combination thereof.
  • purified diet refers to a diet that consists substantially of purified and/or processed food components, as opposed to unprocessed food items (such as fruits, vegetables, whole grains, meats, eggs).
  • Purified components refer to simple sugars, simple refined carbohydrates from which substantial chemical complexity has been intentionally removed (e.g., white flour, white rice), mixtures of fats (such as oils, butters, or creams), particular fibers (e.g., purified cellulose or insulin), or particular proteins or mixtures of proteins (e.g., casein, whey) purified from more complex starting materials (such as corn, fruit, whole grains, beans, milk, or meats).
  • the purified components may be combined together, optionally with water, prior to being fed to a mammal, e.g., in the form of a protein shake or baked good.
  • Processed food components refer to foods comprising a substantial amount (e.g., greater than 50%, 75%, or 90%) of purified components, mixed together optionally with non-purified components.
  • a processed food would be a cake containing sucrose (table sugar, a purified component), butter (a purified component), white flour (a purified component), and eggs (an unprocessed food item).
  • the fraction of purified components may be greater than 25%, 50%, 75%, or 90% of total food intake.
  • the fraction of purified or processed food components may be greater than 50%, 75%, 90%, or 95% of total food intake. Fraction of purified components can optionally be measured by mass, by dry mass, or by calories.
  • ketogenic diet refers to a high fat and low saccharide diet, which is utilized as a diet for treating patients requiring saccharide-restrictive diets, for example, children with epilepsy.
  • Non-limiting examples of the ketogenic diet may include Ketogenic diet (KD, also referred to as KD-LP) - D21111901Mi and Keto normal protein (KD-NP) - D21111902Mi (RESEARCH DIETS) as set forth in Table 1.
  • the ketogenic diet may include 20 wt%, 10 wt%, 5 wt%, or less of proteins. In some embodiments, the ketogenic diet may include about 5 wt% of proteins, about 93 wt% of fat, and about 2 wt% of carbohydrates.
  • control purified diet refers to high protein and high carbohydrate diets.
  • Nonlimiting examples of the control purified diet may include Control purified diet (CPD) - D21111904i, High cellulose with 0% Inulin (HC_InO) - D22040601i, High cellulose with 1.9% Inulin (HC Ini.9) - D22040602i, High cellulose with 1.9% Inulin (HC Ini.9) - D22040602i, High cellulose with 8% Inulin (HC_In8) - D22040603i, and Low cellulose with 2.5% Inulin (LC_In2.5) - D22011102i, as set forth in Table 1.
  • control purified diet may include from about 5 wt% to about 40 wt% (e.g, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%) of proteins.
  • wt% e.g,
  • control purified diet may include about 20 wt% of proteins, about 12 wt% of fat, and about 68 wt% of carbohydrates.
  • Nonlimiting examples of the control purified diet may include those described in Table 1 in Example 1 of this disclosure.
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas, and sarcomas.
  • Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g.
  • ovarian cancer pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer ( .g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma.
  • liver cancer e.g., hepatocellular carcinoma
  • lung cancer .g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma,
  • Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial
  • solid tumor refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign or malignant.
  • solid tumor cancer refers to malignant, neoplastic, or cancerous solid tumors. Solid tumor cancers include, but are not limited to, sarcomas, carcinomas, and lymphomas, such as cancers of the lung, breast, triple-negative breast cancer, prostate, colon, rectum, and bladder.
  • the cancer is selected from cervical cancer, head and neck cancer (including, for example, head and neck squamous cell carcinoma (HNSCC)) glioblastoma, ovarian cancer, sarcoma, pancreatic cancer, bladder cancer, breast cancer, triple-negative breast cancer, and non-small cell lung carcinoma.
  • the tissue structure of solid tumors includes interdependent tissue compartments, including the parenchyma (cancer cells) and the supporting stromal cells in which the cancer cells are dispersed and which may provide a supporting microenvironment.
  • cancer may be chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin’ s lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt’s lymphoma, Waldenstrom’s macroglobulinemia (WM), Burkitt’s lymphoma, multiple myeloma, or myelofibrosis.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic leukemia
  • NHL diffuse large B cell lymphoma
  • FL follicular lymphoma
  • MCL mantle cell lymphoma
  • NHL B cell acute lymphoblastic leukemia
  • WM Waldenstrom’s macroglobulinemia
  • cancer may be a solid tumor selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, glioma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, colon cancer, primary central nervous system lymphoma, and brain cancer.
