The word “substantially” does not exclude “completely,” e.g., a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the invention.

As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In some embodiments, 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). Unless indicated otherwise herein, 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.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

As used herein, the term “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.

The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. When used in this document, the term “exemplary” is intended to mean “by way of example” and is not intended to indicate that a particular exemplary item is preferred or required.

All methods described herein are performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. In regard to any of the methods provided, the steps of the method may occur simultaneously or sequentially. When the steps of the method occur sequentially, the steps may occur in any order, unless noted otherwise.

In cases in which a method comprises a combination of steps, each and every combination or sub-combination of the steps is encompassed within the scope of the disclosure, unless otherwise noted herein.

Each publication, patent application, patent, and other reference cited herein is incorporated by reference in its entirety to the extent that it is not inconsistent with the present disclosure. Publications disclosed herein are provided solely for their disclosure prior to the filing date of the present invention. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Examples

EXAMPLE 1

This example describes the materials and methods used in the subsequent EXAMPLES below.

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. 1), 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)). For the rest of the experiments, KPC K8484 cell line was used. Cells were harvested with trypsin, counted in DMEM, suspended in PBS, and mixed at a 1 : 1 ratio with Matrigel. 0.5-1 * 10⁶ cells were injected subcutaneously into mouse flanks in a volume of 100-200 pl.

Diets and antibiotics treatment. Treatments were started when tumors reached an average volume of- 100 mm³. For experiments with dietary modifications, mice were transferred to a new clean cage with the modified diet and had free access to food throughout the whole experiment, except for some of the pharmacokinetics studies where mice were fasted one time during an experiment for up to seven hours during the light cycle. For experiments containing a ketogenic diet, all mice were fasted overnight one day before the dietary change. Chow was PicoLab Rodent 5053, and all purified diets were purchased from research diets, and provided the following diet codes: Ketogenic diet (KD, also called in fig 1 KD-LP) - D21111901Mi. Keto normal protein (KD- NP) - D21111902Mi. Control purified diet with low protein (CPD-LP) - D21111903i. 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. Low cellulose with 2.5% Inulin (LC_In2.5) - D22011 102i. 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

Administration of PI3K inhibitors and tumor volume measurements. 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). When not stated otherwise, BYL dose was 45 mg/kg, and 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).

BYL and BKM pharmacokinetics (PK) studies. Where indicated, mice were fasted ~2h before drug gavage, and food was put back after the 4h time point when mice were entering the dark cycle. Around 30 pl of blood was collected from the tail snip before gavage (which also represents ~20-24h after previous drug administration) and at the indicated time points after gavage. Blood was allowed to clot for 30 min at room temperature and then put on ice until further processing. Serum was separated by centrifuging blood at 2000 g for 10 min at 4°C, and was stored at -80°C until further analysis. BYL, BKM, and glucose levels were measured by liquid chromatography coupled to mass spectrometry (LC-MS).

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. The acid was then neutralized by adding 15% ammonium bicarbonate (NH4HCO3) aqueous solution (8.75% v/v of extraction buffer). Samples were vortexed and centrifuged at 17,000 g for 10 min at 4°C. The clear supernatant was transferred to MS vials and loaded to the mass-spec. To measure the absolute concentration of glucose, 13C-glucose standard was spiked into the extraction buffer. The absolute concentrations of BYL and BKM were obtained by preparing external standard curves with known amounts of drugs for LC-MS. LC-MS. 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). The flow rate was 150 pl/min. 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.

Statistical analysis. Data are presented as mean ± SEM for bar and line graphs. GraphPad Prism software version 9.0 was used to create figures and calculate statistics. One-way or two-way analysis of variance (ANOVA) with Dunnett’s or Sidak’s post hoc was used for multi pl e-group comparisons. Heatmaps and principal component analyses were generated using Metaboanalyst 5.0 (https://www. metaboanalyst.ca/). All comparisons were two-tailed, and p < 0.05 was considered to be a statistically significant difference. *p < 0.05, **p < 0.01, ***p < 0.001, ****p

< 0.0001.

