WO2023172872A2

WO2023172872A2 - Biomarkers for combination therapies

Info

Publication number: WO2023172872A2
Application number: PCT/US2023/063788
Authority: WO
Inventors: Peter J.P. CROUCHER; Maya RIDINGER; Mark Erlander; Errin SAMUELSZ
Original assignee: Cardiff Oncology, Inc.
Priority date: 2022-03-07
Filing date: 2023-03-06
Publication date: 2023-09-14
Also published as: WO2023172872A3

Abstract

Disclosed herein include methods, compositions, and kits suitable for use in treating a subject having cancer and/or determining the efficacy of treatment to a subject having a cancer. In some embodiments, the method comprises determining the presence or absence of at least one mutation in a gene encoding mechanistic target of rapamycin kinase (mTOR) in the subject; and administering onvansertib and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the mTOR gene is determined to be present in the subject.

Description

BIOMARKERS FOR COMBINATION THERAPIES

RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. 63/317,277, filed March 7, 2022, the content of this related application is incorporated herein by reference in its entirety for all purposes.

BACKGROUND

Field

[0002] The present disclosure relates generally to the field of cancer treatment. More specifically, therapies for treating cancer using the antiandrogen or androgen antagonist abiraterone in combination with the PLK1 inhibitor onvansertib are provided. Methods are provided for predicting effectiveness of treatment of cancer with onvansertib and the antiandrogen or androgen antagonist.

Description of the Related Art

[0003] Prostate cancer is the most frequently diagnosed non-skin related cancer and the second leading cause of cancer related deaths among men. A hallmark of prostate cancer is its dependence on androgen signaling through the androgen receptor (AR). While the efficacy of androgen-depletion therapy for the treatment of metastatic prostate cancer has been known for more than 70 years, patients frequently progress to androgen-independent or castrate-resistant prostate cancer (CRPC).

[0004] Several second line anti-androgen therapies have been developed which further inhibit androgen signaling by competing with androgen for AR binding, disrupting testosterone synthesis, or both. For example, abiraterone has been shown to bind to the androgen receptor (Richards et al., Cancer Res., 72:2176-2182 (2012). While beneficial, the response to these strategies is almost always short lived.

[0005] There exists a need for improved therapies that effectively treat androgenindependent or castrate-resistant prostate cancer, particularly those cancers that are not effectively treated by the second-line anti-androgen therapies discussed above.

[0006] There is also a need for therapies that effectively treat cancers which overexpress AR, or are otherwise dependent on the synthesis of steroid hormones for their growth and survival, such as some breast cancers.

SUMMARY

[0007] Disclosed herein include methods for treating a subject with a cancer. In some embodiments, the method comprises: (a) determining the presence or absence of at least one mutation in a gene encoding mechanistic target of rapamycin kinase (mTOR) in sample nucleic acids from the subject; and (b) administering onvansertib, and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids, thereby reducing or inhibiting progression of the cancer in the subject.

[0008] Disclosed herein include methods for determining the efficacy of treatment to a subject having a cancer. In some embodiments, the method comprises: (a) determining the presence or absence of at least one mutation in a gene encoding mTOR in sample nucleic acids from the subject; and (b) administenng onvansertib, and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids. In some embodiments, the subject has received or is undergoing a cancer treatment. In some embodiments, the cancer treatment comprises onvansertib and an antiandrogen or androgen antagonist. In some embodiments, the cancer treatment does not comprise onvansertib and/or an antiandrogen or androgen antagonist. In some embodiments, each of the at least one mutation is a single nucleotide variant, an insertion mutation, a deletion mutation, an internal tandem duplication, a copy number variant, translocation, or an inversion, relative to the wild type mTOR gene. In some embodiments, the at least one mutation is a single nucleotide variant.

[0009] The method can comprise obtaining the sample nucleic acids from a biological sample of the subject. In some embodiments, the biological sample comprises a bodily fluid, one or more tissues, one or more cells, or a combination thereof. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample comprises genomic DNA, circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), circulating tumor cell (CTC), RNA, or a combination thereof. In some embodiments, the biological sample comprises circulating tumor DNA (ctDNA).

[0010] In some embodiments, the antiandrogen or androgen antagonist is abiraterone. In some embodiments, administering onvansertib, and the antiandrogen or androgen antagonist synergistically reduces or inhibits progression of the cancer relative to onvansertib alone, the antiandrogen or androgen antagonist alone, and/or the additive effect of onvansertib alone and the antiandrogen or androgen antagonist alone.

[0011] In some embodiments, administering onvansertib and the antiandrogen or androgen antagonist improves one or more therapeutic effects in the subject relative to a control or a baseline. In some embodiments, the one or more therapeutic effects comprise complete remission with progression-free survival (PFS), level of prostate-specific antigen (PSA), radiographic or clinical progression, radiographic response, or a combination thereof. In some embodiments, the radiographic response is determined according to response evaluation criteria in solid tumors (RECIST) version 1.1. In some embodiments, administering onvansertib and the antiandrogen or androgen antagonist improves PFS, PSA level, radiographic or clinical progression, radiographic response, or a combination thereof in the subject, relative to subjects who do not have the at least one mutation in the gene encoding mTOR. In some embodiments, administering onvansertib and the antiandrogen or androgen antagonist increases PFS relative to subjects who do not have the at least one mutation in the gene encoding mTOR.

[0012] In some embodiments, onvansertib and the antiandrogen or androgen antagonist are administered simultaneously or sequentially. In some embodiments, the antiandrogen or androgen antagonist is administered to the subject prior to the administration of onvansertib. In some embodiments, the administration of the antiandrogen or androgen antagonist and the administration of onvansertib partially overlap. In some embodiments, onvansertib and the antiandrogen or androgen antagonist are administered to the subject through the same route of administration. In some embodiments, the administration of onvansertib is oral administration. In some embodiments, the administration of the antiandrogen or androgen antagonist is oral administration.

[0013] In some embodiments, onvansertib, the antiandrogen or androgen antagonist, or both are administered in a cycle of at least about 7 days, a cycle of at least about 14 days, a cycle of at least about 21 days, or a cycle of at least about 28 days. In some embodiments, onvansertib is administered on at least four days in the cycle. In some embodiments, the antiandrogen or androgen antagonist is administered daily. In some embodiments, the subject undergoes at least two cycles of administration of onvansertib and the antiandrogen or androgen antagonist.

[0014] In some embodiments, onvansertib is administered at 8 mg/m² - 90 mg/m² and the antiandrogen or androgen antagonist is administered at 10-2,000 mg/patient per day. In some embodiments, the antiandrogen or androgen antagonist is administered at 1000 mg/patient per day. In some embodiments, onvansertib is administrated at 24 mg/m² on days 1-5 of the 21- day cycle. In some embodiments, onvansertib is administrated at 18 mg/m² on days 1-5 of the 14-day cycle. In some embodiments, onvansertib is administrated at 12 mg/m² on days 1-14 of the 21 -day cycle.

[0015] The method can further comprises administering to the subject a steroid, e.g., prednisone or prednisolone. In some embodiments, the steroid is administered with the antiandrogen or androgen antagonist. In some embodiments, the steroid is administered daily. In some embodiments, the steroid is administered to the subject through the same route of administration as onvansertib and/or the antiandrogen or androgen antagonist. In some embodiments, the steroid is administered at 1-100 mg/patient per day. In some embodiments, the steroid is administered at 5 mg/patient per day.

[0016] In some embodiments, the cancer is a solid tumor cancer, e.g., an advanced or metastatic solid tumor cancer. In some embodiments, the solid tumor cancer is prostate cancer, breast cancer, ovarian cancer, or endometrial cancer. In some embodiments, the prostate cancer is selected from the group consisting of prostate intraepithelial neoplasia, neuroendocrine prostate cancer (NEPC), primary prostate cancer, androgen-independent prostate cancer, castrate-resistant prostate cancer, and metastatic prostate cancer. In some embodiments, the solid tumor cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0017] Disclosed herein include kits. In some embodiments, the kit comprises onvansertib; and a manual providing instructions for: a) determining the presence or absence of at least one mutation in a gene encoding mTOR in sample nucleic acids from a subject; and b) administering onvansertib and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids. In some embodiments, the manual comprises instructions for administering onvansertib at 8 mg/m² - 90 mg/m² and administering the antiandrogen or androgen antagonist at 10-2,000 mg/patient per day.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 depicts exemplary data related to progression-free survival (PFS) by arm. PFS differences between arms were analyzed using the Kaplan-Meier method with the logrank test, p-value (p) is indicated in FIG. 1.

[0019] FIG. 2A-FIG. 2C depict exemplary data related to top genomic alterations in each survival group. Patients were divided in short, average and long survival groups based on the interquartile range (IQR) of time on study of the whole cohort. FIG. 2A depicts the top genomic alterations in the short survival group. FIG. 2B depicts the top genomic alterations in the average survival group. FIG. 2C depicts the top genomic alterations in the long survival group.

[0020] FIG. 3A-FIG. 3C depict exemplary data related to heatmaps of residuals based on X² test of independence. FIG. 3A depicts the heatmap of residuals of all survival groups. FIG. 3B depicts a heatmap of residuals of the short survival group versus the long survival group. FIG. 3C depicts a heatmap of residuals of the short survival group versus the average survival group. Heatmaps only include genes where the absolute value of the residual is [0021] FIG. 4A-FIG. 4C depict exemplary data related to top genomic alterations in each survival cohort after reclassification. Patients were divided in short, average and long survival groups based on the interquartile range (IQR) of time on study of each arm. FIG. 4A depicts the top genomic alterations in the short survival group. FIG. 4B depicts the top genomic alterations in the average survival group. FIG. 4C depicts the top genomic alterations in the long survival group.

[0022] FIG. 5A-FIG. 5B depict heatmaps of residuals based on X² test of independence after reclassification. FIG. 5A depicts a heatmap of residuals of the short survival group versus the long survival group. FIG. 5B depicts a heatmap of residuals of the short survival group versus the average survival group. Heatmaps only include genes where the absolute value of the residual is >= 3.

DETAILED DESCRIPTION

[0023] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the Figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein and made part of the disclosure herein.

[0024] All patents, published patent applications, other publications, and sequences from GenBank, and other databases referred to herein are incorporated by reference in their entirety with respect to the related technology.

[0025] Disclosed herein include methods for treating a subject with a cancer. In some embodiments, the method comprises: (a) determining the presence or absence of at least one mutation in a gene encoding a mechanistic target of rapamycin kinase (mTOR) in sample nucleic acids from the subject; and (b) administering onvansertib, and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids, thereby reducing or inhibiting progression of the cancer in the subject.

[0026] Disclosed herein include methods for determining the efficacy of treatment to a subject having a cancer. In some embodiments, the method comprises: (a) determining the presence or absence of at least one mutation in a gene encoding mTOR in sample nucleic acids from the subject; and (b) administering onvansertib, and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids. In some embodiments, the subject has received or is undergoing a cancer treatment.

