WO2024054898A1 - Onvansertib and parp inhibitor combination - Google Patents
Onvansertib and parp inhibitor combination Download PDFInfo
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- WO2024054898A1 WO2024054898A1 PCT/US2023/073622 US2023073622W WO2024054898A1 WO 2024054898 A1 WO2024054898 A1 WO 2024054898A1 US 2023073622 W US2023073622 W US 2023073622W WO 2024054898 A1 WO2024054898 A1 WO 2024054898A1
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- onvansertib
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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Definitions
- the present application generally relates to treatment for cancer. More specifically, combination therapies for treating cancer using PARP inhibitors in combination with the polo-like kinase 1 (PLK1) inhibitor onvansertib are provided.
- PLK1 polo-like kinase 1
- PARP Poly (ADP-ribose) polymerase
- PARP1 is important for the repair of single- stranded DNA breaks (SSBs) through base excision repair. It is recruited at SSBs, and catalyzes the formation of PAR chains on itself and other proteins such as histones.
- PARP1 activity opens chromatin and facilitates recruitment of downstream DNA repair factors.
- PARP inhibitors PARPi can block PARP1 enzymatic activity and trap PARP1 protein to the damaged DNA.
- Non-limiting examples of PARPi include: Talazoparib, Niraparib, Olaparib, Rucaparib and Veliparib. They all block PARP enzymatic activity but differ in their PARP-trapping capacity.
- BRCA1/2 loss of function cell can result in synthetic lethality.
- Breast Cancer 1 and 2 proteins (BRCA1/2) are essential factors of HR and can be inactivated by mutation or promoter hypermethylation.
- BRCA1/2 deficiency induces increased sensitivity to PARP inhibitors due to inhibition of HR.
- PLK1 Upon DNA damage by agents such as Topoisomerase I inhibitors, PARP inhibitors, or radiation, PLK1 is recruited at DSBs, where it promotes DNA repair by homologous recombination.
- PLKl-mediated RAD51 phosphorylation stimulates phosphorylation of RAD51 by the DNA-damage response regulators checkpoint kinase 1 (CHK1) and casein kinase 2 (CK2). This results in recruitment of RAD51 to the site of DNA damage and DNA repair by HR. PLK1 also phosphorylates BRCA1 and promotes its recruitment at DSBs and DNA repair.
- CHK1 checkpoint kinase 1
- CK2 casein kinase 2
- telangiectasia mutated protein ATM and PLK1 counteract the non-homologous end joining (NHEJ) by suppressing RNF168- dependent H2A ubiquitination and BRCA1-A recruitment and thereby promoting replication fork breakage repair by HR.
- NHEJ non-homologous end joining
- the method comprises: administrating onvansertib and a PARP inhibitor selected from olaparib, niraparib, and AZD5305 to a subject with cancer, thereby inhibiting progression of the cancer, wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- a PARP inhibitor selected from olaparib, niraparib, and AZD5305
- the cancer is a homologous recombination-deficient cancer.
- the cancer is a B RCA 1 -homozygous mutant cancer, a BRCA2- homozygous mutant cancer, a BRC Al -heterozygous mutant cancer, a BRCA2-heterozygous mutant cancer, or any combination thereof.
- the cancer is homozygous wild type for BRCA1, BRCA2, or both.
- the inhibition of cancer progression is greater than the combined inhibition of progression caused by the PARP inhibitor alone plus onvansertib alone.
- inhibiting progression of the cancer comprises inhibition of growth of one or more tumors in the subject.
- the inhibition of growth of at least one of the one or more tumors in the subject is about 1.1 times greater, about 1.2 times greater, about 1.3 times greater, about 1.4 times greater, about 1.5 times greater, about 1.6 times greater, about 1.7 times greater, about 1.8 times greater, about 1.9 times greater, about 2 times greater, or more, than the inhibition of growth caused by onvansertib alone or the PARP inhibitor alone, following one or more cycles of treatment.
- the inhibition of growth of at least one of the one or more tumors in the subject is increased by about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% relative to a subject treated with onvansertib alone or the PARP inhibitor alone, following one or more cycles of treatment.
- the growth of at least one of the one or more tumors in the subject is inhibited by about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% relative to an untreated subject, following one or more cycles of treatment.
- the subject is tumor- free following one or more cycles of treatment.
- onvansertib and the PARP inhibitor are co- administered simultaneously. In some embodiments, onvansertib and the PARP inhibitor are administered sequentially. In some embodiments, onvansertib is administered prior to the administration of the PARP inhibitor. In some embodiments, onvansertib is administered prior to the administration of the PARP inhibitor every day on which the subject is administered with onvansertib and the PARP inhibitor. In some embodiments, onvansertib is administered about 30 minutes to about 5 hours prior to the administration of the PARP inhibitor on a given day.
- the administration of onvansertib is oral administration, the administration of the PARP inhibitor is oral administration, or both.
- the subject achieves a complete response.
- the subject has received a prior PARP inhibitor treatment.
- the subject did not respond to treatment with the PARP inhibitor alone.
- the subject is known to be resistant to a PARP inhibitor therapy.
- onvansertib and the PARP inhibitor are each administered to the subject in a cycle of at least twice or at least five times within a week. In some embodiments, onvansertib, the PARP inhibitor, or both are administered in a cycle of at least 7 days. In some embodiments, each cycle of treatment is at least about 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days. In some embodiments, onvansertib is administered on at least four days, at least 14 days, or at least 21 days in the cycle. In some embodiments, onvansertib is not administered on at least one day, at least 7 days, at least 14 days, or at least 21 days in the cycle. In some embodiments, the PARP inhibitor is administered daily. In some embodiments, the subject undergoes at least two cycles of the administration of onvansertib and the PARP inhibitor.
- the PARP inhibitor is selective and/or specific for PARP inhibition.
- onvansertib is administered at 6 mg/m 2 - 90 mg/m 2 .
- a maximum concentration (Cmax) of onvansertib in a blood of the subject is from about 100 nmol/L to about 1500 nmol/L.
- an area under curve (AUC) of a plot of a concentration of onvansertib in a blood of the subject over time is from about 1000 nmol/L.hour to about 400000 nmol/L.hour.
- a time (Tmax) to reach a maximum concentration of onvansertib in a blood of the subject is from about 1 hour to about 5 hours.
- an elimination half-life (T1/2) of onvansertib in a blood of the subject is from about 10 hours to about 60 hours.
- the subject has received at least one prior cancer treatment.
- the prior treatment does not comprise the use of a PARP inhibitor, onvansertib, or both.
- the subject was in remission for cancer.
- the subject in remission for cancer was in complete remission (CR) or in partial remission (PR).
- the method can comprise one or more of (1) determining cancer status of the subject, (2) determining responsiveness of the subject to onvansertib treatment, and (3) administering one or more cancer therapeutics or therapies for the cancer.
- the subject is human.
- the method can comprise: measuring expression of one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof in the subject before and/or after the subject is administered with onvansertib and/or the PARP inhibitor.
- the one or more markers comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof.
- the expression of at least one of the one or more markers in the subject is increased by at least about 1.25 fold after being administered with both the onvansertib and the PARP inhibitor relative to the expression in the subject before being administered with both the onvansertib and the PARP inhibitor. In some embodiments, the expression of at least one of the one or more markers in the subject is increased by at least about 1.25 fold after being administered with both the onvansertib and the PARP inhibitor relative to the expression in a subject being administered with onvansertib alone and/or the expression in a subject being administered with the PARP inhibitor alone.