EXAMPLE 2

To determine the importance of protein restriction on PI3K inhibition efficacy, four matched purified ingredient diets were designed, including either ketogenic or carbohydrate-rich, containing 5% or 20% protein. Using these diets, the efficacy of the FDA-approved PI3K inhibitor BYL-719 (BYL, alpelisib) 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. Nature 560, 499-503 (2018)) where PI3K inhibitors were unresponsive. These results indicate that purified diets, unrelated to their macronutrient composition, increase PI3K inhibition efficacy, while the drugs may be less effective in rodents receiving typical grain-based chow diets. This is the first observation that purified versus grain-based diets can impact the efficacy of targeted anticancer therapies.

To directly test this hypothesis, the effect of three diets, namely standard grain-based chow, ketogenic diet (5% protein) and carbohydrate-rich purified diet (macronutrient composition matched to chow, hereafter termed control purified diet, CPD) were compared on PI3K inhibition efficacy in pancreatic KPC allograft model. Notably, while diets alone did not affect tumor growth, carb-rich purified diet sensitized tumors to PI3K inhibition to a similar degree as the ketogenic diet (Figs. 2A-B). Importantly, while KD mice treated with BYL kept losing weight resulting in study termination for this group, mice on CPD maintained body weight, indicating that BYL is better tolerated in the context of CPD than KD (Fig. 2C). Serum glucose after drug treatment was comparable between chow and KD. CPD, however, resulted in yet higher serum glucose, indicating the drug may have a stronger systemic effect in this diet or that the control purified diet provides yet greater amounts of readily accessible carbohydrates than chow (Fig. 2D).

Next, blood drug levels under different diets were measured. It was found that purified diets led to significantly higher serum BYL levels, with peak drug levels increasing 1.5 and 2 fold and trough drug levels 30 and 70 fold for KD and CPD compared to chow, respectively (Figs. 2E- F). Principal component analysis of the serum metabolome, fecal metabolome, and fecal microbiome demonstrated that KD and CPD cluster closer to each other than to chow, indicating that overall metabolomic impact is more dependent on the diet’s origin (z.c., grain-based vs. purified) than its macronutrient composition (Figs. 2G-I).

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. It was found that PI3K inhibition was still enhanced even when mice consumed purified diets containing high fiber (Fig. 3A). The distinct impact of chow relative to even fiber-rich purified diets was also evident in serum metabolomics, as purified diets containing fiber showed a common metabolite profile which was different from chow (Fig. 3B). These results indicate that there is another hidden factor intrinsic to purified diets besides fiber which may mediate the increased BYL efficacy.

To determine whether gut microbiome, which significantly differed between chow and purified diets (Fig. 21), has a role in the synergy PI3K inhibition with purified diets, 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. Unexpectedly, 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). Importantly, antibiotics alone without BYL administration did not affect tumor growth, ruling out a direct effect of antibiotics on tumor growth (Fig. 4B). These results indicate that the gut microbiome is critical in determining a tumor’s response to PI3K inhibition.

Next, whether a specific subset of the gut microbial community is responsible for the phenotype was studied. To this end, 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). Importantly, the ability of purified diet and ampicillin to enhance PI3K inhibition efficacy and PK was not limited to BYL. Similar results were obtained when another pan-PI3K inhibitor, BKM-120, was tested (Figs. 6A-D). In summary, these results strongly indicate that a chow-abundant ampicillinsensitive microbiome suppresses anti -cancer activities of PI3K inhibitors, at least in part via PK.

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. The results indicate that manipulating the gut microbiome composition by purified diets or antibiotics enhances PI3K efficacy by improving drug pharmacokinetics. Importantly, the combination of PI3K inhibitors with purified diets or ampicillin remains efficacious and tolerable over time.

The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting the present disclosure as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present disclosure as set forth in the claims. Such variations are not regarded as a departure from the scope of the disclosure, and all such variations are intended to be included within the scope of the following claims. All references cited herein are incorporated by reference in their entireties.

Claims

CLAIMS What is claimed is:

1. A method of treating a cancer, comprising 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.

2. The method of claim 1, wherein 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.

3. The method of any one of the preceding claims, wherein 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.

4. The method of any one of the preceding claims, wherein the one or more antibiotics comprises (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.