  • bladder cancer non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, glio
  • the terms “treating,” “treat,” and “treatment” include preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); inhibiting the disease, pathologic or medical condition or arresting its development; relieving or ameliorating the disease, pathologic or medical condition; and/or diminishing symptoms associated with the disease, pathologic or medical condition.
  • the terms “treat,” “treatment,” and “treating” can extend to prophylaxis and can include preventing, prevention, lowering, stopping, or reversing the progression or severity of the condition or symptoms being treated.
  • the term “treatment” can include medical, therapeutic, and/or prophylactic administration, as appropriate.
  • the term “treating” or “treatment” thus can include reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject’s condition.
  • administering refers to the delivery of cells by any route including, without limitation, oral, intranasal, intraocular, intravenous, intraosseous, intraperitoneal, intraspinal, intramuscular, intra-articular, intraventricular, intracranial, intralesional, intratracheal, intrathecal, subcutaneous, intradermal, transdermal, or transmucosal administration.
  • the agent is administered to the subject intratumorally, intravenously, subcutaneously, intraosseously, orally, transdermally, sublingually, in sustained release, in controlled release, in delayed release, or as a suppository.
  • a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • an “effective amount” refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect.
  • an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art.
  • the term “effective amount” is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective in treating or preventing a disease or disorder, or treating the symptoms of the disease or disorder, in a host.
  • an “effective amount” generally means an amount that provides the desired effect.
  • a “therapeutically effective amount” of a compound with respect to the subject method of treatment refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, e.g., a human), alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated, e.g. , at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the actual dosage amount of a composition of this disclosure administered to a subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient, and on the route of administration.
  • the practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
  • the PI3K inhibitor may be administered at one or more doses of from about 5 mg/kg to about 200 mg/kg of body weight of the subject, such as about 5 mg/kg of body weight, about 10 mg/kg of body weight, about 20 mg/kg of body weight, about 30 mg/kg of body weight, about 40 mg/kg of body weight, about 50 mg/kg of body weight, about 75 mg/kg of body weight, about 100 mg/kg of body weight, about 125 mg/kg of body weight, about 150 mg/kg of body weight, about 175 mg/kg of body weight, about 200 mg/kg of body weight, or any range derivable therein.
  • the antibiotics may be administered at one or more doses of from about 10 mg/kg to about 500 mg/kg of body weight of the subject, such as about 10 mg/kg of body weight, about 20 mg/kg of body weight, about 30 mg/kg of body weight, about 40 mg/kg of body weight, about 50 mg/kg of body weight, about 75 mg/kg of body weight, about 100 mg/kg of body weight, about 125 mg/kg of body weight, about 150 mg/kg of body weight, about 175 mg/kg of body weight, about 200 mg/kg of body weight, about 250 mg/kg of body weight, about 300 mg/kg of body weight, about 350 mg/kg of body weight, about 400 mg/kg of body weight, about 450 mg/kg of body weight, about 500 mg/kg of body weight, or any range derivable therein.
  • the purified diet may be administered at one or more doses of from about 10,000 mg/kg to about 500,000 mg/kg of body weight of the subject, such as 10,000 mg/kg of body weight, 11,000 mg/kg of body weight, 12,000 mg/kg of body weight, 13,000 mg/kg of body weight, 14,000 mg/kg of body weight, 15,000 mg/kg of body weight, 16,000 mg/kg of body weight, 17,000 mg/kg of body weight, 18,000 mg/kg of body weight, 19,000 mg/kg of body weight, 20,000 mg/kg of body weight, 21,000 mg/kg of body weight, 22,000 mg/kg of body weight, 23,000 mg/kg of body weight, 24,000 mg/kg of body weight, 25,000 mg/kg of body weight, 26,000 mg/kg of body weight, 27,000 mg/kg of body weight, 28,000 mg/kg of body weight, 29,000 mg/kg of body weight, 30,000 mg/kg of body weight, 31 ,000 mg/kg of body weight, 32,000 mg/kg of body weight, 33,000 mg/kg of body weight, 1
  • a dose may be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete, loosely spaced administrations.