- the method comprises: contacting cancer cells with a composition comprising onvansertib, thereby sensitizing the cancer cells to the PARP inhibitor, wherein the PARP inhibitor is olaparib, niraparib, AZD53O5, or a combination thereof.
- onvansertib and the PARP inhibitor produce an in vitro synergistic effect.
- the in vitro synergistic effect has a synergy score of about 10 to about 80.
- contacting cancer cells with the composition occurs in vitro, ex vivo, and/or in vivo.
- contacting cancer cells with the composition is in a subject.
- the subject did not respond to, or is known to be resistant to, the PARP inhibitor.
- the subject had prior treatment with the PARP inhibitor or a different PARP inhibitor.
- the subject is a mammal. In some embodiments, the mammal is human.
- the method can comprise: determining sensitization of the cancer cells to the PARP inhibitor after being contacted with the composition.
- determining sensitization of the cancer cells to the PARP inhibitor comprises measuring the proportion of cancer cells expressing one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof after the cancer cells are contacted with the composition and/or the PARP inhibitor.
- the one or more markers comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof.
- the proportion of cancer cells expressing at least one of the one or more markers is increased by at least about 1.25 fold after being contacted with the composition relative to cancer cells not contacted with the composition. In some embodiments, the proportion of cancer cells expressing at least one of the one or more markers is increased by at least about 1.25 fold after being contacted with the composition and the PARP inhibitor relative to cancer cells contacted with the composition alone or the PARP inhibitor alone.
- the method can comprise: contacting the cancer cells with the PARP inhibitor. In some embodiments, contacting the cancer cells with the PARP inhibitor occurs in the subject. The method can comprise: determining the response of the subject to the PARP inhibitor. In some embodiments, contacting the cancer cells with the PARP inhibitor is concurrent with the contacting the cancer cells with the composition, or after the contacting the cancer cells with the composition.
- kits can comprise: onvansertib: and a manual providing instructions for co-administrating onvansertib with a Poly-(ADP-ribose) polymerase (PARP) inhibitor to a subject for treating cancer, wherein the PARP inhibitor is olaparib, niraparib, or AZD5305, and wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- PARP Poly-(ADP-ribose) polymerase
- the cancer is a homologous recombination (HR)- deficient cancer.
- the cancer is a B RCA 1 -homozygous mutant cancer, a BRCA2-homozygous mutant cancer, a BRCA1 -heterozygous mutant cancer, a BRCA2- heterozygous mutant cancer or any combination thereof.
- the cancer is homozygous wild type for BRCA1, BRCA2, or both.
- the instructions comprise instructions for coadministrating onvansertib and the PARP inhibitor simultaneously. In some embodiments, the instructions comprise instructions for co-administrating onvansertib and the PARP inhibitor sequentially. In some embodiments, the instructions comprise (1) instructions for administering of onvansertib orally, (2) instructions for administrating the PARP inhibitor orally, or both. In some embodiments, the instructions comprise instructions the subject has received a prior PARP inhibitor treatment. In some embodiments, the instructions comprise instructions the subject did not respond to treatment with the PARP inhibitor alone. In some embodiments, the instructions comprise instructions the subject is known to be resistant to a PARP inhibitor therapy.
- the instructions comprise instructions for administering each of the PARP inhibitor and onvansertib to the subject in a cycle of at least twice or at least five times within a week. In some embodiments, the instructions comprise instructions for administering the PARP inhibitor, onvansertib, or both in a cycle of at least 7 days. In some embodiments, each cycle of treatment is at least about 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days. In some embodiments, the instructions comprise instructions for administering onvansertib on at least four days, at least 14 days, or at least 21 days in the cycle.
- the instructions comprise instructions for not administering onvansertib on at least one day, at least 7 days, at least 14 days, or at least 21 days in the cycle. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor daily. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor and onvansertib for at least two cycles.
- the PARP inhibitor is selective and/or specific for PARP1 and/or PARP2 inhibition.
- the instructions comprise instructions for administering onvansertib at 6 mg/m 2 - 90 mg/m 2 .
- the instructions comprise instructions the subject has received at least one prior treatment for the cancer. In some embodiments, the prior treatment does not comprise the use of a PARP inhibitor, onvansertib, or both.
- the instructions comprise instructions the subject was in remission for cancer. In some embodiments, the subject in remission for cancer was in complete remission (CR) or in partial remission (PR).
- the kit can comprise the PARP inhibitor.
- FIG. 1 depicts an illustration of the mechanisms of action of some PARP Inhibitors.
- FIG. 2 depicts an non-limiting exemplary illustration of how PLK1 promotes DNA repair by homologous recombination.
- FIG. 3 depicts an exemplary embodiment of how PLK1 inhibition can resensitize tumor cells to PARP inhibitors.
- PARP is essential for repair of single strand DNA breaks (SSBs). Failure to repair SSBs through PARP inhibition results in double strand DNA breaks (DSBs).
- FIG. 4A-FIG. 4B display data related to Onvansertib + Olaparib efficacy in BRCAl-mutated and Olaparib-resistant HGSOC PDX models.
- FIG. 5A-FIG. 5B depict data related to Onvansertib + Olaparib efficacy in BRCAl-mutated and Olaparib-resistant HGSOC PDX model PDX#218ola.
- FIG. 6A-FIG. 6B display data related to body weight of animals and efficacy of Onvansertib + Olaparib in BRCAl-wildtype Olaparib-resistant HGSOC PDX models MNHOC316DDP.
- FIG. 7 depicts data related to Onvansertib + Olaparib efficacy in BRCA1- wildtype Olaparib-resistant HGSOC PDX model MNHOC124.
- FIG. 8A-FIG. 8B depict data related to body weight of animals and efficacy of Onvansertib + Olaparib in BRCA1 -wildtype Olaparib-resistant HGSOC PDX model MNHOC239.
- FIG. 9A-FIG. 9C depict synergy scores for Onvansertib and three different PARP inhibitors in the indicated Ovarian Cancer cell line, OVCAR3.
- FIG. 10A-FIG. 10D display data related to Onvansertib + Olaparib efficacy in Prostate Cancer PDX models CWR22-RH, LgCaP-CR, LuCaP86.2, and BCAP.
- FIG. 11 shows results from a synergy screen for the combination of Onvansertib and Olaparib in breast, ovarian, prostate and pancreatic cancer cell lines.
- FIG. 12A-FIG. 12C depict synergy score data for Onvansertib and three different PARP inhibitors in the indicated Breast Cancer cell line, DU4475.
- FIG. 13A-FIG. 13C display data showing Onvansertib + Olaparib induces an increase in apoptosis.
- FIG. 14A-FIG. 14C depict data showing that Onvansertib + Olaparib induces an increase in cells expressing the DNA Damage/ Apoptotic Marker y-H2AX.
- FIG. 15 depicts exemplary western blot analysis showing that ATR-CHK1 and ATM-CHK2 pathways are activated by Olaparib and Olaparib+Onvansertib treatments.
- FIG. 16A-FIG. 16C depict exemplary data showing that Onvansertib + Olaparib induces an increase in G2/M and S Phase.
- FIG. 17A-FIG. 17B depict data related to in vivo studies in a Breast Cancer model.
- FIG. 18 A- FIG. 18C show synergy score data for Onvansertib and three different PARP inhibitors in indicated Pancreatic Cancer Cell Lines.
- FIG. 19A-FIG. 19D display exemplary data related to Onvansertib and Olaparib Synergy in Pancreatic Cancer cell lines.