[0027] Disclosed herein include kits. In some embodiments, the kit comprises onvansertib; and a manual providing instructions for: a) determining the presence or absence of at least one mutation in a gene encoding mTOR in sample nucleic acids from a subject; and b) administering onvansertib and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids.

Definitions

[0028] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. See, e.g. Singleton et al., Dictionary' of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory' Manual, Cold Spring Harbor Press (Cold Spring Harbor, NY 1989). For purposes of the present disclosure, the following terms are defined below.

[0029] As used herein, a “patient” refers to a subject that is being treated by a medical professional, such as a Medical Doctor (i.e., Doctor of Allopathic medicine or Doctor of Osteopathic medicine) or a Doctor of Veterinary' Medicine, to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place. In some embodiments, the patient is a human or an animal. In some embodiments, the patient is a mammal. As used herein, the terms “individual,” “host,” “subject,” and “patient” are used interchangeably.

[0030] As used herein, “administration” or “administering” refers to a method of giving a dosage of a pharmaceutically active ingredient to a vertebrate.

[0031] As used herein, a “dosage” can refer to the combined amount of the active ingredients (e g., PLK1 inhibitor (e.g., onvansertib), antiandrogen or androgen antagonist (e.g., abiraterone) or steroid (e.g., prednisone)) or the amount of onvansertib, the amount of abiraterone or the amount of prednisone.

[0032] As used herein, the term “delivery” refers to approaches, formulations, technologies, and systems for transporting a pharmaceutical composition or a therapeutic agent into the body of a patient as needed to safely achieve its desired therapeutic effect. In some embodiments, an effective amount of the composition or agent is formulated for delivery into the blood stream of a patient. [0033] As used herein, the term “formulated” or “formulation” refers to the process in which different chemical substances, including one or more pharmaceutically active ingredients, are combined to produce a dosage form. In some embodiments, two or more pharmaceutically active ingredients can be co-formulated into a single dosage form or combined dosage unit, or formulated separately and subsequently combined into a combined dosage unit. A sustained release formulation is a formulation which is designed to slowly release a therapeutic agent in the body over an extended period of time, whereas an immediate release formulation is a formulation which is designed to quickly release a therapeutic agent in the body over a shortened period of time.

[0034] As used herein, the term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially stenle.

[0035] As used herein, the term “pharmaceutically acceptable carrier” refers to pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any supplement or composition, or component thereof, from one organ, or portion of the body, to another organ, or portion of the body, or to deliver an agent to a diseased tissue or a tissue adjacent to the diseased tissue. Carriers or excipients can be used to produce compositions. The carriers or excipients can be chosen to facilitate administration of a drug or pro-drug. Examples of earners include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. Examples of physiologically compatible solvents include sterile solutions of water for injection (WFI), saline solution, and dextrose.

[0036] As used herein, the term “pharmaceutically acceptable salt” refers to any acid or base addition salt whose counter-ions are non-toxic to the patient in pharmaceutical doses of the salts. A host of pharmaceutically acceptable salts are well known in the pharmaceutical field. If pharmaceutically acceptable salts of the compounds of this disclosure are utilized in these compositions, those salts are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, hydrohalides (e.g., hydrochlorides and hydrobromides), sulphates, phosphates, nitrates, sulphamates, malonates, salicylates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p- toluoyltartrates, ethanesulphonates, cyclohexylsulphamates, qumates, and the like. Pharmaceutically acceptable base addition salts include, without limitation, those derived from alkali or alkaline earth metal bases or conventional organic bases, such as triethylamine, pyridine, piperidine, morpholine, N-methylmorpholine, ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.

[0037] The pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, p. 704; and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” P. Heinrich Stahl and Camille G. Wermuth, Eds., Wiley-VCH, Weinheim, 2002.

[0038] As used herein, the term “hydrate” refers to a complex formed by combination of water molecules with molecules or ions of the solute. As used herein, the term “solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvate is meant to include hydrate, hemi-hydrate, channel hydrate etc. Some examples of solvents include, but are not limited to, methanol, A. Wdmielhyl formamide, tetrahydrofuran, dimethylsulfoxide, and water.

[0039] As used herein, “therapeutically effective amount” or “pharmaceutically effective amount” refers to an amount of therapeutic agent, which has a therapeutic effect. The dosages of a pharmaceutically active ingredient which are useful in treatment when administered alone or in combination with one or more additional therapeutic agents are therapeutically effective amounts. Thus, as used herein, a therapeutically effective amount refers to an amount of therapeutic agent which produces the desired therapeutic effect as judged by clinical trial results and/or model animal studies. The therapeutically effective amount will vary depending on the compound, the disease, disorder or condition and its severity and the age, weight, etc., of the mammal to be treated. The dosage can be conveniently administered, e.g., in divided doses up to four times a day or in sustained-release form.

[0040] As used herein, the term “dosage regime” refers to drug administration regarding formulation, route of administration, drug dose, dosing interval and treatment duration.

[0041] As used herein, the term “treat,” “treatment,” or “treating,” refers to administering a therapeutic agent or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes. The term “prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease or condition. As used herein, a “therapeutic effect” relieves, to some extent, one or more of the symptoms of a disease or disorder. For example, a therapeutic effect may be observed by a reduction of the subjective discomfort that is communicated by a subject (e.g., reduced discomfort noted in selfadministered patient questionnaire). “Pre-treatment” or “baseline,” as used herein, refers to the status of a subject prior to administration of a particular therapy, e.g., onvansertib and abiraterone.

[0042] As used herein, the term “combination therapy” refers to treatment of a disease or symptom thereof, or a method for achieving a desired physiological change, including administering to an animal, such as a mammal, especially a human being, an effective amount of two or more chemical agents or components to treat the disease or symptom thereof, or to produce the physiological change, wherein the chemical agents or components are administered together, such as part of the same composition, or administered separately and independently at the same time or at different times (e.g., administration of each agent or component is separated by a finite period of time from each other).

[0043] As used herein, the term “characterizing” or “characterized” refers to assessing a patient, tissue sample, nucleic acid sample or cell for the presence or absence of a mutation.

Cancer

[0044] The combination therapies are typically used to treat cancer, preferably a hormone-sensitive or hormone-dependent cancer that has become hormone-insensitive. Typically, hormone-sensitive cancers are initially dependent on a hormone for cancer growth. Altenng the cancer’s hormone supply through hormone therapy such as radiation therapy, drugs that alter hormone production, anti-hormones, aromatase inhibitors, Luteinizing hormone- releasing hormone (LH-RH) agonists and antagonists, or surgery to remove hormone producing tissue or organs, can make the tumors shrink and even lead to cancer remission. However, the effects of hormone therapy can be limited. Hormone sensitive cancers often become hormone- insensitive, meaning the cancer is no longer responsive to hormone therapy, although in most cases the tumor is still driven by intracellular hormonal signaling. The combination therapies are particularly effective for treating hormone-sensitive cancers that have become hormoneinsensitive. Exemplary cancers include, but are not limited to, prostate cancer, breast cancer, ovarian cancer, and endometrial cancer.

[0045] When hormone therapy is no longer effective, subjects with hormoneinsensitive cancers are typically administered a first line therapy. However, in many cases, the cancer cells also develop resistance to the first line therapy. For some hormone-insensitive cancers there are second line therapies available, however, over time the cancer cells can also develop resistance to the second line therapy. As discussed in more detail below, the combination therapies can re-sensitize cancer cells to a first or second-line therapy. Therefore, in some embodiments, the combination therapies are used to treat subjects with a hormoneinsensitive cancer that is also resistant to a first line therapy, a second line therapy, or a combination thereof. In some cases, the first line therapy, second line therapy, or a combination thereof includes the administration of one of the active agents of the combination therapy without co-administration of the other active agent. Therefore, in some embodiments administration of the combination therapy re-sensitizes the cancer cells to an active agent that was previously administered to the subject as a first or a second line therapy. In preferred embodiments, the re-sensitization is effective even in the presence of rising hormone levels.

[0046] In preferred embodiments, the cancer cells can express the androgen receptor, and/or the cancer is an androgen-sensitive cancer that has become androgen-insensitive (also referred to as an androgen-independent cancer). Androgen-independent cancer is typically a cancer that has reacquired an ability to grow following temporary suppression of the cancer's ability to grow by inhibiting androgen production or function. In some embodiments, suppression of the cancer's ability to grow refers to suppression of tumor growth or another symptom of the cancer, for example, amelioration of ostealgia.

[0047] Suppression of the cancer’s ability to grow using a hormone therapy or physical castration (e.g., orchiectomy), can be measured using a biochemical assay, for example, measuring a decline in the prostate specific antigen (PSA) concentration in the blood, or by a morphometric analysis, for example by computerized tomography (CT), magnetic resonance imaging (MRI) or ultrasound. A decline in the blood PSA concentration effective to reduce an androgen sensitive cancer’s ability to grow is typically a blood PSA concentration of about or below 5 ng/mL, about or below 1 ng/ml, about or below 0.5 ng/ml, about or below 0.2 ng/ml, about or below 0.1 ng/ml, or undetectable.

[0048] A cancer that has reacquired an ability to grow can be an increase in tumor growth, the emergence, reemergence, or aggravation of other symptoms such as ostealgia, new sites of metastasis, or a rise in blood PSA. A sustained rise in blood PSA concentration observed in the course of periodic tests can indicate that the cancer has reacquired the ability to grow. A blood PSA concentration of, for example, about 5 ng/mL or more can also indicate that the cancer has reacquired the ability to grow. Because various factors (such as sexual activities) can cause PSA levels to fluctuate, one abnormal PSA test does not necessarily indicate a problem.

[0049] The cancer can be advanced, metastatic, refractory, or relapsed. “Refractory” as used herein can refer to a disease, e.g., cancer, that does not respond to a treatment. In some embodiments, a refractory cancer can be resistant to a treatment before or at the beginning of the treatment. In other embodiments, the refractory cancer can become resistant dunng a treatment. A refractory cancer is also called a resistant cancer. “Relapsed” as used herein refers to the return of a disease (e.g., cancer) or the signs and symptoms of a disease such as cancer after a period of improvement, e.g., after prior treatment of a therapy, e.g., cancer therapy.

[0050] The cancer can be a solid tumor cancer, for example an advanced or metastatic solid tumor cancer. The solid tumor cancer can be prostate cancer, breast cancer, ovarian cancer, or endometrial cancer. The prostate cancer can be selected from \ prostate intraepithelial neoplasia, neuroendocrine prostate cancer (NEPC), primary prostate cancer, androgen-independent prostate cancer, castrate-resistant prostate cancer, and metastatic prostate cancer. The solid tumor cancer can be metastatic castration-resistant prostate cancer (mCRPC).