  • one or more doses of PI3K inhibitors, antibiotics, or purified diets may be administered at least every 1 day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 15 days, every 16 days, every 17 days, every 18 days, every 19 days, every 20 days, every 21 days, every 22 days, every 23 days, every 24 days, every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, every 31 days, every 32 days, every 33 days, every 34 days, every 35 days, every 36 days, every 37 days, every 38 days, every 39 days, every 40 days, every 41 days, every 42 days, every 43 days, every 44 days, every 45 days, every 46 days, every 47 days, every 48 days, every 49 days, every 50 days, every 51 days, every 52 days, every 53 days, every 54 days, every 55 days, every 56 days,
  • the method may include administering to the subject an additional therapeutic agent or therapy.
  • the additional therapeutic agent may include a second PI3K inhibitor, a second antibiotic, a second purified diet, or a combination thereof.
  • Combination therapy is meant to encompass administration of two or more therapeutic agents in a coordinated fashion and includes, but is not limited to, concurrent dosing.
  • combination therapy encompasses both co-administration (e.g., administration of a co-formulation or simultaneous administration of separate therapeutic compositions) and serial or sequential administration, provided that administration of one therapeutic agent is conditioned in some way on the administration of another therapeutic agent.
  • one therapeutic agent may be administered only after a different therapeutic agent has been administered and allowed to act for a prescribed period of time. See, e.g., Kohrt et al. (2011) Blood 117:2423.
  • co-administration refers to the administration of at least two agent(s) or therapies to a subject. In some embodiments, the coadministration of two or more agents/therapies is concurrent. In some embodiments, a first agent/therapy is administered prior to a second agent/therapy.
  • PI3K inhibitor PI3K inhibitor, antibiotic, purified diet
  • active ingredients e.g., antibiotic, purified diet
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • the combination therapy may provide synergy and be synergistic, i.e., the effect achieved when the active ingredients used together are greater than the sum of the effects that result from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills, capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas, in combination therapy, effective dosages of two or more active ingredients are administered together.
  • a synergistic effect denotes an effect that is greater than the predicted purely additive effects of the individual compounds of the combination.
  • Combination therapy is further described by U.S. Pat. Nos. 11103514, 10702495, 9382215, and 6833373, which include additional active agents that can be combined with the compounds described herein, and additional types of ailments and other conditions that can be treated with a compound or combination of compounds described herein.
  • An active agent may precede or follow treatment of the other agent by intervals ranging from minutes to weeks.
  • the other agent and expression construct are applied separately to a cell, one would generally ensure that a significant period of time did not elapse between the time of each delivery, such that the agent and expression construct would still be able to exert an advantageously combined effect on the cell.
  • one or more agents may be administered within about 1 minute, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 9 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 28 hours, about 31 hours, about 35 hours, about 38 hours, about 42 hours, about 45 hours, to about 48 hours or more prior to and/or after administering the disclosed active agent.
  • an agent may be administered within from about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 8 days, about 9 days, about 12 days, about 15 days, about 16 days, about 18 days, about 20 days, to about 21 days prior to and/or after administering the disclosed active.
  • it may be desirable to extend the time period for treatment significantly; however, where several weeks (e.g., about 1, about 2, about 3, about 4, about 6, or about 8 weeks or more) lapse between the respective administrations.
  • compositions to a patient will follow general protocols for the administration of therapeutics, taking into account the toxicity, if any. It is expected that the treatment cycles will be repeated as necessary. It also is contemplated that various standard therapies or adjunct therapies, as well as surgical intervention, may be applied in combination with the described active agent. These therapies include but are not limited to chemotherapy, radiotherapy, immunotherapy, gene therapy, and surgery.
  • composition comprising: (a) a PI3K inhibitor, a stereoisomer thereof, an analog thereof, a derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, and (b) one or more antibiotics or a purified diet.
  • composition or “pharmaceutical composition” refers to a mixture of at least one component useful within the disclosure with other components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of one or more components of the invention to an organism.
  • the PI3K inhibitor may include Serabelisib, BEZ235, LY294002, GDC-0941, BYL719, GSK2636771, TGX-221, AS25242, CAL-101, IP1-145, MK-2206, GSK690693, GDC-0068, A-674563, CCT128930, AZD8O55, INK128, rapamycin, PF-04691502, everolimus, BI-D1870, H89, PF-4708671, FMK, AT7867, NU7441, PI-103, NU7026, PIK-75, ZSTK474, PP-121, or a combination thereof.