- compositions, and kits for treating cancer include methods, compositions, and kits for treating cancer. Some embodiments provide a method of treating cancer comprising administrating a Poly-(ADP- ribose) polymerase (PARP) inhibitor and a Polo-like kinase 1 (PLK1) inhibitor to a subject.
- PARP Poly-(ADP- ribose) polymerase
- PLAK1 Polo-like kinase 1
- the compositions and kits provided herein comprise a PARP inhibitor and a PLK1 inhibitor.
- the method comprises: administrating onvansertib and a PARP inhibitor selected from the group consisting of olaparib, niraparib, and AZD5305 to a subject with cancer, thereby inhibiting progression of the cancer, wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- a PARP inhibitor selected from the group consisting of olaparib, niraparib, and AZD5305 to a subject with cancer, thereby inhibiting progression of the cancer, wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- Also disclosed herein include methods and compositions for sensitizing cancer cells to a PARP inhibitor.
- the method comprises: contacting cancer cells with a composition comprising onvansertib, thereby sensitizing the cancer cells to the PARP inhibitor, wherein the PARP inhibitor is olaparib, niraparib, AZD53O5, or a combination thereof.
- the kit comprises: onvansertib; and a manual providing instructions for co-administrating onvansertib with a PARP inhibitor to a subject for treating cancer, wherein the PARP inhibitor is olaparib, niraparib, or AZD5305, and wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- the PARP inhibitor is olaparib, niraparib, or AZD5305
- the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- a “subject” refers to an animal that is the object of treatment, observation or experiment.
- Animals include cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
- “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
- 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.
- 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.
- the patient is a human or an animal.
- the patient is a mammal.
- administering refers to a method of giving a dosage of a pharmaceutically active ingredient to a vertebrate.
- a “dosage” refers to the combined amount of the active ingredients (e.g., PLK1 inhibitor (e.g., onvansertib) or PARP inhibitor (e.g., olaparib)).
- PLK1 inhibitor e.g., onvansertib
- PARP inhibitor e.g., olaparib
- a “unit dosage” refers to an amount of therapeutic agent administered to a patient in a single dose.
- the term “daily dose” or “daily dosage” refers to a total amount of a pharmaceutical composition or a therapeutic agent that is to be taken within 24 hours.
- 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.
- an effective amount of the composition or agent is formulated for delivery into the blood stream of a patient.
- formulated refers to the process in which different chemical substances, including one or more pharmaceutically active ingredients, are combined to produce a dosage form.
- 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
- 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.
- 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 sterile.
- 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 carriers 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.
- physiologically compatible solvents include sterile solutions of water for injection (WFI), saline solution, and dextrose.
- 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.
- acid salts include 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,
- 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.
- 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
- hydrate refers to a complex formed by combination of water molecules with molecules or ions of the solute.
- 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.
- solvents include, but are not limited to, methanol, A,A-di methyl formamide, tetrahydrofuran, dimethylsulfoxide, and water.
- terapéuticaally 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.
- 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.
- 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.
- therapeutic treatment refers to administering treatment to a subject already suffering from a disease or condition.
- 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 self-administered patient questionnaire).
- the term “prophylaxis,” “prevent,” “preventing,” “prevention,” and grammatical variations thereof as used herein refers the preventive treatment of a subclinical disease-state in a subject, e.g., a mammal (including a human), for reducing the probability of the occurrence of a clinical disease-state.
- the method can partially or completely delay or preclude the onset or recurrence of a disorder or condition and/or one or more of its attendant symptoms or barring a subject from acquiring or reacquiring a disorder or condition or reducing a subject’s risk of acquiring or requiring a disorder or condition or one or more of its attendant symptoms.
- the subject is selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population.
- “Prophylaxis” therapies can be divided into (a) primary prevention and (b) secondary prevention.
- Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
- each of the terms “partial response” and “partial remission” refers to the amelioration of a cancerous state, as measured by, for example, tumor size and/or cancer marker levels, in response to a treatment.
- a “partial response” means that a tumor or tumor-indicating blood marker has decreased in size or level by about 50% in response to a treatment.
- the treatment can be any treatment directed against cancer, including but not limited to, chemotherapy, radiation therapy, hormone therapy, surgery, cell or bone marrow transplantation, and immunotherapy.
- the size of a tumor can be detected by clinical or by radiological means.
- Tumor-indicating markers can be detected by means well known to those of skill, e.g., ELISA, FACS, or other antibody-based tests.
- each of the terms “complete response” or “complete remission” means that a cancerous state, as measured by, for example, tumor size and/or cancer marker levels, has disappeared following a treatment, including but are not limited to, chemotherapy, radiation therapy, hormone therapy, surgery, cell or bone marrow transplantation, and immunotherapy.
- the presence of a tumor can be detected by clinical or by radiological means.
- Tumor-indicating markers can be detected by means well known to those of skill, e.g., ELISA, FACS or other antibody-based tests.
- a “complete response” does not necessarily indicate that the cancer has been cured, however, as a complete response can be followed by a relapse.
- compositions and kits disclosed herein can be used for treating cancer.
- the method comprises: administrating onvansertib or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof and a Poly-(ADP- ribose) polymerase (PARP) inhibitor selected from olaparib, niraparib, and AZD53O5 or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof to a subject (e.g., a patient) with cancer, thereby inhibiting progression of the cancer.
- the cancer can be ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- melanoma e.g., metastatic malignant melanoma
- renal cancer e.g., clear cell carcinoma
- prostate cancer e.g., hormone refractory prostate adenocarcinoma
- pancreatic adenocarcinoma breast cancer, colon cancer
- lung cancer e.g., nonsmall cell lung cancer (NSCLC) and small-cell lung cancer (SCLC)
- esophageal cancer squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and other neoplastic malignancies.
- the disease or condition provided herein includes refractory or recurrent malignancies whose growth may be inhibited using the methods and compositions disclosed herein.
- the cancer is carcinoma, squamous carcinoma, adenocarcinoma, sarcomata, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, hematological cancer, leuk
- the cancer is carcinoma, squamous carcinoma (e.g., cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and adenocarcinoma (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary).
- the cancer is sarcomata (e.g., myogenic sarcoma), leukosis, neuroma, melanoma, and lymphoma.
- the cancer can be a solid tumor, a liquid tumor, or a combination thereof.
- the cancer is a solid tumor, including but not limited to, 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.
- the cancer is a liquid tumor.
- the cancer is a hematological cancer.
- Non-limiting examples of hematological cancer include Diffuse large B cell lymphoma (“DLBCL”), Hodgkin's lymphoma (“HL”), NonHodgkin's lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), and Multiple myeloma (“MM”).
- DLBCL Diffuse large B cell lymphoma
- HL Hodgkin's lymphoma
- NHL NonHodgkin's lymphoma
- FL Follicular lymphoma
- AML acute myeloid leukemia
- MM Multiple myeloma
- the cancer can be, for example, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- the cancer can be pancreatic ductal carcinoma, pancreatic adenocarcinoma, ovary serous adenocarcinoma, breast ductal carcinoma, a high-grade serous ovarian adenocarcinoma, or a combination thereof.
- the cancer is ovarian cancer.
- the cancer is breast cancer.
- the cancer is prostate cancer.
- the cancer can be a homologous recombination-deficient cancer.
- the cancer can be a BRCA1 mutant cancer, a BRCA2 mutant cancer, or both.