Prostate Cancer

[0051] The cancer can be prostate cancer. Prostate cancer is the most frequently diagnosed malignancy in men in Western countries. Examples of prostate cancer include prostate intraepithelial neoplasia, neuroendocrine prostate cancer (NEPC), primary prostate cancer, androgen-independent prostate cancer, castrate-resistant prostate cancer, and metastatic prostate cancer. While localized prostate cancer can be effectively treated with surgery or radiation therapy, metastatic prostate cancer still remains incurable. For locally advanced or widespread disease, suppressing the tumor growth by hormone ablation therapy represents the common first therapeutic option (Beltran, et al., European Urology, 60:279-290 (2011)). Although initial therapy can lead to long-term remission, development of hormone ablation resistance can eventually occur, a standing referred to as castration-resistant prostate cancer (CRPC). Therefore, in some embodiments, the subject has a CRPC. Unlike early prostate cancer, CRPC is an aggressive disease that progresses despite castrate levels of testosterone (<50 ng/ml). It is diagnosed by one or more of the following discussed above for androgeninsensitive cancers (e.g., sustained rise in serum levels of prostate-specific antigen (PSA), progression of pre-existing disease, the appearance of new metastases, or a combination thereof).

[0052] Subjects with CRPC are typically administered a first line therapy. Docetaxel and sipuleucel-T are exemplary first line treatment options for patients with CRPC. Second-line treatments following first line treatment failure include cabazitaxel and abiraterone acetate. The history of first and second line therapeutic options for subjects with CRPC are reviewed in Shapiro and Tareen, Expert Rev. Anticancer Ther., 12(7):951-964 (2012) and Heidegger, et al., J. Steroid Biochem. Mol. Biol., 138(100): 248-256 (2013), which are both specifically incorporated by reference herein in their entireties. The combination therapies can be administered to subjects which have previously been administered a first line therapy for CRPC and/or a second line therapy for CRPC. In a particular embodiment, the combination therapy is administered to a subject when a first line therapy and/or a second line therapy have become ineffective to treat or prevent progression of the cancer. The combination is particularly effective in treating prostate cancers characterized by one or more mutations in the gene encoding mTOR.

[0053] In a particular embodiment, the combination therapy is administered to a subject that was previously administered an agent that targets and inhibits androgen receptor activity. The agent can target androgen receptor activity directly, or indirectly, for example by inhibiting androgen synthesis. In a particular preferred embodiment, the subject was previously administered an abiraterone-based therapy such as ZYTIGA® (abiraterone acetate). Abiraterone has been administered to subjects as a first line therapy and as a second line therapy, typically following chemotherapy, for treatment of CRPC. The data presented in the working Examples below illustrates that the combination therapies are effective to treat cancers that have become resistant to abiraterone.

Breast Cancer

[0054] The cancer can be breast cancer, preferably a breast cancer characterized by breast cancer cells that expresses the androgen receptor. Androgens play a role in normal breast phy siology and AR signaling is recognized as an important contributor in breast carcinogenesis (Garay, et al., Am. J. Cancer Res., 2(4):434-445 (2012)). The androgen receptor is expressed in most breast cancers, and although the mechanism underlying the androgen receptor's role in cancer progression remains unclear, it has been identified as a potential therapeutic target for breast cancer treatment. Therefore, in some embodiments, the combination therapy is administered to treat a breast cancer, preferably, but not limited to, an androgen receptorpositive breast cancer.

[0055] The success of estrogen receptor/progesterone receptor (ER/PR) and HER2 targeted therapies has shifted interest in androgen receptor to those breast cancers that lack ER/PR and/or HER2 expression, often referred to as “triple negative breast cancer” or “triple negative disease”. In addition, AR targeted therapies may also be important for breast cancers that have developed resistance to current hormone and HER2 directed therapies. Therefore, in some embodiments, the breast cancer lacks ER, PR, or HER2 expression, or a combination thereof (e.g., triple negative disease), is a hormone-insensitive cancer, is resistant to a HER2 directed therapy, or any combination thereof.

[0056] It has also been shown both in vitro and in vivo that combinatorial therapy targeting both the MAP kinase pathway and AR is an effective means of reducing tumor cell viability and tumor burden (Naderi and Liu, Cancer Lett., 298: 74-87 (2010)). Therefore, in some embodiments, the combination therapies include an inhibitor of the MAP kinase pathway.

Other Cancers

[0057] The compositions and methods described can be used to treat multiple types of cancer. It has been established that an androgen receptor antagonist or anti-androgen, or a derivative, analog or prodrug, or a pharmacologically active salt thereof in combination with one or more PLK inhibitors can give rise to profound greater than additive killing of cancers that are not associated with consistent expression of androgen receptor signaling or other steroid hormone or growth factors. Therefore, multiple non-hormonal cancers can be treated using the compositions and methods described herein.

[0058] The combination is particularly effective in treating cancers characterized by up-regulated expression of genes that are involved in the Retinoic Acid Receptor (RA) signaling pathway, specifically genes including the Retinoic Acid Receptor Alpha (RARA); Retinoic Acid Receptor Gamma (RARG); Retinol Dehydrogenase (ADH4); and Retinaldehyde Reductase (DHRS3). Cancers that have been identified as having up-regulated expression of genes that are involved in the Retinoic Acid Receptor (RA) signaling pathway include multiple types of cancers, including but not limited to prostate, breast, and pancreatic cancers.

[0059] Pancreatic cancers include pancreatic adenocarcinoma or pancreatic exocrine cancer, and often have a poor prognosis, even when diagnosed early. Pancreatic cancer typically spreads rapidly and is seldom detected in its early stages, and pancreatic carcinoma is a leading cause of cancer death. Signs and symptoms can include upper abdominal pain; bowel obstruction; back pain; yellow discoloration of the skin and whites of the eye (i.e., jaundice); reduced appetite; weight loss; depression; and blood clots. Symptoms may not appear until pancreatic cancer is quite advanced and complete surgical removal is not possible.

[0060] Gene expression profiles for cancer cells within a tumor or for cells within the tumor microenvironment can be determined in vitro or in vivo by any means known in the art. Genomic databases can also be used as a guide for the selection of pharmacologic vulnerabilities to genomic paterns. Such databases include the Cancer Cell Line Encyclopedia (CCLE), including gene expression profile information for human cancer cell lines (Stransky, et al. Nature 483, 603-307 (2012)).

[0061] The cancer that can be treated using the disclosed compositions and methods can be a solid tumor cancer. A representative, but non-limiting, list of cancers that the disclosed compositions and methods can be used to treat include melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary' gland cancer, prostate cancer, pancreatic cancer, Merkel cell carcinoma, brain and central nervous system cancers, and any combination thereof.

Mechanistic Target of Rapamycin Kinase (mTOR)

[0062] Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopicus having the structure shown in Formula A.

(A)

[0063] In mammalian cells, the target of rapamycin kinase (mTOR) exists as a multiprotein complex described as the mTORCl complex or mTORC2 complex, which senses the availability of nutrients and energy and integrates inputs from growth factors and stress signaling. The mTORCl complex is sensitive to allosteric mTOR inhibitors such as rapamycin, is composed of mTOR, G L, and regulatory associated proteins of mTOR (raptor), and binds to the peptidyl-prolyl isomerase FKBP12 protein (a FK506-binding protein 1 A, 12 kDa). In contrast, the mT0RC2 complex is composed ofmTOR, GPL, and rapamycin-insensitive companion proteins of mTOR (rictor), and does not bind to the FKBP12 protein in vitro.

[0064] The mTORCl complex has been shown to be involved in protein translational control, operating as a growth factor and nutrient sensitive apparatus for growth and proliferation regulation. mTORCl regulates protein translation via two key downstream substrates: P70 S6 kinase, which in turn phosphorylates ribosomal protein P70 S6, and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), which plays a key role in modulating eIF4E regulated cap-dependent translation. The mTORCl complex regulates cell growth in response to the energy and nutrient homeostasis of the cell, and the deregulation of mTORCl is common in a wide variety of human cancers. The function of mT0RC2 involves the regulation of cell survival via phosphorylation of Akt and the modulation of actin cytoskeleton dynamics.

[0065] The mTORCl complex is sensitive to allosteric mTOR inhibitors such as rapamycin and derivatives in large part due to rapamycm's mode of action, which involves the formation of an intracellular complex with the FKBP12 and binding to the FKBP12-rapamycin binding (FRB) domain of mTOR. This results in a conformational change in mTORCl which is believed to alter and w eaken the interaction with its scaffolding protein raptor, in turn impeding substrates such as P70 S6K1 from accessing mTOR and being phosphorylated. Thus, mutations affecting the activities of mTOR can be associated with both benign and malignant proliferation disorders, such as cancers.

Detection of mTOR Mutations

[0066] Disclosed herein include methods for treating a subject with a cancer. In some embodiments, the method comprises: (a) determining the presence or absence of at least one mutation in a gene encoding mTOR in sample nucleic acids from the subject; and (b) administering onvansertib, and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids, thereby reducing or inhibiting progression of the cancer in the subject.

[0067] Each of the at least one mutation can be a single nucleotide variant, an insertion mutation, a deletion mutation, an internal tandem duplication, a copy number variant, or an inversion, relative to the corresponding wdld type gene. In some embodiments, the mutation can result in loss-of-function (If) or gain-of-function (gf) of the protein encoded by the gene relative to the corresponding wild type protein. In some embodiments, the mutation can result in a truncated protein product. In some embodiments, the mutation is a missense mutation (e.g., results in an amino acid change at a particular residue). A mutation can be a single nucleotide variant, an insertion mutation, a deletion mutation, an internal tandem duplication, a copy number variant, translocation, or an inversion, relative to the wild type mTOR gene. In some embodiments, the at least one mutation can be a single nucleotide variant.

[0068] Sample nucleic acids can also be analyzed for the presence or absence of a gene expression signature. The term “gene expression signature,” as used herein can refer to a unique pattern of gene expression in a cell, e.g., in a biological sample obtained from a subject with cancer.

[0069] The method can comprise obtaining the sample nucleic acids from a biological sample of the subject. The biological sample can comprise a bodily fluid, one or more tissues, one or more cells, or a combination thereof. The biological sample can be a blood sample. Mutations in a gene encoding mTOR can be detected in a biological sample (including but not limited to a bodily fluid (e.g., a blood sample)) from a subject of interest (e.g., a subject with a hematological cancer). For example, the mutations can be detected in genomic DNA, the circulating tumor cells (CTCs), cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), RNA, or a combination thereof, obtained from plasma fraction, serum fraction, or both, of a blood sample. In some embodiments, the bodily sample is whole blood, serum, plasma, cerebrospinal fluid synovial fluid, lymphatic fluid, ascites fluid, interstitial or extracellular fluid, the fluid in spaces between cells, including gingival crevicular fluid, bone marrow, pleural effusions, cerebrospinal fluid, saliva, mucous, sputum, semen, sweat, urine, or any combination thereof. In some embodiments, the sample is obtained from blood and fractions thereof. A sample can be isolated or obtained from a subject and transported to a site of sample analysis. The sample may be preserved and shipped at a desirable temperature, e.g., room temperature, 4°C, -20°C, and/or -80°C. A sample can be isolated or obtained from a subject at the site of the sample analysis. The subject can be a human, a mammal, an animal, a companion animal, a service animal, or a pet. The subject may not have cancer or a detectable cancer symptom. The subject may have been treated with one or more cancer therapy, e.g., any one or more of chemotherapies, antibodies, vaccines or biologies. The subject may be in remission. The subject may be suspected to have cancer or any cancer-associated genetic mutations/disorders.