  • the PI3K inhibitor may include a PI3K-alpha inhibitor. In some embodiments, the PI3K inhibitor may include a pan-PI3K inhibitor. In some embodiments, the PI3K inhibitor may include BYL-719, BKM-120, or a combination thereof.
  • antibiotics may include ampicillin, neomycin, metronidazole, vancomycin, amoxicillin, piperacillin, ticarcillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a combination thereof.
  • one or more antibiotics may include ampicillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • one or more antibiotics may include (a) ampicillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (b) any one of neomycin, metronidazole, vancomycin, amoxicillin, piperacillin, ticarcillin, a stereoisomer thereof, a derivative thereof, an analog thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a combination thereof.
  • the purified diet may include a ketogenic diet, a control purified diet, or a combination thereof.
  • the ketogenic diet may include Ketogenic diet (KD, also referred to as KD-LP) - D21111901Mi and Keto normal protein (KD-NP) - D21111902Mi (RESEARCH DIETS) as set forth in Table 1.
  • the ketogenic diet may include 20 wt%, 10 wt%, 5 wt%, or less of proteins.
  • the ketogenic diet may include about 5 wt% of proteins, about 93 wt% of fat, and about 2 wt% of carbohydrates.
  • Non-limiting examples of the control purified diet may include Control purified diet (CPD) - D21111904i, High cellulose with 0% Inulin (HC_InO) - D2204060H, High cellulose with 1.9% Inulin (HC_Inl.9) - D22040602i, High cellulose with 1.9% Inulin (HC_Inl.9) - D22040602i, High cellulose with 8% Inulin (HC_In8) - D22040603i, and Low cellulose with 2.5% Inulin (LC_In2.5) - D22011102i, as set forth in Table 1.
  • CPD Control purified diet
  • HC_InO High cellulose with 0% Inulin
  • HC_InO High cellulose with 1.9% Inulin
  • HC_Inl.9 High cellulose with 1.9% Inulin
  • HC_In8 High cellulose with 8% Inulin
  • LC_In2.5 Control purified diet
  • control purified diet may include from about 5 wt% to about 40 wt% (e.g., 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%) of proteins.
  • the agents can be formulated in liquid solutions, e.g., in physiologically compatible buffers such as Hank’s solution or Ringer’s solution.
  • the agents may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms are also included.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid.
  • the pharmaceutical composition is, e.g., made in the form of a dosage unit containing a particular amount of the active ingredient.
  • the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, e.g., from about 0.25 to 250 mg, and, e.g., from about 0.5 to 100 mg.
  • a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, can be determined using routine methods.
  • any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations.
  • Exemplary oral preparations include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs.
  • Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration.
  • a pharmaceutical composition in accordance with the disclosure can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.
  • a tablet can, for example, be prepared by admixing at least one compound and/or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.
  • excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium croscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc.
  • a tablet can either be uncoated or coated by known techniques to either mask the bad taste of an unpleasant-tasting drug or delay disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby sustaining the effects of the active ingredient for a longer period.
  • exemplary water-soluble taste-masking materials include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose.
  • Exemplary time delay materials include, but are not limited to, ethylcellulose and cellulose acetate butyrate.
  • Hard gelatin capsules can, for example, be prepared by mixing at least one compound and/or at least one salt thereof with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.
  • Soft gelatin capsules can, for example, be prepared by mixing at least one compound and/or at least one pharmaceutically acceptable salt thereof with at least one water-soluble carrier, such as, for example, polyethylene glycol, and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.
  • at least one water-soluble carrier such as, for example, polyethylene glycol
  • at least one oil medium such as, for example, peanut oil, liquid paraffin, and olive oil.
  • An aqueous suspension can be prepared, for example, by admixing at least one compound and/or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension.
  • excipients suitable for the manufacture of an aqueous suspension may include suspending agents, such as, for example, sodium carboxymethylcellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinyl -pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long-chain aliphatic alcohols, such as, for example, heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids
  • An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • the active ingredient may also be administered by injection as a composition with suitable carriers, including saline, dextrose, or water, or with cyclodextrin i.e., Captisol), cosolvent solubilization (i.e., propylene glycol) or micellar solubilization (i.e., Tween 80).