- the cancer can be a BRCA1- homozygous mutant cancer, a BRCA2 -homozygous mutant cancer, a BRCA1 -heterozygous mutant cancer, a BRCA2-heterozygous mutant cancer, or any combination thereof.
- the cancer can be homozygous wild type for BRCA1, BRCA2, or both.
- the cancer is a BRCA2-mutant prostate cancer.
- the cancer is a BRCAl-mutant ovarian cancer.
- the cancer can be a BRCA wild type cancer with wildtype BRCA1 and/or BRCA2 sequence, such as BRCA1 wild type ovarian cancer and/or BRCA2 wild type ovarian cancer.
- the cancer is a BRCAl-wild type prostate cancer.
- the cancer is sensitive to a PARP inhibitor treatment.
- the cancer is characterized by deficiencies in DNA repair.
- the cancer can be a homologous recombination (HR) -deficient cancer with impaired HR-mediated DNA repair functionality.
- the subject having the cancer has one or more pathogenic variants of one or more genes involved in the HR-mediated DNA repair mechanism including but not limited to, BRCA1, BRCA2, 53BP1, ATM, ATR, ATRIP, BARD1, BLM, BRIP1, DMC1, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RIF1, RMI1, RMI2, RPA1, TOP3A, TOPBP1, XRCC2, and XRCC3.
- the cancer is BRCA1- and/or BRCA2-deficient.
- HRDetect score can be calculated for a cancer or tumor to detect BRACAl/BRCA2-deficient tumors.
- HRDetect is a whole-genome sequencing based classifier designed to predict BRCA1 and BRCA2 deficiency based on six mutational signatures. Details about the HRDetect method are described in Davies H et al., Nat Med. 2017; 23:517-25, the content of which is incorporated herein by reference in its entirety.
- a HRDetect score equal to or greater than about 0.7 suggest a HR deficiency, while less than about 0.7 indicates HR proficiency.
- a cancer has a HRDetect score equal to or greater than 0.7.
- a cancer has a HRDetect score less than 0.7.
- the cancer can be a PARP inhibitor resistant cancer or has developed resistance to a PARP inhibitor.
- the cancer can be a PARP inhibitor resistant (e.g., olaparib resistant) breast cancer, a PARP inhibitor resistant (e.g., olaparib resistant) ovarian cancer, a PARP inhibitor resistant (e.g., olaparib resistant) pancreatic cancer, or a PARP inhibitor resistant (e.g., olaparib resistant) prostate cancer.
- the combinatorial inhibition of PLK1 and PARP can effectively treat PARP inhibitor resistant cancer by significantly reducing the tumor size, increasing survival rate of a subject with cancer, and prolonging survival duration of a subject with cancer in comparison with a single agent treatment (a PARP inhibitor or a PLK1 inhibitor).
- RAD51 foci assay is conducted to discriminate between PARP inhibitor- sensitive and PARP inhibitor-resistant cancer.
- RAD51 refers to a homologous recombination DNA repair protein forming nuclear foci after DNA damage and can be used as an indicator of homologous recombination DNA repair functionality.
- RAD51 foci can be quantified using an immunofluorescence-based method in formalin-fixed paraffin-embedded tumor samples treated with vehicle or a PARP inhibitor.
- Low RAD51 score can be associated with PARP inhibitor (e.g., olaparib, niraparib, and AZD5305) sensitivity, while high RAD51 score can be associated with PARP inhibitor (e.g., olaparib, niraparib, and AZD5305) resistance.
- PARP inhibitor e.g., olaparib, niraparib, and AZD5305
- Details about the RAD51 foci assay can be found, for example, in Guffanti F et al., Br J Cancer, 2022 Jan; 126(1): 120- 128, the content of which is incorporated by reference herein.
- the cancer has a RAD51 foci level equal to or greater than 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%. In some embodiments, the cancer has a RAD51 foci level less than 30%, 25%, 20%, 155, 10%, 5%, 2%, or 1%.
- a method for treating cancer comprises administrating a PARP inhibitor (e.g., olaparib, niraparib, and AZD5305), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and a PLK1 inhibitor (e.g., onvansertib), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, to a subject (e.g., a patient) in need thereof.
- the method can comprise administering a pharmaceutically effective amount of the PARP inhibitor and a pharmaceutically effective amount of the PLK1 inhibitor.
- Table 1 shows several PARPi that are FDA- approved for cancer treatment.
- resistance to PARPi can occur in cancer patients.
- initial response rate to PARPi is high but patients will eventually develop mechanisms of resistance and relapse (progression free survival ⁇ 8 months).
- mechanisms of resistance include restoration of HR, decreased PARP trapping, stabilization of stalled forks, and increased drug efflux.
- combination therapies have the potential to prolong the effect of PARPi and/or overcome resistance.
- Poly-(ADP-ribose) polymerase plays a key role in the DNA damage response and either directly or indirectly affects numerous DNA damage repair (DDR) pathways, including base excision repair (BER), homologous recombination (HR), nucleotide excision repair (NER), non-homologus end joining (NHEJ) and DNA mismatch repair (MMR).
- DDR DNA damage repair
- HR homologous recombination
- NER nucleotide excision repair
- NHEJ non-homologus end joining
- MMR DNA mismatch repair
- PARP inhibitors are inhibitors of PARP, which are developed for multiple indications, including treatment of cancer.
- PARP is essential for repair of single strand DNA breaks (SSBs). Failure to repair SSBs through PARP inhibition results in double strand DNA breaks (DSBs). In cells with functional homologous recombination (HR) pathway, the DSB are repaired. In cells with a dysfunctional HR pathway, such as BRCA1 and/or
- PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction, as well as for long-term neurodegenerative diseases.
- DNA is damaged thousands of times during each cell cycle, and that damage must be repaired.
- BRCA1, BRCA2 and PALB2 are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombination repair, or HRR, pathway.
- HRR homologous recombination repair
- PARPI is a protein that is important for repairing single-strand breaks (“nicks” in the DNA). If such nicks persist unrepaired until DNA is replicated (which must precede cell division), then the replication itself can cause double strand breaks to form. Drugs that inhibit PARPI cause multiple double strand breaks to form in this way, and in tumors with BRCA1, BRCA2 or PALB2 mutations these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that don't replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2, still have homologous repair operating, which allows them to survive the inhibition of PARP.
- PARP inhibitors are PARP inhibitors effective against one or more PTEN-defective tumors (e.g. some aggressive prostate cancers). Cancer cells that are low in oxygen (e.g. in fast growing tumors) are sensitive to PARP inhibitors. PARP inhibitors were originally thought to work primarily by blocking PARP enzyme activity, thus preventing the repair of DNA damage and ultimately causing cell death. PARP inhibitors have an additional mode of action: localizing PARP proteins at sites of DNA damage, which has relevance to their anti-tumor activity.
- the trapped PARP protein-DNA complexes are highly toxic to cells because they block DNA replication.
- the PARP family of proteins in humans includes PARP1 and PARP2, which are DNA binding and repair proteins. When activated by DNA damage, these proteins recruit other proteins that do the actual work of repairing DNA. Under normal conditions, PARP1 and PARP2 are released from DNA once the repair process is underway. But when they are bound to PARP inhibitors, PARP1 and PARP2 become trapped on DNA. It was shown that trapped PARP-DNA complexes are more toxic to cells than the unrepaired single-strand DNA breaks that accumulate in the absence of PARP activity, indicating that PARP inhibitors act as PARP poisons.