5. The method of any one of the preceding claims, wherein the one or more antibiotics are administered at one or more doses of from about 10 mg/kg to about 500 mg/kg of body weight of the subject.

6. The method of any one of the preceding claims, wherein the purified diet comprises a ketogenic diet, a control purified diet, or a combination thereof.

7. The method of claim 6, wherein the ketogenic diet comprises 20 wt%, 10 wt%, 5 wt%, or less of proteins.

8. The method of any one of claims 6-7, wherein the ketogenic diet comprises about 5 wt% of proteins, about 93 wt% of fat, and about 2 wt% of carbohydrates.

9. The method of any one of claims 6-8, wherein the control purified diet comprises from about 5 wt% to about 40 wt% of proteins.

10. The method of any one of claims 6-9, wherein the control purified diet comprises about 20 wt% of proteins, about 12 wt% of fat, and about 68 wt% of carbohydrates.

11. The method of any one of the preceding claims, wherein 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.

12. The method of any one of the preceding claims, wherein the PI3K inhibitor comprises a PI3K-alpha inhibitor.

13. The method of any one of the preceding claims, wherein the PI3K inhibitor comprises a pan-PI3K inhibitor.

14. The method of any one of the preceding claims, wherein the PI3K inhibitor comprises BYL-719, BKM-120, or a combination thereof.

15. The method of any one of the preceding claims, wherein the PI3K inhibitor is administered at one or more doses of from about 5 mg/kg to about 200 mg/kg of body weight of the subject.

16. The method of any one of the preceding claims, wherein the PI3K inhibitor is administered to the subject before or after the one or more antibiotics or the purified diet.

17. The method of any one of the preceding claims, wherein the PI3K inhibitor is administered to the subject concurrently with the one or more antibiotics or the purified diet.

18. The method of any one of the preceding claims, wherein the PI3K inhibitor is contained in the same composition with the one or more antibiotics or the purified diet.

19. The method of any one of the preceding claims, wherein 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.

20. The method of any one of the preceding claims, wherein 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.

21. The method of any one of the preceding claims, wherein 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.

22. The method of any one of the preceding claims, wherein 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.

23. The method of any one of the preceding claims, wherein the subject is a mammal.

24. The method of any one of the preceding claims, wherein the subject is a human.

25. The method of any one of the preceding claims, further comprising administering to the subject an additional therapeutic agent or therapy.

26. The method of claim 25, wherein the additional therapeutic agent comprises a second PI3K inhibitor, a second antibiotic, a second purified diet, or a combination thereof.

27. Use of a 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 according to any one of the preceding claims.

28. 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.

29. The pharmaceutical composition of claim 28, wherein 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.

30. The pharmaceutical composition of any one of claims 28-29, wherein 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.

31. The pharmaceutical composition of any one of claims 28-30, wherein 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.

32. The pharmaceutical composition of any one of claims 28-31, wherein the purified diet comprises a ketogenic diet, a control purified diet, or a combination thereof.

33. The pharmaceutical composition of claim 32, wherein the ketogenic diet comprises 20 wt%, 10 wt%, 5 wt%, or less of proteins.

34. The pharmaceutical composition of any one of claims 32-33, wherein the ketogenic diet comprises about 5 wt% of proteins, about 93 wt% of fat, and about 2 wt% of carbohydrates.

35. The pharmaceutical composition of any one of claims 32-34, wherein the control purified diet comprises from about 5 wt% to about 40 wt% of proteins.

36. The pharmaceutical composition of any one of claims 32-35, wherein the control purified diet comprises about 20 wt% of proteins, about 12 wt% of fat, and about 68 wt% of carbohydrates.

37. The pharmaceutical composition of any one of claims 28-36, wherein the PI3K inhibitor comprises a PT3K-alpha inhibitor.

38. The pharmaceutical composition of any one of claims 28-37, wherein the PI3K inhibitor comprises a pan-PI3K inhibitor.

39. The pharmaceutical composition of any one of claims 28-38, wherein the PI3K inhibitor comprises BYL-719, BKM-120, or a combination thereof.

40. A kit comprising the pharmaceutical composition of any one of claims 28-39.