  • suitable carriers including saline, dextrose, or water, or with cyclodextrin i.e., Captisol), cosolvent solubilization (i.e., propylene glycol) or micellar solubilization (i.e., Tween 80).
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • a non-toxic, parenterally acceptable diluent or solvent for example, as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil, such as cremophor surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
  • Cyclodextrins such as alpha-, beta-, and gammacyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • the pharmaceutically active compounds of this disclosure can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
  • the pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as additives, preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings.
  • Such compositions may also include adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
  • compositions of this disclosure may include at least one compound and/or at least one pharmaceutically acceptable salt thereof, and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle.
  • Alternate compositions of this disclosure may include a compound described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • kits can include (a) a container that contains the composition and optionally (b) informational material.
  • the informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the agents for therapeutic benefit.
  • kits may include instructions for the manufacturing, the therapeutic regimen to be used, and periods of administration.
  • the kit may also include an additional therapeutic agent.
  • the kit may include one or more containers, each with a different reagent.
  • the kit may include a first container that contains the composition and a second container for the additional therapeutic agent.
  • the containers may include a unit dosage of the pharmaceutical composition.
  • the kit can include other ingredients, such as a solvent or buffer, an adjuvant, a stabilizer, or a preservative.
  • the kit may optionally include a device suitable for administration of the composition, e.g.. a syringe or other suitable delivery device.
  • the device may be provided pre-loaded with one or both of the agents or can be empty, but suitable for loading.
  • a “subject” or “subject in need thereof’ refers to a human and a non-human animal.
  • a non-human animals include all vertebrates, e.g., mammals, such as non- human mammals, non-human primates (particularly higher primates), dog, rodent (e.g., mouse or rat), guinea pig, cat, and rabbit, and non-mammals, such as birds, amphibians, reptiles, etc.
  • the subject is a human.
  • the subject is an experimental animal or animal suitable as a disease model.
  • the term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • agent is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule (such as a nucleic acid, an antibody, a protein or portion thereof, e.g. , a peptide), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. The activity of such agents may render it suitable as a “therapeutic agent,” which is a biologically, physiologically, or pharmacologically active substance (or substances) that acts locally or systemically in a subject.
  • therapeutic agent refers to a molecule or compound that confers some beneficial effect upon administration to a subject.
  • the beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder, or condition; and generally counteracting a disease, symptom, disorder, or pathological condition.
  • sample can be a sample of serum, urine plasma, amniotic fluid, cerebrospinal fluid, cells (e.g., antibody-producing cells), or tissue.
  • cells e.g., antibody-producing cells
  • tissue e.g., tissue
  • sample can be used directly as obtained from a patient or can be pre-treated, such as by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents, and the like, to modify the character of the sample in some manner as discussed herein or otherwise as is known in the art.
  • sample and biological sample as used herein, generally refer to a biological material being tested for and/or suspected of containing an analyte of interest.
  • the sample may be any tissue sample from the subject.
  • the sample may comprise protein from the subject.
  • inhibitor and “antagonize,” as used herein, mean to reduce a molecule, a reaction, an interaction, a gene, an mRNA, and/or a protein’s expression, stability, function, or activity by a measurable amount or to prevent entirely.
  • Inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down- regulate a protein, a gene, and an mRNA stability, expression, function, and activity, e.g., antagonists.
  • the term “z/z vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.
  • in vivo refers to events that occur within a multi-cellular organism, such as a non-human animal.
  • the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • the term “about” is intended to include values, e.g., weight percents, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment.
  • each when used in reference to a collection of items, is intended to identify an individual item in the collection but does not necessarily refer to every item in the collection. Exceptions can occur if explicit disclosure or context clearly dictates otherwise.
  • mice Mouse husbandry and PDAC tumor models. All mouse work was approved by the Institute Animal Care and Use Committee (IACUC) at Princeton University. Wild type C57BL/6 mice were obtained at 6 to 8 weeks of age from Charles River Laboratories, and tumor inoculations were performed up to a few weeks after arrival. Mice were housed under normal light cycle (7:00- 19:00) and fed chow diet ad lib (PicoLab Rodent 205053*, LabDiet) and had free access to reverse osmosis drinking water until experiments began. For experiments using the tumor chunk model (Fig.