- PARP inhibitors there are two classes of PARP inhibitors: (1) catalytic inhibitors that act mainly to inhibit PARP enzyme activity and do not trap PARP proteins on DNA, and (2) dual inhibitors that both block PARP enzyme activity and act as PARP poison.
- Non-limiting examples of PARP inhibitors include: Iniparib (BSI 201) (for example, for breast cancer and squamous cell lung cancer); Olaparib (AZD-2281) (for example, for breast, ovarian and colorectal cancer); Rucaparib (AG014699, PF- 01367338, for example, for metastatic breast and ovarian cancer); Veliparib (ABT-888) (for example, for metastatic melanoma and breast cancer); CEP 9722 (for example, for non-small-cell lung cancer (NSCLC)); MK 4827 which inhibits both PARP1 and PARP2; BMN-673 (for example, for advanced hematological malignancies and for advanced or recurrent solid tumors); and 3-amin
- the methods and compositions for treating cancer in combination with one or more PLK1 inhibitors disclosed herein can include one or more PARP inhibitors (including but not limited to, olaparib, talazoparib (BMN-673), AZD5305, rucaparib, veliparib, niraparib, CEP 9722, MK 4827, BGB-290 (pamiparib), ABT-888, AG014699, BSI-201, CEP-8983, E7016, NMS-P293, and 3-aminobenzamide).
- PARP inhibitors are known to exhibit synthetic lethality, for example in tumors with mutations in BRCA1/2.
- Olaparib has received FDA approval for treatment of ovarian cancer patients with mutations in BRCA1 or BRCA2.
- other FDA-approved PARP inhibitors for ovarian cancer include nirapirib and rucaparib.
- Talazoparib was recently approved for treatment of breast cancer with germline BRCA mutations and is in phase III trials for hematological malignancies and solid tumors and has reported efficacy in SCLC, ovarian, breast, and prostate cancers.
- Veliparib is in phase III trials for advanced ovarian cancer, TNBC and NSCLC.
- NMS-P293 was described in, for example, Abstract 4843: NMS-P293, a PARP-1 selective inhibitor with no trapping activity and high CNS penetration, possesses potent in vivo efficacy and represents a novel therapeutic option for brain localized metastases and glioblastoma, Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL.
- PARP inhibitors have been approved for BRCA1/2 mutant ovarian, breast, prostate and pancreatic cancer patients. Although initial response to PARP inhibitors is high, patients will eventually develop resistance. Mechanisms of resistance to PARP inhibitors include restoration of homologous recombination (HR).
- HR homologous recombination
- the PARP inhibitor can be, for example, Iniparib (BSI 201), Talazoparib (BMN-673), AZD5305, Olaparib (AZD-2281), Rucaparib (AG014699, PF-01367338), ABT-888, Veliparib (ABT-888), niraparib, CEP 9722, MK 4827, BGB-290 (pamiparib), BSI-201, CEP- 8983, E7016, 3-aminobenzamide, or a combination thereof.
- the PARP inhibitor is niraparib.
- the PARP inhibitor is AZD53O5.
- the PARP inhibitor is olaparib.
- Polo-like kinases are a family of five highly conserved serine/threonine protein kinases.
- PLK1 is a master regulator of mitosis and is involved in several steps of the cell cycle, including mitosis entry, centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis.
- PLK1 has been shown to be overexpressed in solid tumors and hematologic malignancies, including AML.
- PLK1 inhibition induces G2-M-phase arrest with subsequent apoptosis in cancer cells, and has emerged as a promising targeted therapy.
- Several PLK inhibitors have been studied in clinical trials.
- pan-PLK inhibitor volasertib (BI6727)
- LDAC double Strand DNA Break
- Onvansertib (also known as PCM-075, NMS-1286937, NMS-937, “compound of formula (I)” in US Patent No. 8,927,530, IUPAC name l-(2-hydroxyethyl)-8- ⁇ [5-(4- methylpiperazin-l-yl)-2-(trifhioromethoxy) phenyl] amino ⁇ -4,5-dihydro-lH-pyrazolo[4,3-h] quinazoline-3 -carboxamide) is a selective ATP-competitive PLK1 inhibitor.
- Biochemical assays demonstrated high specificity of onvansertib for PLK1 among a panel of 296 kinases, including other PLK members.
- Onvansertib has potent in vitro and in vivo antitumor activity in models of both solid and hematologic malignancies.
- Onvansertib is the first PLK1 specific ATP competitive inhibitor administered by oral route to enter clinical trials with proven antitumor activity in different preclinical models.
- Onvansertib inhibited cell proliferation at nanomolar concentrations in AML cell lines and tumor growth in xenograft models of AML.
- Onvansertib also significantly increased cytarabine antitumor activity in disseminated models of AML.
- Onvansertib shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid as well as hematologic tumors. Onvansertib potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with a clear PLK1 -related mechanism of action at well tolerated doses in mice after oral administration.
- onvansertib shows activity in combination therapy with approved cytotoxic drugs, such as irinotecan, in which there is enhanced tumor regression in HT29 human colon adenocarcinoma xenografts compared to each agent alone, and shows prolonged survival of animals in a disseminated model of AML in combination therapy with cytarabine.
- Onvansertib has favorable pharmacologic parameters and good oral bioavailability in rodent and nonrodent species, as well as proven antitumor activity in different nonclinical models using a variety of dosing regimens, which can provide a high degree of flexibility in dosing schedules, warranting investigation in clinical settings.
- Onvansertib has several advantages over volasertib (BI6727, another PLK1 inhibitor), including a higher degree of potency and specificity for the PLK1 isozyme, and oral bioavailability.
- a phase I, first-in-human, dose-escalation study of onvansertib in patients with advanced/metastatic solid tumors identified neutropenia and thrombocytopenia as the primary dose-limiting toxicities. These hematologic toxicities were anticipated on the basis of the mechanism of action of the drug and were reversible, with recovery occurring within 3 weeks.
- the half-life of onvansertib was established between 20 and 30 hours. The oral bioavailability of onvansertib plus its short half-life provide the opportunity for convenient, controlled, and flexible dosing schedules with the potential to minimize toxicities and improve the therapeutic window.
- a combination therapy of a PARP inhibitor and onvansertib can result in significantly enhanced efficacy against cancer (e.g., ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof), causing tumor regression and cancer survival.
- cancer e.g., ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof
- the resulted tumor regression and cancer survival rate/duration by the combination can be surprisingly synergistic (i.e., more than additive, superior to the cumulated anti-tumor efficacy caused by the PARP inhibitor and the PLK1 inhibitor separately).
- Provided herein include methods, compositions and kits for treating cancer in a subject (e.g., a human patient suffering from cancer).
- the method comprises administrating a PARP inhibitor and onvansertib to the patient in a manner sufficient to inhibit or reduce progression of the cancer.
- the PARP inhibitor and onvansertib can be administrated to a subject with cancer simultaneously, separately, or sequentially.
- the resulted tumor regression and cancer survival rate/duration by the combination is more than additive, i.e., superior to the cumulated anti-tumor efficacy caused by the PARP inhibitor and onvansertib separately.
- Provided herein include methods, compositions and kits for treating cancer in a subject (for example, a human patient suffering from cancer ).
- the method comprises administrating a PARP inhibitor and onvansertib to the patient in a manner sufficient to inhibit progression of the cancer.
- the PARP inhibitor and onvansertib can be administrated to a subject with cancer simultaneously, separately, or sequentially.
- 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 PARP inhibitor alone plus onvansertib alone).
- the enhanced or synergistic efficacy or inhibition of any combination of a PARP inhibitor and onvansertib of the present disclosure can be different in different embodiments.