[0070] The sample can comprise nucleic acids. The terms “nucleic acid” and “nucleic acid molecule” may be used interchangeably herein. The terms refer to nucleic acids of any composition, such as DNA (e.g., complementary DNA (cDNA), genomic DNA (gDNA) and the like), RNA (e.g., message RNA (mRNA), short inhibitory RNA (siRNA), ribosomal RNA (rRNA), tRNA, microRNA, and/or DNA or RNA analogs (e.g., containing base analogs, sugar analogs and/or a non-native backbone and the like), RNA/DNA hybrids and polyamide nucleic acids (PNAs), all of which can be in single- or double-stranded form, and unless otherwise limited, can encompass known analogs of natural nucleotides that can function in a similar manner as naturally occurring nucleotides. A nucleic acid can be, or can be from, a plasmid, phage, autonomously replicating sequence (ARS), centromere, artificial chromosome, chromosome, or other nucleic acid able to replicate or be replicated in vitro or in a host cell, a cell, a cell nucleus, a mitochondria, or cytoplasm of a cell. Unless specifically limited, the term encompasses nucleic acids containing known analogs of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, single nucleotide polymorphisms (SNPs), and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues. The term nucleic acid may be used interchangeably with locus, gene, cDNA, and mRNA encoded by a gene. The term also may include, as equivalents, derivatives, variants and analogs of RNA or DNA synthesized from nucleotide analogs, single-stranded (“sense” or “antisense”, “plus” strand or “minus” strand, “forward” reading frame or “reverse” reading frame, “forward” strand or “reverse” strand) and double-stranded polynucleotides. The term “gene” can refer to the segment of DNA involved in producing a “gene product” such as a miRNA or a polypeptide. Generally, a gene includes regions preceding and following, e.g., the coding region (leader and trailer) involved in the transcription/translation of the gene product and the regulation of the transcription/translation, as well as intervening sequences (introns) between individual coding segments (exons). A nucleotide or base generally refers to the purine and pyrimidine molecular units of nucleic acid (e.g., adenine (A), thymine (T), guanine (G), and cytosine (C)). For RNA, the base thymine is replaced with uracil. Nucleic acid length or size may be expressed as a number of bases. A sample can include sample nucleic acids (e.g., a plurality of sample nucleic acids). The term “plurality” is used herein to mean two or more. Thus, in some embodiments, a sample includes two or more (e g., 3 or more, 5 or more, 10 or more, 20 or more, 50 or more, 100 or more, 500 or more, 1,000 or more, or 5,000 or more) sample nucleic acids (e.g., DNAs/RNAs). A disclosed method can be used as a very sensitive way to detect a target nucleic acid present in a sample (e.g., in a complex mixture of nucleic acids such as DNAs/RNAs). In some embodiments, the sample includes 5, 10, 20, 25, 50, 100, 500, 10³, 5* 10³, 10⁴, 5*10⁴, 10⁵, 5>< 10⁵, 10⁶, or 10⁷, or more, DNAs/RNAs that differ from one another in sequence. In some embodiments, the sample includes DNAs/RNAs from a cell lysate (e.g., a eukaryotic cell lysate, a mammalian cell lysate, a human cell lysate, a prokaryotic cell lysate, a plant cell lysate, and the like). For example, in some embodiments, the sample includes DNA/RNA from a cell such as a eukaryotic cell, e.g., a mammalian cell such as a human cell.

[0071] The term “sample” as used herein shall be given its ordinary meaning and shall include any sample that includes DNA and/or RNA (e.g., in order to determine the presence or absence of at least one mutation in a gene encoding mTOR). The sample can be derived from any source, e.g., the sample can be a synthetic combination of purified DNAs and/or RNAs; the sample can be a cell lysate, an DNA/RNA-enriched cell lysate, or DNAs/RNAs isolated and/or purified from a cell lysate. The sample can be from a subject (e.g., a patient). The sample can be from permeabilized cells. The sample can be from crosslinked cells. The sample can be in tissue sections. The sample can be from tissues prepared by crosslinking followed by delipidation and adjustment to make a uniform refractive index. A “sample” can include a target nucleic acid (e.g., target DNA/RNA) and a plurality of non-target DNAs/RNAs. In some embodiments, the target DNA/RNA is present in the sample at one copy per 10, 20, 25 , 50, 100, 500, 10³, 5*10³, 10⁴, 5x l0⁴, 10⁵, 5* 10⁵, 10⁶, or 10⁷, non-target DNAs/RNAs.

[0072] Suitable samples include but are not limited to saliva, blood, serum, plasma, urine, aspirate, and biopsy samples. The term “sample” with respect to a patient encompasses blood and other liquid samples of biological origin, solid tissue samples such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof. The definition also includes samples that have been manipulated in any way after their procurement, such as by treatment with reagents; washed; or enrichment for certain cell populations, such as cancer cells. The definition also includes sample that have been enriched for particular types of molecules, e.g., DNAs. A sample can comprise a biological sample such as a clinical sample such as blood, plasma, serum, aspirate, cerebral spinal fluid (CSF), and also includes tissue obtained by surgical resection, tissue obtained by biopsy, cells in culture, cell supernatants, cell lysates, tissue samples, organs, bone marrow, and the like. A biological sample can comprise biological fluids derived therefrom, cells (e.g., cancerous cells, infected cells) or DNAs that is obtained from such cells (e.g., a cell lysate or other cell extract comprising DNAs). In some embodiments, the source of the sample is a (or is suspected of being) a diseased cell, fluid, tissue, or organ. In some embodiments, the source of the sample is a normal (non-diseased) cell, fluid, tissue, or organ.

[0073] In some embodiments, the sample comprises cell-free nucleic acids. Cell-free nucleic acids are nucleic acids not contained within or otherwise bound to a cell or in other words nucleic acids remaining in a sample after removing intact cells. Cell-free nucleic acids include DNA, RNA, and hybrids thereof, including genomic DNA, mitochondrial DNA, siRNA, miRNA, circulating RNA (cRNA), tRNA, rRNA, small nucleolar RNA (snoRNA), Piwi- interacting RNA (piRNA), long non-coding RNA (long ncRNA), or fragments of any of these. Cell-free nucleic acids can be double-stranded, single-stranded, or a hybrid thereof. A cell-free nucleic acid can be released into bodily fluid through secretion or cell death processes, e.g., cellular necrosis and apoptosis. Some cell-free nucleic acids are released into bodily fluid from cancer cells e.g., ctDNA. Others are released from healthy cells. cfDNA can be obtained from a bodily fluid without the need to perform an in vitro cell lysis step, and thus presents a non- invasive option for genomic analysis. Provided herein include methods, compositions, kits and systems for detecting and/or analyzing cell free nucleic acids (e.g., ctDNA) in bodily fluid (e.g., peripheral blood) for clinical outcome prediction/determination. The methods can comprise combined analysis of single cells and cell-free nucleic acids.

[0074] Various assays (e.g., sequencing assays) can be used to detect and analyze sample nucleic acids. The methods provided herein can comprise isolation and analysis of nucleic acids from the blood (e.g., plasma and/or serum) of a subject of interest (e.g., a subject with hematological cancer), employing the use of molecular barcoding and sequencing as a readout (e.g., next generation sequencing). The nucleic acid can be obtained from a sample by known methods, and can be analyzed by methods including but not limited to polymerase chain reaction (PCR) and next generation sequencing (NGS). In some embodiments, the nucleic acids are analyzed using targeted NGS (e.g., against a specific panel of mutations). In some embodiments, the nucleic acids are analyzed using droplet digital PCR (ddPCR).

[0075] The nucleic acids can carry one or more types of mutations, for example, germline mutations, somatic mutations, or both. Germline mutations refer to mutations existing in germline DNA of a subject. Somatic mutations refer to mutations originating in somatic cells of a subject (e.g., non-germline cells). The sample nucleic acids from a subject can carry one or more mutations in one or more genes, for example a gene encoding mTOR. In some embodiments, the mutation can be a prostate cancer-associated mutation in a gene encoding mTOR. Each of the at least one mutation can be a single nucleotide variant, an insertion mutation, a deletion mutation, an internal tandem duplication, a copy number variant, or an inversion, relative to the corresponding wild type gene.

Administration

[0076] As disclosed herein, a combination therapy of an antiandrogen or androgen antagonist (e.g., abiraterone) and a PLK1 inhibitor (e.g., onvansertib) can surprisingly result in significantly enhanced efficacy against solid tumor cancer (e.g., prostate cancer) in a subject that is refractory and/or recurring. The therapeutic effect can be surprisingly synergistic (e.g., more than additive, superior to the cumulated anti-cancer efficacy caused by the antiandrogen or androgen antagonist and the PLK1 inhibitor separately). The PLK1 inhibitor can be onvansertib. The antiandrogen or androgen antagonist can be abiraterone. Provided herein include methods, compositions and kits for treating solid tumor cancer in a subject (e.g., a human patient suffering from prostate cancer). Provided herein include methods, compositions and kits for treating cancer in a subject (for example, a human patient suffering from cancer) if at least one mutation in a gene encoding mTOR is determined to be present in sample nucleic acids obtained from the subject. The method comprises administrating an antiandrogen or androgen antagonist (e.g., abiraterone) and a PLK1 inhibitor (e.g., onvansertib) to the subject in a manner sufficient to inhibit progression of the cancer. For example, the onvansertib and abiraterone can be administrated to a subject with cancer simultaneously, separately, or sequentially.

[0077] In some embodiments, administering the PLK inhibitor and the antiandrogen or androgen antagonist synergistically reduces or inhibits progression of the cancer relative to the PLK1 inhibitor treatment alone, the antiandrogen or androgen antagonist treatment alone, and/or the additive effect of the PLK1 inhibitor treatment alone and the antiandrogen or androgen antagonist treatment alone. For example, administering onvansertib, and the antiandrogen or androgen antagonist synergistically can reduce or inhibit progression of the cancer relative to onvansertib alone, the antiandrogen or androgen antagonist alone, and/or the additive effect of onvansertib alone and the antiandrogen or androgen antagonist alone.