  • syngeneic PDAC allograft tumors were established by harvesting tumors from KPC (LSL- Kras G12L) , p53 R172H , Pdx-Cre) mice, mincing the tissue with surgical scissors into ⁇ 3mm pieces able to pass through a 16g needle, suspending in DMEM medium, mixing with Matrigel (Corning Cat #354234) at a 1 : 1 ratio (v/v), and then injecting 200ul of the mixture subcutaneously into the mouse flank (Yang, L. et al. Med 3, 119-136. e8 (2022)).
  • KPC K8484 cell line was used for the rest of the experiments.
  • Cells were harvested with trypsin, counted in DMEM, suspended in PBS, and mixed at a 1 : 1 ratio with Matrigel. 0.5-1 * 10 6 cells were injected subcutaneously into mouse flanks in a volume of 100-200 pl.
  • ketogenic diet all mice were fasted overnight one day before the dietary change.
  • Antibiotics were administered in the drinking water as a cocktail of ampicillin (1 g/L), neomycin (1 g/L), metronidazole (1 g/L), and vancomycin (0.5 g/L) or as individual antibiotics. To make the drinking water more palatable, 5% aspartame was added. Drinking water with 5% aspartame was used as control. Table 1. Example purified diets and their ingredients
  • PI3K inhibitors BYL-719 (BYL) and BKM-120 (BKM) were dissolved in 0.5% carboxymethylcellulose, sonicated, and given by daily oral gavage (lOul/gr) for 5 days a week (5 days on, 2 days off).
  • BYL dose was 45 mg/kg
  • BKM dose was 25 mg/kg.
  • Tumor volumes were measured twice a week with a caliper, and tumor size was calculated by the formula: 0.5 x (Length x Width x Height).
  • mice were fasted ⁇ 2h before drug gavage, and food was put back after the 4h time point when mice were entering the dark cycle.
  • PK pharmacokinetics
  • Metabolite extraction for LC-MS For serum samples, 3 pl samples were mixed 117 pl with methanol, vortexed for 30 seconds, and centrifuged at 17,000 g for 10 min at 4°C.
  • For fecal samples 10-20 mg of fecal pellets were weighed and ground under liquid nitrogen using a cryomill (Restch, Newtown, PA). Next, x40 volume (40 pl extraction solvent per 1 mg tissue) of 40:40:20 methanol: acetonitrile: water with 0.5% formic acid pre-cooled to -20°C was added to the fecal powder, vortexed and incubated on ice for 10 min.
  • Water soluble metabolite measurements were obtained by running samples on Orbitrap Exploris 240 mass spectrometer (Thermo Scientific) coupled with hydrophilic interaction chromatography (HILIC) with electrospray ionization.
  • LC separation was performed on an XBridge BEH Amide column (2.13150 mm, 2.5 pm particle size, 130 A pore size; Waters Corporation) using a gradient of solvent A (95:5 water: acetonitrile with 20 mM of ammonium acetate and 20 mM of ammonium hydroxide, pH 9.45) and solvent B (acetonitrile).
  • solvent A 95:5 water: acetonitrile with 20 mM of ammonium acetate and 20 mM of ammonium hydroxide, pH 9.45
  • solvent B acetonitrile
  • the LC gradient was: 0 min, 90% B; 2 min, 90% B; 3 min, 75%; 7 min, 75% B; 8 min, 70%; 9 min, 70% B; 10 min, 50% B; 12 min, 50% B; 13 min, 25% B; 14 min, 25% B; 16 min, 0.5% B, 20.5 min, 0.5% B; 21 min, 90% B; 25 min, 90% B.
  • Injection volume was 5-10 pl, and autosampler temperature was 4°C.
  • MS scans were in negative and positive ion switching mode with a resolution of 120,000 at m/z 200 and a scan range of m/z 70-1000 for neg mode and m/z 58-116.5 and m/z 120-1000 for pos mode. Mass spec data was analyzed using El-Maven (v0.12.0, Elucidata).
  • 16S sequencing Bacterial DNA was extracted from fecal samples using the Power Soil DNA Isolation kit (QIAGEN). A section of the 16S rRNA gene (-250 bp, V4 region) was amplified, and Illumina sequencing libraries were prepared from these amplicons according to previously published protocols and primers. Libraries were further pooled together at equal molar ratios and sequenced on an Illumina HiSeq 2500 Rapid Flowcell or MiSeq as paired-end reads. These reads were 2x150 bp with an average depth of -20,000 reads. Also included were 8 bp index reads, following the manufacturer’s protocol (Illumina, USA).