- the enhanced or synergistic efficacy or inhibition of any combination of a PARP inhibitor and onvansertib 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 the PARP inhibitor alone plus onvansertib alone.
- the molar ratio of the PLK1 inhibitor (e.g., onvansertib) to the PARP inhibitor (e.g., olaparib, niraparib, and AZD53O5) 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.
- the enhanced or synergistic efficacy or inhibition of cancer progression caused by a combination of the PARP inhibitor and onvansertib 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 the PARP inhibitor alone plus onvansertib alone.
- a combination of the PARP inhibitor and onvansertib 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 PARP inhibitor alone plus onvansertib alone can be 10%, 20%, 25%, 30%, or less) inhibition of cancer progression (cancer cell viability of 90%, 80%, 75%, 70%, or more).
- the enhanced or synergistic efficacy or inhibition of cancer progression caused by the combination of the PARP inhibitor and the PLK1 inhibitor can be, for example, 50%, 60%, 70%, 80%, 90%, 100%, or more higher than the combined inhibition of progression caused by the PARP inhibitor alone plus onvansertib alone.
- the PARP inhibitor is olaparib.
- the method described herein using the combination of the PARP inhibitor and the PLK1 inhibitor is expected to be effective with various cancers, for example head and neck cancer, non-small cell lung cancer, intrahepatic cholangiocarcinoma, gastric cancer, urothelial cancer, small cell lung cancer, breast cancer, endometrial cancer, cervical cancer, rhabdomyosarcoma, cholangiocarcinoma, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, prostate cancer, or a combination thereof.
- various cancers for example head and neck cancer, non-small cell lung cancer, intrahepatic cholangiocarcinoma, gastric cancer, urothelial cancer, small cell lung cancer, breast cancer, endometrial cancer, cervical cancer, rhabdomyosarcoma, cholangiocarcinoma, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, prostate cancer, or a combination thereof.
- the patient can achieve complete response or partial response after treatment with the PARP inhibitor and onvansertib. In some embodiments, the patient achieves a complete response. In some embodiments, the patient achieves a partial response. In some embodiments, the subject has received a prior PARP inhibitor treatment. In some embodiments, the patient did not respond to treatment with only PARP inhibitor(s). In some embodiments, the patient did not respond to treatment with the PARP inhibitor alone. In some embodiments, the subject is known to be resistant to a PARP inhibitor therapy. In some embodiments, the subject has received at least one prior cancer treatment. In some embodiments, the prior treatment does not comprise the use of a PARP inhibitor, onvansertib, or both. In some embodiments, the subject was in remission for cancer. In some embodiments, the subject in remission for cancer was in complete remission (CR) or in partial remission (PR).
- CR complete remission
- PR partial remission
- the PARP inhibitor and the PLK1 inhibitor can be administered to the patient in any manner deemed effective to treat the cancer.
- the PARP inhibitor can be administered together with, or separately from, onvansertib.
- the PARP inhibitor can be administered before or after onvansertib, or in different administration cycles.
- Onvansertib and the PARP inhibitor can be co-administered (i.e., simultaneously) or sequentially.
- the PARP inhibitor e.g., olaparib, niraparib, or AZD5305
- onvansertib can sensitize cells (e.g., cancer cells) to the PARP inhibitor (e.g., through impairment of HR) to achieve effective treatment.
- the time interval between the administration of onvansertib and the administration of the PARP inhibitor 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, a range between any two of these values, or any value between 30 minutes and 12 hours.
- onvansertib and the PARP inhibitor 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 onvansertib is administered to the subject prior to the PARP inhibitor 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 the PARP inhibitor.
- the PARP inhibitor e.g., olaparib
- the PARP inhibitor 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.
- the PARP inhibitor and onvansertib are each administered to the patient in a cycle of at least twice within a week.
- the PARP inhibitor and onvansertib are each administered to the patient in a cycle of at least five times within a week.
- the patient undergoes at least two cycles of administration.
- 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.
- two adjacent cycles of administration have a break between them, i.e., an interval between the last day of the first cycle and the first day of the second cycle.
- the break i.e., the interval
- the break 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.
- 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.
- one of the cycle in the multi-cycle administration can be five continuous days of daily administration of onvansertib and PARP inhibitor 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 PARP inhibitor in a four-week period.
- the PARP inhibitor (e.g., olaparib, niraparib, and AZD5305) can be administered to the patient at any appropriate dosage, e.g., a dosage of about, at least or at most 0.1 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 200 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, 1000 mg/kg, 1500 mg/kg, 2000 mg/kg, or a number between any two of these values.
- the dosage unit based on the body weight (mg/kg) can be converted to another unit (e.g., mg/m 2 ) using a conversion chart such as the body surface area (BSA) conversion chart as will be understood by a person skilled in the art.
- the PARP inhibitor is olaparib, niraparib, or AZD5305, which is administered at a dosage of about, at least or at most 1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 200 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, 1000 mg/kg, or a number between any two of these values.
- the PARP inhibitor (e.g., olaparib, niraparib, or AZD5305) can be administrated to the patient once daily, twice daily, or three times daily.
- the PARP inhibitor is administered in a cycle of 7-56 days of daily administration.
- the PARP inhibitor 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.
- the PARP inhibitor 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.
- the PARP inhibitor 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.
- the PARP inhibitor 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
- day 38 day 39, day 40, day 41, day 42, day 43, day 44, day 45, day 46, day 47, day 48, day
- olaparib, niraparib, or AZD5305 can be administered in a cycle of 5, 6, 7, 8, 9, or 10 days.
- Olaparib can be administrated daily on each day or on selected days of the administration cycle.
- olaparib is administered in a cycle of 7 days with a daily administration for 5 days (e.g., days 1-5) and no administration for two days (e.g., days 6-7).
- any PARP inhibitor can be used in these methods, including PARP inhibitors that are selective for PARP (e.g., PARP1, PARP2 or both), and PARP inhibitors that also inhibit the activity of other proteins.
- PARP inhibitors include Iniparib (BSI 201), Talazoparib (BMN-673), AZD5305, Olaparib (AZD-2281), Rucaparib (AG014699, PF-01367338), ABT-888, Veliparib (ABT-888), niraparib, CEP 9722, MK 4827, BGB-290 (pamiparib), BSI-201, CEP-8983, E7016, 3 -aminobenzamide, and combinations thereof.
- the PARP inhibitor is 2X 121, ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib (ZEJULA) (MK-4827), NMS-P293, NOV- 140101, NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), 0N02231, pamiparib, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699, PF-01367338), SBP 101, SC 101914, simmiparib, talazoparib (BMN- 673), AZD53O5, veliparib
- any PLK1 inhibitor 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.
- the PLK1 inhibitor is a dihydropteridinone, a pyridopyrimidine, a aminopyrimidine, a substituted thiazolidinone, a pteridine derivative, a dihydroimidazo[l,5-f]pteridine, a metasubstituted thiazolidinone, a benzyl styryl sulfone analogue, a stilbene derivative, or a combination thereof.
- 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.
- the PLK1 inhibitor is onvansertib.
- the onvansertib is administered to the patient at any appropriate dosage, e.g., a dosage of less than 12 mg/m 2 , less than or equal to 24 mg/m 2 , or greater than 24 mg/m 2 .
- the onvansertib is administered to the patient daily.
- the onvansertib is administered in a cycle of 3-10 days of daily onvansertib administration with 2-16 days with no onvansertib administration.