[0078] In some embodiments, the inhibition or reduction of cancer progression is not merely additive, but is enhanced or synergistic (that is, the inhibition is greater than the combined inhibition of progression caused by the onvansertib and abiraterone alone). The enhanced or synergistic efficacy or inhibition of any combination of an antiandrogen or androgen antagonist and a PLK1 inhibitor of the present disclosure can be different in different embodiments. In some embodiments, the enhanced or synergistic efficacy or inhibition of any combination of a PLK1 inhibitor and an antiandrogen or androgen antagonist (e.g., onvansertib and abiraterone) of the present disclosure is, is about, is at least, is at least about, is at most, or is at most about, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values, higher than the combined inhibition of progression caused by onvansertib and abiraterone alone.

[0079] The molar ratio of the PLK1 inhibitor (e.g., onvansertib) to the antiandrogen or androgen antagonist (e.g., abiraterone) can be, for example, about 1:200, 1 :100, 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1 : 10, 1: 1, 10: 1, 20:1, 30:1, 40:1, 50:1, 100: 1, 1000:1, 2000: 1, or 5000: 1, or a number or a range between any two of these values. In some embodiments, the enhanced or synergistic efficacy or inhibition of cancer progression caused by a combination of onvansertib and abiraterone is, is about, is at least, is at least about, is at most, or is at most about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, or a number or a range between any two of these values, higher than the combined inhibition of progression caused by abiraterone alone plus onvansertib alone. For example, a combination of onvansertib and abiraterone can cause a 50%, 60%, 70%, 80%, 90%, or more, inhibition of cancer progression (cancer cell viability of 50%, 40%, 30%, 20%, 10%, or less), whereas under the same conditions the combined inhibition of the abiraterone alone plus the onvansertib alone can be 10%, 20%, 25%, 30%, or less) inhibition of cancer progression (cancer cell viability of 90%, 80%, 75%, 70%, or more). Thus, the enhanced or synergistic efficacy or inhibition of cancer progression caused by the combination of onvansertib and abiraterone for example, 50%, 60%, 70%, 80%, 90%, 100%, or more higher than the combined inhibition of progression caused by the decitabine alone plus the onvansertib alone.

[0080] The antiandrogen or androgen antagonist (e.g., abiraterone) and the PLK1 inhibitor (e.g., onvansertib) can be administered to the patient in any manner deemed effective to treat the cancer. The abiraterone can be administered together with, or separately from, onvansertib. When administered separately, abiraterone can be administered before or after the onvansertib, or in different administration cycles. The administration of the antiandrogen or androgen antagonist (e.g., abiraterone) and the administration of onvansertib can partially overlap. The administration of onvansertib can be oral administration. The administration of the abiraterone can be intravenous administration or oral administration.

[0081] The PLK1 inhibitor and the antiandrogen or androgen antagonist can be coadministered (e.g., simultaneously) or sequentially. In some embodiments, it can be advantageous to administer the PLK1 inhibitor (e.g., onvansertib) to the subject before the antiandrogen or androgen antagonist (e.g., abiraterone), e.g., on one or more days, or each day, of the days on which onvansertib and the antiandrogen or androgen antagonist are administered to the subject. The time interval between the administration of onvansertib and the administration of the antiandrogen or androgen antagonist can be, for example, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or a value or a range between any two of these values. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) and the antiandrogen or androgen antagonist (e.g., abiraterone) are both administered to the subject on, or on at least about, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the days in a cycle (e.g., in each cycle during the combination treatment), and optionally the onvansertib is administered to the subject prior to the decitabine on each of the days both are administered, for example onvansertib is administered 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, a range between any two of these values, or any value between 30 minutes and 12 hours, prior to the administration of abiraterone.

[0082] The abiraterone and onvansertib can each be administered in any schedule, e.g., once or multiple times per day or week; once, twice, three times, four times, five times, six times or seven times (daily) per week; for one or multiple weeks; etc. In some embodiments, the abiraterone and onvansertib are each administered to the patient in a cycle of at least twice within a week. In other embodiments, the abiraterone and onvansertib are each administered to the patient in a cycle of at least five times within a week. In some embodiments, onvansertib is administered daily, and abiraterone is administered daily, weekly, bi-weekly, every four weeks, every five weeks, or monthly. In some embodiments, the abiraterone is administered twice daily. In further embodiments, the patient undergoes at least two cycles of administration. Onvansertib, the antiandrogen or androgen antagonist, or both can be administered in a cycle of at least about 7 days, a cycle of at least about 14 days, a cycle of at least about 21 days, or a cycle of at least about 28 days. The patient can undergo one cycle or more than one cycle of administrations, for example, two cycles, three cycles, three cycles, four cycles, five cycles, or more. Two adjacent cycles of administration can be continuous, i.e., no break between the last day of the first cycle and the first day of the second cycle. In some embodiments, two adjacent cycles of administration have a break between them (e.g., an interval between the last day of the first cycle and the first day of the second cycle). The break (e.g., the interval) can be or be at least, one day, two days, three days, five days, seven days, ten days, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months, or a number or a range between any two of these values. In some embodiments, the patient undergoes three or four cycles of administration in which each cycle comprises at least five times within a week (e.g., 5 days per week). Each of the cycle in a multi-cycle administration can have the same dosing schedule, or different. For example, one of the cycle in the multi-cycle administration can be five continuous days of daily administration of onvansertib and decitabine and two days of break in one week for four weeks, and one or more other cycles in the same multi-cycle administration be 28 continuous days of daily administration of onvansertib and decitabine in a four-week period. The onvansertib can be administered on at least four days in the cycle. In some embodiments, onvansertib is not administered on at least one day in the cycle.

[0083] The antiandrogen or androgen antagonist can be administered to the patient at any appropriate dosage, e.g., a dosage of about, at least or at most 0.1 mg/patient per day, 1 mg/patient per day, 5 mg/patient per day, 10 mg/patient per day, 20 mg/patient per day, 30 mg/patient per day, 40 mg/patient per day, 50 mg/patient per day, 60 mg/patient per day, 70 mg/patient per day, 80 mg/patient per day, 90 mg/patient per day, 100 mg/patient per day, 200 mg/patient per day, 300 mg/patient per day, 400 mg/patient per day, 500 mg/patient per day, 600 mg/patient per day, 700 mg/patient per day, 800 mg/patient per day, 900 mg/patient per day, 1000 mg/patient per day, 1500 mg/patient per day, 2000 mg/patient per day, or a number between any two of these values. The dosage unit can be converted to another unit (e.g., mg/kg or mg/m²) using a conversion chart such as the body surface area (BSA) conversion chart as will be understood by a person skilled in the art. Suitable dosages of abiraterone when used as a first or second line therapy for treatment of cancer are also known in the art. For example, U.S. Pat. No. 5,604,213 teaches that a therapeutically effective dose can be in the range 0.001-0.04 mmole/kg body weight, preferably 0.001-0.01 mmole/kg, administered daily or twice daily during the course of treatment. In some embodiments the dosage is 10-2,000 mg/patient per day, 100-1,500 mg/patient per day, 250-1,250 mg/patient per day, or 500-1000 mg/patient per day.

[0084] The antiandrogen or androgen antagonist (e.g., abiraterone) can be administrated to the patient once daily, twice daily, or three times daily. The antiandrogen or androgen antagonist can be administered daily, weekly, bi-weekly, every three weeks, every four weeks, or every month. In some embodiments, the antiandrogen or androgen antagonist is administered in a cycle of 7-56 days of daily, weekly, bi-weekly, tri-weekly, every four weeks, or monthly. In some embodiments, the antiandrogen or androgen antagonist is administered in a cycle of 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 32 days, 35 days, 42 days, 49 days, or 56 days. In some embodiments, the antiandrogen or androgen antagonist is administered in 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 32 days, 35 days, 42 days, 49 days, or 56 days, in a cycle. In some embodiments, the antiandrogen or androgen antagonist is administered in day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21, day 22, day 23, day 24, day 25, day 26, day 27, day 28, day 29, day 30, day 31, day 32, day 33, day 34, day 35, day 36, day 37, day 38, day 39, day 40, day 41, day 42, day 43, day 44, day 45, day 46, day 47, day 48, day 49, day 50, day 51, day 52, day 52, day 53, day 54, day 55, and/or day 56. In some embodiments, the antiandrogen or androgen antagonist is not administered in day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21, day 22, day 23, day 24, day 25, day 26, day 27, day 28, day 29, day 30, day 31, day 32, day 33, day 34, day 35, day 36, day 37, day 38, day 39, day 40, day 41, day 42, day 43, day 44, day 45, day 46, day 47, day 48, day 49, day 50, day 51, day 52, day 52, day 53, day 54, day 55, and/or day 56.

[0085] In some embodiments, the subject has not received any pnor treatment comprising administration of the antiandrogen or androgen antagonist. In some embodiments, the subject has received a prior treatment comprising administration of the antiandrogen or androgen antagonist. In the most preferred embodiments, the antiandrogen or androgen antagonist is abiraterone, or a prodrug, analog, or derivative, or pharmaceutically acceptable salt thereof.

[0086] Similarly, any PLK1 inhibitor, now known or later discovered, can be used in these methods, including PLK1 inhibitors that are selective for PLK1, and PLK1 inhibitors that also inhibit the activity of other proteins. In some embodiments, the PLK1 inhibitor is a dihydroptendinone, a pyndopynmidine, a aminopynmidine, a substituted thiazohdmone, a pteridine derivative, a dihydroimidazo[l,5-f|pteridine, a metasubstituted thiazolidinone, a benzyl styryl sulfone analogue, a stilbene derivative, or a combination thereof. In some of these embodiments, the PLK1 inhibitor is onvansertib, BI2536, Volasertib (BI 6727), GSK461364, AZD1775, CYC140, HMN-176, HMN-214, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960 or Ro3280.

[0087] Onvansertib can be administered to the patient at any appropriate dosage, e.g., from 8 mg/m² to 90 mg/m², including but are not limited to, a dosage of less than 12 mg/m², less than or equal to 24 mg/m², or greater than 24 mg/m². In some embodiments, the onvansertib is administered to the patient at about 8 mg/m², at about 9 mg/m², at about 12 mg/m², at about 15 mg/m², at about 18 mg/m², or at a value or a range between any two of these values. In some embodiments, the onvansertib is administered at a dose of, of at most, or of at least, about 60 mg/m². In some embodiments, the onvansertib is administered to the patient daily. In some embodiments, the onvansertib is administered in a cycle of 3-10 days of daily onvansertib administration with 2-16 days with no onvansertib administration. In some embodiments, the onvansertib is administered to the patient in a cycle of at least five times within a week. The patient can undergo two, three, or four cycles of administration. In some embodiments, the patient undergoes four cycles of administration in a cycle of at least five days of daily onvansertib administration with 1-2 days with no onvansertib administration. In some preferred embodiments, onvansertib can be administrated at 24 mg/m² on days 1-5 of the 21 -day cycle. Onvansertib can be administrated at 18 mg/m² on days 1-5 of the 14-day cycle. Onvansertib can be administrated at 12 mg/m² on days 1-14 of the 21-day cycle. [0088] In some embodiments, a PLK1 inhibitor alone or in combination with an antiandrogen or androgen antagonist is administrated to a patient who has taken a drug holiday after undergoing one or more cycles of administration. A drug holiday as used herein refers to a period of time when a patient stops taking a PLK1 inhibitor and/or an antiandrogen or androgen antagonist. A drug holiday can be a few days to several months. In some embodiments, the drug holiday can be 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or any value or a range between any two of these values.