  • Pass-Filter reads were generated from raw sequencing reads using Illumina HiSeq Control Software. Samples were de-multiplexed using the index reads. The DADA2 plugin within QIIME2 version 2018.6 was used to infer Amplicon sequencing variants (ASVs) from the unmerged paired-end sequences. The forward reads were trimmed at 150 bp, and the reverse reads were trimmed at 140 bp, with all other DADA2 as default. Taxonomy was assigned to the resulting ASVs with a naive Bayes classifier trained on the Greengenes database version 13.8, with only the target region of the 16S rRNA gene used to train the classifier. Downstream analyses were performed with MATLAB.
  • PI3K inhibition efficacy was tested in a pancreatic KPC allograft model. Notably, BYL showed a similar degree of tumor growth inhibition in all four diets. Unexpectedly, similar efficacy was seen even with the high carb 20% protein diet (Fig. 1), despite the macronutrient composition in this diet being similar to the chow used previously (Hopkins, B. D et al.
  • a major difference between grain-based chow and purified diets is dietary fiber, which is typically high in chow and low in the purified diets (Pellizzon, M. A. & Ricci, M. R. Nutr. Metab. 15, 1-6 (2018)). Indeed, while the chow that was used contained 15.5% (w/w) insoluble fiber and -1.9% soluble fiber, CPD had 2.6% insoluble fiber (as cellulose) and no soluble fiber. To test the importance of fiber on the interplay of PI3K inhibition with purified diets, insoluble fiber was added to a similar level as chow and different amounts of soluble fiber back to CPD, and the effect of BYL treatment on KPC allografts was monitored.
  • mice bearing KPC allografts were fed either chow or CPD and were treated with an antibiotics cocktail which ablates the gut microbiome or control, followed by BYL administration.
  • chow-fed mice receiving antibiotics and BYL showed complete tumor control, similar to mice on CPD with or without antibiotics (Fig. 4A).
  • BYL pharmacokinetics (PK) under these conditions were also monitored, and it was found that similar to CPD, antibiotics treatment led to increased peak, and most notably trough serum BYL levels (Figs. 4C-D).
  • antibiotics alone without BYL administration did not affect tumor growth, ruling out a direct effect of antibiotics on tumor growth (Fig. 4B).
  • each of the antibiotics used in the antibiotics cocktail was individually tested for its ability to enhance BYL efficacy. It was found that ampicillin, but not the three other antibiotics tested, enhanced BYL efficacy to the same levels as the antibiotics cocktail (Fig. 5A). BYL was better tolerated with ampicillin than with the antibiotics cocktail, as depicted by body weight profile over the course of the experiment (Fig. 5B). BYL PK was enhanced by ampicillin, although to a lesser extent than the antibiotics cocktail (Figs. 5C-D).
  • This example shows purified diets and antibiotics, such as ampicillin, significantly enhance PI3K inhibition efficacy in pancreatic ductal adenocarcinoma (PDAC) mouse models, as demonstrated for the FDA-approved PI3K-alpha-specific BYL-719 (alpelisib) and for the pan- PI3K inhibitor BKM-120 that is now undergoing phase III clinical trials.
  • PDAC pancreatic ductal adenocarcinoma
  • the results indicate that manipulating the gut microbiome composition by purified diets or antibiotics enhances PI3K efficacy by improving drug pharmacokinetics.
  • the combination of PI3K inhibitors with purified diets or ampicillin remains efficacious and tolerable over time.

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Abstract

La présente invention concerne une découverte inattendue selon laquelle des antibiotiques ou des régimes alimentaires purifiés améliorent significativement l'efficacité d'inhibition de la phosphoinositide 3-kinase (PI3K) dans le traitement du cancer. En conséquence, la présente invention concerne une nouvelle méthode de traitement d'un cancer à l'aide d'inhibiteurs de PI3K en combinaison avec des antibiotiques ou des régimes alimentaires purifiés.
PCT/US2023/081396 2023-01-30 2023-11-28 Traitement du cancer à l'aide d'inhibiteurs de pi3k en combinaison avec des antibiotiques ou des régimes alimentaires purifiés Ceased WO2024163039A1 (fr)

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