- 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.
- 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.
- a PLK1 inhibitor alone e.g., onvansertib
- a PARP inhibitor 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 a PARP inhibitor.
- 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.
- the amount of co-administration of the PARP inhibitor and onvansertib, and the timing of co-administration 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 PARP inhibitor and onvansertib can 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.
- colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
- 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.
- the cancer can be ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- the cancer can be a BRCA mutant cancer, for example a BRCA1 homozygous mutant cancer, a BRAC2 homozygous mutant cancer, or a BRAC1 and BRAC2 homozygous mutant cancer.
- the cancer can be a BRCA wild type cancer (e.g., no BRCA mutation), for example a BRCA1 wild type cancer or a BRCA2 wild type cancer.
- the cancer can be a BRCAl-heterozygous mutant cancer or a BRCA2 -heterozygous mutant cancer, or both.
- the cancer can be heterozygous mutant for BRCA1 and/or 2 and/or homozygous mutant for BRCA 1 and/or 2.
- the methods can further comprise administering an additional therapeutic intervention to the subject.
- the additional therapeutic intervention can comprise a different therapeutic intervention than administering onvansertib and the PARP inhibitor, an antibody, an adoptive T cell therapy, a chimeric antigen receptor (CAR) T cell therapy, an antibody-drug conjugate, a cytokine therapy, a cancer vaccine, a checkpoint inhibitor, a radiation therapy, surgery, a chemotherapeutic agent, or any combination thereof.
- the therapeutic intervention can be administered at any time of the treatment, for example at a time when the subject has an early-stage cancer, and wherein the therapeutic intervention is more effective that if the therapeutic intervention were to be administered to the subject at a later time.
- the PLK1 inhibitor e.g., onvansertib
- can sensitize cells e.g., cancer cells
- PARP inhibitor treatment e.g., through impairment of HR
- the treatment of the present disclosure can comprise administration of a PLK1 inhibitor (e.g., onvansertib) for a desired duration in one or more cycles of treatment, and administration of a PARP inhibitor.
- a PLK1 inhibitor e.g., onvansertib
- the administration of onvansertib can be oral administration.
- the administration of the PARP inhibitor can be oral administration. Both onvansertib and the PARP inhibitor can be administered orally.
- the treatment can, for example, comprise daily administration of a PARP inhibitor (e.g., olaparib) at, or at about, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 5mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, or a number or a range between any two of these values.
- a PARP inhibitor e.g., olaparib
- the daily dose of the PARP inhibitor can be adjusted (e.g., increased or decreased with the range) during the treatment of the subject.
- the daily administration of the PARP inhibitor can be at different amounts on different days or during different weeks.
- the treatment can comprise daily administration of the PARP inhibitor (e.g., olaparib) at 0.1 mg to 20 mg during week 1, 0.25 mg to 50 mg during week 2, 0.5 mg to 100 mg during week 3, 1 mg to 200 mg during week 4, and 2 mg to 400 mg during week 5 and beyond.
- the treatment can comprise daily administration of the PARP inhibitor (e.g., olaparib) at 300 mg on day 1, 450 mg on day 2, 600 mg on day 3, and 750 mg or 600 mg on day 4 and beyond.
- the PARP inhibitor e.g., olaparib
- the PARP inhibitor is administered to the subject orally twice daily (two 150 mg tablets each time), with or without food, for a total daily dose of 600 mg.
- the PARP inhibitor (e.g., olaparib) is administered to the subject orally twice daily (one 100 mg tablet and one 150 mg tablets each time), with or without food, for a total daily dose of 500 mg.
- the PARP inhibitor (e.g., olaparib) is administered to the subject orally twice daily (two 100 mg tablets each time), with or without food, for a total daily dose of 400 mg.
- a maximum concentration (Cmax) of the PARP inhibitor (e.g., olaparib) in a blood of the subject (during the treatment and/or after the treatment) when the PARP inhibitor is administered alone or in combination with onvansertib can be from about 0.1 pg/mL (picogram per mL) to about 10 pg/mL (microgram per mL).
- the Cmax of the PARP inhibitor (e.g., olaparib) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib can be, or be about, 0.1 pg/mL, 0.2 pg/mL, 0.3 pg/mL, 0.4 pg/mL, 0.5 pg/mL, 0.6 pg/mL, 0.7 pg/mL, 0.8 pg/mL, 0.9 pg/mL, 1 pg/mL, 1.1 pg/mL, 1.2 pg/mL, 1.3 pg/mL, 1.4 pg/mL, 1.5 pg/mL, 1.6 pg/mL, 1.7 pg/mL, 1.8 pg/mL, 1.9 pg/mL, 2 pg/mL, 2.1 pg/mL, 2.2 pg/mL, 2.3 pg/
- An area under curve (AUC) of a plot of a concentration of the PARP inhibitor (e.g., olaparib) in a blood of the subject over time (e.g., AUC0-24 for the first 24 hours after administration) when the PARP inhibitor is administered alone or in combination with onvansertib can be from about 1 pg.h/mL to about 100 pg.h/mL.
- the AUC of a plot of a concentration of the PARP inhibitor (e.g., olaparib) in a blood of the subject overtime (e.g., AUCo- 24 for the first 24 hours after administration) when the PARP inhibitor is administered alone or in combination with onvansertib can be, or be about, 1 pg.h/mL, 5 pg.h/mL, 10 pg.h/mL, 20 pg.h/mL, 30 pg.h/mL, 40 pg.h/mL, 50 pg.h/mL, 60 pg.h/mL, 70 pg.h/mL, 80 pg.h/mL, 90 pg.h/mL, 100 pg.h/mL, 200 pg.h/mL, 300 pg.h/mL, 400 pg.h/mL, 500 pg.h/mL, 600 pg.h/mL, 700
- the PARP inhibitor is olaparib
- the AUC of a plot of a concentration of olaparib in a blood of the subject over time (e.g., AUCo-ioh for the first 10 hours after administration) when olaparib is administered alone or in combination with onvansertib can be, or be about, 0.5 pg.h/mL, 1 pg.h/mL, 1.5 pg.h/mL, 2 pg.h/mL, 2.5 pg.h/mL, 3 pg.h/mL, 3.5 pg.h/mL, 4 pg.h/mL, 4.5 pg.h/mL, 5 pg.h/mL, 5.5 pg.h/mL, 6 pg.h/mL, 6.5 pg.h/mL, 7 pg.h/mL, 8 pg.h/mL, 9 pg.h/mL, 10
- a time (T ma x) to reach a maximum concentration of the PARP inhibitor e.g., olaparib, niraparib, or AZD5305
- a maximum concentration of the PARP inhibitor e.g., olaparib, niraparib, or AZD5305
- the time (Tinas) to reach a maximum concentration of the PARP inhibitor (e.g., olaparib) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib can be, or be about, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, a range between any two of these values, or any value between 2 hours and 24 hours.
- the PARP inhibitor is olaparib
- the time (Tmax) to reach a maximum concentration of olaparib in a blood of the subject when olaparib is administered alone or in combination with onvansertib can be, or be about 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, or a number or a range between any two of these values.
- An elimination half-life (T1/2) of the PARP inhibitor (e.g., olaparib, niraparib, or AZD5305) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib can be from about 10 hours to about 100 hours.