[0089] As can be appreciated by one of skill in the art, the amount of coadministration of the hypomethylating agent and the PLK1 inhibitor, and the timing of coadministration, can depend on the type (species, gender, age, weight, etc.) and condition of the subject being treated and the severity of the disease or condition being treated. The antiandrogen or androgen antagonist and the PLK1 inhibitor can be formulated into a single pharmaceutical composition, or two separate pharmaceutical compositions. The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interracial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. In some embodiments, the onvansertib is formulated for oral administration. In some embodiments, abiraterone is formulated for oral administration.

[0090] Methods, compositions, kits and systems disclosed herein can be applied to different types of subjects. For example, the subject can be a subject receiving a cancer treatment, a subject at cancer remission, a subject has received one or more cancer treatment, or a subject suspected of having cancer. The subject can have a stage I cancer, a stage II cancer, a stage III cancer, and/or a stage IV cancer. In some embodiments, the subject has advanced, metastatic, refractory, or relapsed cancer. In some embodiments, at least one mutation in a gene encoding mTOR is determined to be present in the sample nucleic acids obtained from the subject.

[0091] The treatment of the present disclosure can comprise administration of a PLK1 inhibitor (e.g., onvansertib) for a desired duration in a cycle. The administration of onvansertib (and/or abiraterone) can be daily or with break(s) between days of administrations. The break can be, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or more. The administration can be once, twice, three times, four times, or more on a day when onvansertib (and/or abiraterone) is administered to the patient. The administration can be, for example, once every two days, every three days, every four days, every five days, every six days, or every seven days. The length of the desired duration can vary, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, or more days. Each cycle of treatment can have various lengths, for example, at least 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, or more. For example, a single cycle of the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) and/or abiraterone for four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, fourteen days, fifteen days, sixteen days, seventeen days, eighteen days, nineteen days, twenty days, twenty-one days, twenty-two days, twenty-three days, twenty-four days, twenty- five days, twenty-six days, twenty-seven days, twenty-eight days, or more in a cycle (e.g., in a cycle of at least 21 days (e.g., 21 to 28 days)). In some embodiments, the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) and/or abiraterone for, or for at least, four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, fourteen days, fifteen days, sixteen days, seventeen days, eighteen days, nineteen days, twenty days, or a range between any two of these values, in a cycle (e.g., a cycle of at least 21 days (e.g., 21 to 28 days)). The administration of the PLK1 inhibitor (e.g., onvansertib) and/or abiraterone in a single cycle of the treatment can be continuous or with one or more intervals (e.g., one day or two days of break). In some embodiments, the treatment comprises administration of the PLK1 inhibitor (e.g., onvansertib) for five days in a cycle of 21 to 28 days.

[0092] In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered to the subject in need thereof on twenty days (e.g., Days 1-10 and 15-24) during a 28-day cycle. The twenty days can be, for example, a continuous daily administration for ten days (e.g., Days 1-10) and another continuous daily administration (e.g., Days 15-24) for ten days, or a continuous daily administration for four sets of five days (e.g., Days 1-5, 8-12, 15-19, and 22- 26). In some embodiments, for example when the patient is identified to have low tolerance to the PLK1 inhibitor (e g., onvansertib), the PLK1 inhibitor is administered to the subject in need thereof on ten days (e.g., Days 1-5 and 15-19) during a 28-day cycle. The ten days can be, for example, a continuous daily administration for ten days (e.g., Days 1-10) or two continuous daily admiration for five days each (e.g., Days 1-5 and Days 15-19). In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered to the subject in need thereof on five days (e.g., Days 1-5) during a 28-day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered to the subject in need thereof daily throughout the whole cycle (e.g., daily for 28 days in a cycle of 28 days). Depending on the needs of inhibition/reversion of cancer progression in the subject, the subject can receive one, two, three, four, five, six, or more cycles of treatment. For combination treatment, the administration cycles, dosing schedules, and/or dosage amounts of the antiandrogen or androgen antagonist and the PLK1 inhibitor can be the same or different. For combination treatment, the administration cycle, dosing schedule, and/or dosage amount of the hypomethylating agent can be adjusted according to the administration cycle, dosing schedule, and/or dosage amount of the PLK1 inhibitor. For example, decitabine can be administered in four 7-day cycles (e.g., daily dose on Days 1-5 and no dose on Days 6-7, repeated for 4 weeks), which corresponds to a 28-day cycle for administration of the PLK1 inhibitor (e.g., onvansertib).

[0093] The treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 6 mg/m² - 90 mg/m², for example, as a daily dose. For example, the treatment can comprise daily administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 6 mg/m², 8 mg/m², 10 mg/m², 12 mg/m², 14 mg/m², 16 mg/m², 18 mg/m², 20 mg/m², 23 mg/m², 27 mg/m², 30 mg/m², 35 mg/m², 40 mg/m², 45 mg/m², 50 mg/m², 55 mg/m², 60 mg/m², 65 mg/m², 70 mg/m², 80 mg/m², 85 mg/m², 90 mg/m², a number or a range between any two of these values, or any value between 8 mg/m² - 90 mg/m². In some embodiments, the daily dose of the PLK1 inhibitor (e.g., onvansertib) can be adjusted (e.g., increased or decreased with the range) during the treatment, or during a single cycle (e.g., the first cycle, the second cycle, the third cycle, and a subsequent cycle) of the treatment, for the subject. In some embodiments, the PLK inhibitor (e.g., onvansertib) is administered at 12 mg/m² on twenty days (e.g., Days 1-10 and 15-24) during a 28-day cycle. In some embodiments, the PLK inhibitor (e.g., onvansertib) is administered at 15 mg/m² on ten days (e.g., Days 1-5 and 15-19) during a 28-day cycle. In some embodiments, the PLK inhibitor (e.g., onvansertib) is administered at 8 mg/m² or 10 mg/m² everyday (e.g., Days 11-28) during a 28-day cycle. In some embodiments, the daily dose of the PLK1 inhibitor (e.g., onvansertib) can be adjusted (e.g., increased or decreased with the range) during the treatment, or during a single cycle (e.g., the first cycle, the second cycle, the third cycle, and a subsequent cycle) of the treatment, for the subject. In some embodiments, the PLK1 inhibitor is administered at or at about 12 mg/m². In some embodiments, the PLK1 inhibitor is administered at or at about 15 mg/m². In some embodiments, the PLK1 inhibitor is administered at or at about 18 mg/m². In some embodiments, the onvansertib is administered at 60 mg/m² for at least four days in a cycle. In some embodiments, the onvansertib is administered at 60 mg/m² for five days in a cycle.

[0094] A maximum concentration (Cmax) of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject (during the treatment or after the treatment) when the PLK1 inhibitor is administered alone or in combination with the hypomethylating agent can be from about 100 nmol/L to about 1500 nmol/L. For example, the Cmax of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the hypomethylating agent can be, or be about, 100 nmol/L, 200 nmol/L, 300 nmol/L, 400 nmol/L, 500 nmol/L, 600 nmol/L, 700 nmol/L, 800 nmol/L, 900 nmol/L, 1000 nmol/L, 1100 nmol/L, 1200 nmol/L, 1300 nmol/L, 1400 nmol/L, 1500 nmol/L, a range between any two of these values, or any value between 200 nmol/L to 1500 nmol/L.

[0095] An area under curve (AUC) of a plot of a concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject over time (e.g., AUC0-24 for the first 24 hours after administration) when the PLK1 inhibitor is administered alone or in combination with the hypomethylating agent can be from about 1000 nmol/L.hour to about 400000 nmol/L.hour. For example, the AUC of a plot of a concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject over time (e.g., AUC0-24 for the first 24 hours after administration) when the PLK1 inhibitor is administered alone or in combination with the hypomethylating agent can be, or be about, 1000 nmol/L.hour, 5000 nmol/L.hour, 10000 nmol/L.hour, 15000 nmol/L.hour, 20000 nmol/L.hour, 25000 nmol/L.hour, 30000 nmol/L.hour, 35000 nmol/L.hour, 40000 nmol/L.hour, a range between any two of these values, or any value between 1000 nmol/L.hour and 400000 nmol/L.hour.

[0096] A time (Tmax) to reach a maximum concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the hypomethylating agent can be from about 1 hour to about 5 hours. For example, the time (Tmax) to reach a maximum concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the hypomethylating agent can be, or be about, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, a range between any two of these values, or any value between 1 hour and 5 hours.

[0097] An elimination half-life (T1/2) of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the hypomethylating agent can be from about 10 hours to about 60 hours. For example, the elimination half-life (T1/2) of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the hypomethylating agent can be, or be about, 10 hours, 15 hours, 20 hours, 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, 50 hours, 55 hours, 60 hours, a range between any two of these values, or any value between 10 hours and 60 hours.

[0098] In some embodiments, the combination therapy includes additional active agents. In addition to one or more antiandrogen or androgen antagonist, and one or more PLK inhibitors, the combination therapies can include any of the additional agents or components discussed herein, or known in the art to be co-administered with an antiandrogen or androgen antagonist, or with a PLK inhibitor. For example, abiraterone acetate is routinely administered in combination with a steroid such as prednisone or prednisolone. Therefore, in some embodiments, the combination includes prednisone or prednisolone.

[0099] The steroid can be administrated to the patient once daily, twice daily, or three times daily. The steroid can be administered daily, weekly, bi-weekly, every three weeks, every four weeks, or every month. In some embodiments, the steroid is administered in a cycle of 7-56 days of daily, weekly, bi-weekly, tri-weekly, every four weeks, or monthly. In some embodiments, the steroid is administered in a cycle of 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 32 days, 35 days,

42 days, 49 days, or 56 days. In some embodiments, the steroid is administered in 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days,

25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 32 days, 35 days, 42 days, 49 days, or 56 days, in a cycle.

[0100] The steroid can be administered to the patient at any appropriate dosage, e.g., a dosage of about, at least or at most 0. 1 mg/patient per day, 1 mg/patient per day, 5 mg/patient per day, 10 mg/patient per day, 20 mg/patient per day, 30 mg/patient per day, 40 mg/patient per day, 50 mg/patient per day, 60 mg/patient per day, 70 mg/patient per day, 80 mg/patient per day, 90 mg/patient per day, 100 mg/patient per day, 200 mg/patient per day, 300 mg/patient per day, or a number between any two of these values.

[0101] The steroid can be administered to the patient in any manner deemed effective to treat the cancer. The abiraterone can be administered together with, or separately from, antiandrogen or androgen antagonist (e.g., abiraterone). The steroid can be administered to the subject through the same route of administration as onvansertib and/or the antiandrogen or androgen antagonist. The administration of the steroid can be intravenous administration or oral administration.

Methods for Predicting/Determining Treatment Efficacy and Status for Cancer

[0102] Disclosed herein include methods for determining the efficacy of treatment to a subject having a cancer. In some embodiments, the method comprises: (a) determining the presence or absence of at least one mutation in a gene encoding mTOR in sample nucleic acids from the subject; and (b) administenng onvansertib, and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids. In some embodiments, the subject has received or is undergoing a cancer treatment. The cancer treatment can comprise onvansertib and an antiandrogen or androgen antagonist. The cancer treatment does not comprise onvansertib and/or an antiandrogen or androgen antagonist. In some embodiments, the presence of at least one mutation in a gene encoding mTOR in the sample nucleic acids obtained from a subject with cancer is predictive of response to treatment with onvansertib and abiraterone in the subject (e.g., in some embodiments, the absence of the least the at least one mutation in the mTOR gene is not predictive of a response to the treatment described herein).

[0103] The method can comprise one or more of (1) determining cancer status of the subject and (2) determining responsiveness of the subject to a PLK1 inhibitor and antiandrogen or androgen antagonist treatment. In some embodiments, administering onvansertib and abiraterone synergistically reduces or inhibits progression of the prostate cancer relative to onvansertib alone, abiraterone alone, and/or the additive effect of onvansertib alone and abiraterone alone. In some embodiments, administering onvansertib and abiraterone improves one or more therapeutic effects in the subject relative to a control or a baseline. The one or more therapeutic effects can comprise complete remission. Administering onvansertib and the antiandrogen or androgen antagonist can improve one or more therapeutic effects in the subject relative to a control or a baseline. The one or more therapeutic effects can comprise complete remission with progression-free survival (PFS), level of prostate-specific antigen (PSA), radiographic or clinical progression, radiographic response, or a combination thereof. The radiographic response can be determined according to response evaluation criteria in solid tumors (RECIST) version 1.1. In some embodiments, determining the responsiveness of the subject comprises determining if the subject is a responder of the treatment, if the subject is or is going to be in complete recovery (CR), or if the subject is or is going to be in partial remission (PR). In some embodiments, determining the responsiveness of the subject comprises determining the PFS, PSA level, radiographic or clinical progression, radiographic response, or a combination thereof of the subject. In some embodiment, administering onvansertib and the antiandrogen or androgen antagonist can improve PFS, PSA level, radiographic or clinical progression, radiographic response, or a combination thereof in the subject, relative to subjects who do not have the at least one mutation in the mTOR gene. Administering onvansertib and the antiandrogen or androgen antagonist can increase PFS relative to subjects who do not have the at least one mutation in the mTOR gene.

[0104] In some embodiments, the therapeutic effect comprises improvement in PFS in a subject or a cohort of subjects by at least about 50% (e.g., about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values) relative to a control or baseline. In some embodiments, the therapeutic effect comprises improvement in PSA level in a subject or a cohort of subjects by at least about 50% (e.g., about

50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%,

66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,

82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,

98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values) relative to a control or baseline. In some embodiments, the therapeutic effect comprises improvement in radiographic or clinical progression in a subject or a cohort of subjects by at least about 50% (e.g., about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values) relative to a control or baseline. In some embodiments, the therapeutic effect comprises improvement in radiographic response in a subject or a cohort of subjects by at least about 50% (e.g., about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values) relative to a control or baseline.

[0105] In some embodiments, administering onvansertib and decitabine improves PFS, PSA level, radiographic or clinical progression, radiographic response, or a combination thereof in the subject, if the at least one mutation in the mTOR gene is determined to be present in the sample nucleic acids from the subject, relative to subjects who do not have the at least one mutation in the gene encoding mTOR. In some embodiments, the therapeutic effect comprises improvement in PFS in a subject or a cohort of subjects, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids from the subject or cohort of subjects, by at least about 50% (e.g., about 50%, 51%, 52%, 53%, 54%, 55%, 56%,

57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,

73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,

89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%,

140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values) relative to subjects who do not have the at least one mutation in the mTOR gene. In some embodiments, the therapeutic effect comprises improvement in PSA level in a subject or a cohort of subjects, if the at least one mutation in the mTOR gene is determined to be present in the sample nucleic acids from the subject or cohort of subjects, by at least about 50% (e.g., about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values) relative to subjects who do not have the at least one mutation in the mTOR gene. In some embodiments, the therapeutic effect comprises improvement in radiographic or clinical progression in a subject or a cohort of subjects, if the at least one mutation in the mTOR gene is determined to be present in the sample nucleic acids from the subject or cohort of subjects, by at least about 50% (e.g., about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%,

61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%,

77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,

93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values) relative to subj ects who do not have the at least one mutation in the mTOR gene. In some embodiments, the therapeutic effect comprises improvement in radiographic response in a subject or a cohort of subjects, if the at least one mutation in the mTOR gene is determined to be present in the sample nucleic acids from the subject or cohort of subjects, by at least about 50% (e.g., about 50%, 51%, 52%, 53%, 54%,

55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,

71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,

87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values) relative to subjects who do not have the at least one mutation in the mTOR gene. [0106] In some embodiments, administering onvansertib and abiraterone produces a significant improvement in PFS, PSA level, radiographic or clinical progression, radiographic response, or a combination thereof in a cohort of subjects, if the at least one mutation in the mTOR gene is determined to be present in the sample nucleic acids from a subject or cohort of subjects, relative to subjects who do not have the at least one mutation in the mTOR gene. In some embodiments, the therapeutic effect comprises an improvement in PFS, PSA level, radiographic or clinical progression, and/or radiographic response in a cohort of subjects of at least about 30% (e.g., about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%,

41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,

57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,

73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,

89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% or a number or a range between any two of these values). In some embodiments, a subject having an improvement in PFS, PSA level, radiographic or clinical progression, radiographic response, or a combination thereof is at least 2.5 times (e.g., 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 times, or a number or a range between any two of these values) more likely to carry the at least one mutation in the mTOR gene than not.

Composition and Kits

[0107] Compositions for use in the treatment of the disclosed diseases are also provided. For example, a composition including an antiandrogen or androgen antagonist for use in a method of treating a subject with cancer, wherein the subject is one whom a composition including a PLK inhibitor has previously been or is concurrently being administered, if at least one mutation in the gene encoding mTOR is determined to be present in the subject. The response achieved following the administration of antiandrogen or androgen antagonist is greater than the response achieved by administering either the antiandrogen or androgen antagonist alone or the PLK inhibitor alone.

[0108] In another embodiment, a composition including a PLK inhibitor for use in a method of treating a subject with cancer, wherein the subject is one whom a composition including an antiandrogen or androgen antagonist has previously been or is currently being administered, if at least one mutation in the gene encoding mTOR is determined to be present in the subject. The response achieved following the administration of the PLK inhibitor is greater than the response achieved by administering either the antiandrogen or androgen antagonist alone or the PLK inhibitor alone.

[0109] Compositions for use in the determination of treatment of the disclosed diseases are also provided. For example, a composition including an antiandrogen or androgen antagonist for use in a method of treating a subject with cancer, wherein the subject is one whom a composition including a Plk inhibitor has previously been or is concurrently being administered, if at least one mutation in the gene encoding mTOR is determined to be present in the subject. The response achieved following the administration of antiandrogen or androgen antagonist is greater than the response achieved by administering either the antiandrogen or androgen antagonist alone or the PLK inhibitor alone.

[0110] In another embodiment, a composition including a PLK inhibitor for use in a method of determining the treatment to a subject with cancer, wherein the subject is one whom a composition including an antiandrogen or androgen antagonist has previously been or is currently being administered, if at least one mutation in the gene encoding mTOR is determined to be present in the subject. The response achieved following the administration of the PLK inhibitor is greater than the response achieved by administering either the antiandrogen or androgen antagonist alone or the PLK inhibitor alone. Suitable methods, cancers to be treated, dosage regimes, and responses achieved by administering the combinations are discussed at length above. In particular embodiments the subject may have been previously administered one or more of the drugs, but not in combination.

[0111] Furthermore, it will be appreciated as discussed above, that the cancer may have developed a resistance to the previously administered active agent. The active agent is administered in the absence of the combination. Therefore, in some embodiments, the subject population being treated is defined as one in which the cancer being treated is resistant or insensitive to one or the other of the active agent when administered alone.

[0112] Medical kits are also disclosed. The medical kits can include, for example, a dosage supply of an antiandrogen or androgen antagonist, a polo-like kinase inhibitor, or a combination thereof separately or together in the same admixture. The active agents can be supplied alone (e.g., lyophilized), or in a pharmaceutical composition. The active agents can be in a unit dosage, or in a stock that should be diluted prior to administration. In some embodiments, the kit includes a supply of pharmaceutically acceptable carrier. The kit can also include devices for administration of the active agents or compositions, for example, syringes. The kits can include printed instructions for determining the presence or absence of one or more mutations in the gene encoding mTOR in sample nucleic acids from a subject and administering the compound in a use as described above. For instance, the kit comprises onvansertib; and a manual providing instructions for: a) determining the presence or absence of at least one mutation in a gene encoding mTOR in sample nucleic acids from a subject; and b) administering onvansertib and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids. The manual can comprise instructions for administering onvansertib at 8 mg/m² - 90 mg/m² and administering the antiandrogen or androgen antagonist at 10-2,000 mg/patient per day.

EXAMPLES

[0113] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the present disclosure.

Example 1

Genomic Analyses

[0114] Genomic analyses in this example suggest that in mCRPC patients with early resistance to abiraterone, mutations in the mTOR gene were associated with increased clinical benefits from onvansertib in combination with abiraterone.

Clinical Study Design and Correlatives Studies:

[0115] The safety and efficacy of onvansertib in combination with the standard dose of abiraterone and prednisone in patients with mCRPC were evaluated. Patients entered the study had early progressive disease, with rising prostate-specific antigen (PSA) level but minimal or no symptom, while receiving androgen-deprivation therapy in addition to abiraterone and prednisone. The progressive disease must have been demonstrated by two rising PSA values separated by at least 1 week, one showing a rise of at least 0.3 ng/mL and one confirmatory value not showing a decline, while on abiraterone therapy. The patients received no prior treatment with enzalutamide or apalutamide.

[0116] Three onvansertib dosing schedules were tested in noncomparative arms: Arm A - 24 mg/m² on days 1-5 of a 21-day cycle; Arm B - 18 mg/m² on days 1-5 of a 14-day cycle; and Arm C - 12 mg/m² on days 1-14 of a 21-day cycle. Abiraterone (lOOOmg) and prednisone (5mg) were administered orally daily.

[0117] The primary efficacy endpoint was disease control evaluated as PSA decline or stabilization and no radiographic or clinical progression after 12 weeks of treatment. PSA stabilization is defined as PSA rise <25% over baseline. The secondary efficacy endpoints included PFS and radiographic response per RECIST v.1.1. PFS is defined as the time between the start of treatment and progression or death.

[0118] Blood samples were collected at baseline for genomic profiling of circulating tumor DNA (ctDNA) by targeted sequencing using Guardant Health platform.

Efficacy

[0119] A total of 72 patients were enrolled in the study: 24 in Arm A, 20 in Arm B and 28 in Arm C. At the data cutoff date, 6 patients (1 in Arm B and 5 in Arm C) remained on treatment.

[0120] The median PFS for all 72 patients was 6.74 months (95% confidence interval: 4.87-9.7). Patients in Arm C had a PFS of l l.24 months which was significantly longer than the PFS of patients enrolled in Arm A (3.94 months) and Arm B (5.06 months) (Error! Reference source not found, and FIG. 1). In Table 1, LCL refers to lower confidence interval, and UCL refers to upper confidence interval.

TABLE 1: MEDIAN PFS BY ARM

Genomic analysis

[0121] Baseline genomic profiles were obtained from 52 patients evaluable for efficacy (e.g., patients who either completed 12 weeks of treatment or progressed within 12 weeks). Patients were distributed between arms as follows: 16 patients in Arm A, 18 patients in Arm B and 18 patients in Arm C. The most common genomic alterations across arms were TP53 mutations (56%), AR mutations and amplifications (38%) and TMPRSS2 fusions (23%).

[0122] The IQR of the time on study was calculated for the 52 patients, and patients were classified into 3 survival groups: short (<Q1, 15 patients), average (>Q1 and <Q3, 22 patients) or long (>Q3, 15 patients). The genomic profiles of the short, average and long survival groups were compared to identify potential genomic biomarkers associated with treatment benefits, as shown in FIG. 2A-FIG. 2C. An X² test of independence was used to statistically test the association between gene alterations and survival groups. Heatmaps of residuals illustrate the level of association with a particular survival group, as shown in FIG. 3A-FIG. 3C. Mutations in the mTOR gene were found to be the most significantly enriched in the average and long survival groups compared to the short survival group. Five of these six mTOR mutations detected were predicted to have a deleterious functional impact on the protein.

[0123] Patients treated in Arm C had significantly higher PFS than patients in Arms A and B. Without intending to be bound by any theories, the difference between Arm C and Arm A/B could be resulted from the increase in onvansertib dosing intensity in Arm C (14 days out of the 21 days cycle) versus Arm A (5 days out of the 21 days cycle) and Arm B (5 days out of the 14 days cycle). Consequently, in the above analysis, the long survival group was composed of 10 Arm C patients and 5 Arms A and B patients. To avoid this imbalance, the IQR of time on study was calculated for each arm, and patients were reclassified into short, average and long survival groups based on the IQR of their respective arms. Consequently, nine patients were reclassified to a different survival group, as shown in FIG. 4A-FIG. 4C. As shown in FIG. 5A and FIG. 5B, mTOR remained one of the most significantly enriched genes in the average and long survival groups compared to the short survival group.

[0124] In at least some of the previously described embodiments, one or more elements used in an embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims.

[0125] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The vanous singular/plural permutations may be expressly set forth herein for sake of clarity. As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Any reference to “or” herein is intended to encompass “and/or” unless otherwise stated.

[0126] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g, bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and/or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g, the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms.

[0127] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0128] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0129] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a subject with a cancer, comprising:

(a) determining the presence or absence of at least one mutation in a gene encoding a mechanistic target of rapamycin kinase (mTOR) in sample nucleic acids from the subject; and

(b) administering onvansertib, and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids, thereby reducing or inhibiting progression of the cancer in the subject.

2. A method for choosing treatment to a subject having a cancer, comprising:

(a) determining the presence or absence of at least one mutation in a gene encoding a mechanistic target of rapamycin kinase (mTOR) in sample nucleic acids from the subject, wherein the subj ect has received or is undergoing a prior cancer treatment; and

(b) administering onvansertib, and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids.

3. The method of claim 2, wherein the prior cancer treatment comprises onvansertib and an antiandrogen or androgen antagonist.

4. The method of claim 2, wherein the prior cancer treatment does not comprise onvansertib and/or an antiandrogen or androgen antagonist.

5. The method of any one of claims 1-4, wherein each of the at least one mutation is a single nucleotide variant, an insertion mutation, a deletion mutation, an internal tandem duplication, a copy number variant, translocation, or an inversion, relative to the wild type mTOR gene.

6. The method of any one of claim 1-5, wherein the at least one mutation is a single nucleotide variant.

7. The method of any one of claims 1-6, comprising obtaining the sample nucleic acids from a biological sample of the subject, and wherein the biological sample comprises a bodily fluid, one or more tissues, one or more cells, or a combination thereof.

8. The method of claim 7, wherein the biological sample is a blood sample or a sample from tissue biopsy.

9. The method of claims 7-8, wherein the biological sample comprises genomic DNA, circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), circulating tumor cell (CTC), RNA, or a combination thereof.

10. The method of any one of claims 7-9, wherein the biological sample comprises circulating tumor DNA (ctDNA).

11. The method of any one of claims 1-10, wherein the antiandrogen or androgen antagonist is abiraterone.

12. The method of any one of claims 1-11, wherein administering onvansertib, and the antiandrogen or androgen antagonist synergistically reduces or inhibits progression of the cancer relative to onvansertib alone, the antiandrogen or androgen antagonist alone, and/or the additive effect of onvansertib alone and the antiandrogen or androgen antagonist alone.

13. The method of any one of claims 1-12, wherein administering onvansertib and the antiandrogen or androgen antagonist improves one or more therapeutic effects in the subject relative to a control or a baseline, wherein the one or more therapeutic effects comprise complete remission with progression-free survival (PFS), level of prostate-specific antigen (PSA), radiographic or clinical progression, radiographic response, or a combination thereof.

14. The method of claim 13, wherein the radiographic response is determined according to response evaluation criteria in solid tumors (RECIST) version 1.1.

15. The method of any one of claims 1-14, wherein administering onvansertib and the antiandrogen or androgen antagonist improves PFS, PSA level, radiographic or clinical progression, radiographic response, or a combination thereof in the subject, relative to subjects who do not have the at least one mutation in the gene encoding mTOR.

16. The method of any one of claims 1-15, wherein administering onvansertib and the antiandrogen or androgen antagonist increases PFS relative to subjects who do not have the at least one mutation in the gene encoding mTOR.

17. The method of any one of claims 1-16, wherein onvansertib and the antiandrogen or androgen antagonist are administered simultaneously or sequentially.

18. The method of any one of claims 1-17, wherein the antiandrogen or androgen antagonist is administered to the subject prior to the administration of onvansertib.

19. The method of any one of claims 1-18, wherein the administration of the antiandrogen or androgen antagonist and the administration of onvansertib partially overlap.

20. The method of any one of claims 1-19, wherein onvansertib and the antiandrogen or androgen antagonist are administered to the subject through the same route of administration.

21. The method of any one of claims 1-20, wherein the administration of onvansertib is oral administration.

22. The method of any one of claims 1-21, wherein the administration of the antiandrogen or androgen antagonist is oral administration.

23. The method of any one of claims 1-22, wherein onvansertib, the antiandrogen or androgen antagonist, or both are administered in a cycle of at least about 7 days, a cycle of at least about 14 days, a cycle of at least about 21 days, or a cycle of at least about 28 days.

24. The method of claim 23, wherein onvansertib is administered on at least four days in the cycle.

25. The method of any one of claims 1-23, wherein the antiandrogen or androgen antagonist is administered daily.

26. The method any one of claims 23-25, wherein the subject undergoes at least two cycles of administration of onvansertib and the antiandrogen or androgen antagonist.

27. The method of any one of claims 1-26, wherein onvansertib is administered at 8 mg/m² - 90 mg/m² and the antiandrogen or androgen antagonist is administered at 10-2,000 mg/patient per day.

28. The method of any one of claims 1-27, wherein the antiandrogen or androgen antagonist is administered at 1000 mg/patient per day.

29. The method of any one of claims 23-28, wherein onvansertib is administrated at 24 mg/m² on days 1-5 of the 21-day cycle.

30. The method of any one of claims 23-28, wherein onvansertib is administrated at 18 mg/m² on days 1-5 of the 14-day cycle.

31. The method of any one of claims 23-28, wherein onvansertib is administrated at 12 mg/m² on days 1-14 of the 21-day cycle.

32. The method of any one of claims 1-31, further comprising administering to the subject a steroid.

33. The method of claim 32, wherein the steroid is prednisone or prednisolone.

34. The method of claims 32 or 33, wherein the steroid is administered with the antiandrogen or androgen antagonist.

35. The method of any one of claims 32-34, wherein the steroid is administered daily.

36. The method of any one of claims 32-35, wherein the steroid is administered to the subject through the same route of administration as onvansertib and/or the antiandrogen or androgen antagonist.

37. The method of any one of claims 32-36, wherein the steroid is administered at 1- 100 mg/patient per day.

38. The method of any one of claims 32-37, wherein the steroid is administered at 5 mg/patient per day.

39. The method of any one of claims 1-38, wherein the cancer is a solid tumor cancer.

40. The method of claim 39, wherein the solid tumor cancer is an advanced or metastatic solid tumor cancer.

41. The method of claims 39 or 40, wherein the solid tumor cancer is prostate cancer, breast cancer, ovarian cancer, or endometrial cancer.

42. The method of any one of claims 39-41, wherein the prostate cancer is selected from the group consisting of prostate intraepithelial neoplasia, neuroendocrine prostate cancer (NEPC), primary prostate cancer, androgen-independent prostate cancer, castrate-resistant prostate cancer, and metastatic prostate cancer.

43. The method of any one of claims 39-42, wherein the solid tumor cancer is metastatic castration-resistant prostate cancer (mCRPC).

44. A kit, comprising onvansertib; and a manual providing instructions for: a) determining the presence or absence of at least one mutation in a gene encoding a mechanistic target of rapamycin kinase (mTOR) in sample nucleic acids from a subject; and b) administering onvansertib and an antiandrogen or androgen antagonist to the subject, if the at least one mutation in the gene encoding mTOR is determined to be present in the sample nucleic acids.

45. The kit of claim 44, wherein the manual comprises instructions for administering onvansertib at 8 mg/m² - 90 mg/m² and administering the antiandrogen or androgen antagonist at 10-2,000 mg/patient per day.