- the elimination half-life (T1/2) of the PARP inhibitor e.g., olaparib
- T1/2 the elimination half-life (T1/2) of the PARP inhibitor (e.g., olaparib) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib
- T1/2 the elimination half-life (T1/2) of the PARP inhibitor (e.g., olaparib) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib
- T1/2 the elimination half-life (T1/2) of the PARP inhibitor (e.g., olaparib) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib
- T1/2 the elimination half-life (T1/2) of the PARP inhibitor (e.g., olaparib) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib
- T1/2 the
- the PARP inhibitor is olaparib
- the elimination half-life (T 1/2) of olaparib in a blood of the subject when olaparib is administered alone or in combination with onvansertib can be, or be about, 40 hours, 50 hours, 60 hours, 70 hours, 80 hours, 90 hours, 100 hours, or a number or a range between any two of these values.
- the treatment of the present disclosure can comprise administration of a PLK1 inhibitor (e.g., onvansertib) for a desired duration in a cycle.
- a PLK1 inhibitor e.g., onvansertib
- the administration of the onvansertib (and/or the one or more chemotherapeutic agents) 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 the one or more chemotherapeutic agents) 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.
- a single cycle of the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) and/or the one or more chemotherapeutic agents 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)).
- the PLK1 inhibitor e.g., on
- the treatment can comprise administration of onvansertib and/or the one or more chemotherapeutic agents 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 onvansertib and/or the one or more chemotherapeutic agents 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).
- the treatment comprises administration of the PLK1 inhibitor (e.g., onvansertib) for five days in a cycle of 21 to 28 days.
- 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),
- 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).
- 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).
- the subject can receive one, two, three, four, five, six, or more cycles of treatment.
- the administration cycles, dosing schedules, and/or dosage amounts of the PARP inhibitor and onvansertib can be the same or different.
- the administration cycle, dosing schedule, and/or dosage amount of the PARP inhibitor can be adjusted according to the administration cycle, dosing schedule, and/or dosage amount of onvansertib.
- the PARP inhibitor e.g., olaparib, niraparib, or AZD5305
- the PARP inhibitor 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).
- the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 6 mg/m 2 - 90 mg/m 2 , for example, as a daily dose.
- the treatment can comprise daily administration of onvansertib at, or at about, 6 mg/m 2 , 8 mg/m 2 , 10 mg/m 2 , 12 mg/m 2 , 14 mg/m 2 , 16 mg/m 2 , 18 mg/m 2 , 20 mg/m 2 , 23 mg/m 2 , 27 mg/m 2 , 30 mg/m 2 , 35 mg/m 2 , 40 mg/m 2 , 45 mg/m 2 , 50 mg/m 2 , 55 mg/m 2 , 60 mg/m 2 , 65 mg/m 2 , 70 mg/m 2 , 80 mg/m 2 , 85 mg/m 2 , 90 mg/m 2 , a number or a range between any two of these values, or any value between 8 mg
- the daily dose of 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.
- onvansertib is administered at 12 mg/m 2 on twenty days (e.g., Days 1-10 and 15-24) during a 28-day cycle.
- onvansertib is administered at 15 mg/m 2 on ten days (e.g., Days 1-5 and 15-19) during a 28-day cycle.
- onvansertib is administered at 8 mg/m 2 or 10 mg/m 2 everyday (e.g., Days 11-28) during a 28-day cycle.
- the daily dose of 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.
- onvansertib is administered at or at about 12 mg/m 2 .
- onvansertib is administered at or at about 15 mg/m 2 .
- onvansertib is administered at or at about 18 mg/m 2 .
- 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 PARP inhibitor can be from about 100 nmol/L to about 1500 nmol/L.
- the Cmax of onvansertib in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor 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.
- An area under curve (AUC) of a plot of a concentration of the PLK1 inhibitor (e.g., onvanserib) 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 PARP inhibitor can be from about 1000 nmol/L.hour to about 400000 nmol/L.hour.
- the AUC of a plot of a concentration of onvansertib in a blood of the subject over time when onvansertib is administered alone or in combination with the PARP inhibitor 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.
- a time (T ma x) to reach a maximum concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor can be from about 1 hour to about 5 hours.
- the time (T max ) to reach a maximum concentration of onvansertib in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor 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.
- An elimination half-life (T1/2) of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor can be from about 10 hours to about 60 hours.
- the elimination half-life (T1/2) of onvansertib in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor 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.
- a method for treating cancer comprises administrating a PARP inhibitor (e.g., olaparib, niraparib, or AZD53O5) and a PLK1 inhibitor (e.g., onvansertib) to a subject (e.g., a patient) in need thereof.
- the method can comprise administering a therapeutically effective amount of the PARP inhibitor and a therapeutically effective amount of onvansertib.
- the treatment can comprise administration of at least one additional cancer therapeutics or cancer therapy.
- the treatment can comprise administration of a therapeutically effective amount of at least one additional cancer therapeutics or cancer therapy.
- the PARP inhibitor and the cancer therapeutics or cancer therapy can, for example, co-administered simultaneously or sequentially.
- the PLK1 inhibitor (e.g., onvansertib) and the cancer therapeutics or cancer therapy can, for example, be co-administered simultaneously or sequentially.
- the additional cancer therapeutics is cytarabine, low-dose cytarabine (LDAC) and/or decitabine.
- LDAC low-dose cytarabine
- decitabine decitabine
- the treatment comprises administration of LDAC at, or at about, 20 mg/m 2 subcutaneous (SC) once a day (qd) for seven, eight, night, ten, eleven, twelve, or thirteen days in a cycle.
- the treatment comprises administration of decitabine at, or at about, 20 mg/m 2 intravenous (IV) qd for three, four, five, six, or seven days in a cycle.
- the treatment comprises administration of LDAC at, or at about, 20 mg/m 2 subcutaneous (SC) once a day (qd) for ten days in a cycle, and administration of decitabine at 20 mg/m 2 intravenous (IV) qd for five days in a cycle.
- Also disclosed herein include methods, compositions, kits, and systems for predicting/determining clinical outcome for a combination treatment of cancer of the present disclosure, monitoring of the combination treatment, predicting/determining responsiveness of a subject to the combination treatment, determining the status of the cancer in a subject, and improving combination treatment outcome.
- the methods, compositions, kits and systems can be used to guide the combination treatment, provide combination treatment recommendations, and/or reduce or avoid unnecessary ineffective combination treatment for patients.
- predicting/determining clinical outcome for a combination treatment of cancer of the present disclosure monitoring of the combination treatment, predicting/determining responsiveness of a subject to the combination treatment, and/or determining the status of the cancer in a subject comprises measure tumor size and/or inhibition of tumor growth.
- Inhibiting progression of the cancer can comprise inhibition of growth of one or more tumors in the subject.
- the term “inhibition of tumor growth” can refer to causing a reduction in or complete cessation of tumor growth and/or causing a regression in tumor size (e.g., volume).
- tumor volume or “tumor size” can refer to the total size of the tumor, which can include the tumor itself plus affected lymph nodes if applicable.
- Tumor size can be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of the tumor using calipers, computed tomography (CT) or magnetic resonance imaging (MRI) scans, mammography, and X- ray; and calculating the volume using equations based on, for example, the z-axis diameter, or on standard shapes such as the sphere, ellipsoid, or cube.
- Tumor size may be assessed at any time before, during or following at least one cycle of treatment with onvansertib and/or a PARP inhibitor.
- Tumor size can be assessed at a first timepoint, and at one or more additional timepoints.
- tumor size can be assessed in the subject and, e.g., an untreated subject at equivalent timepoints (e.g., at a first timepoint, and at one or more additional timepoints).
- Tumor growth can be determined by, e.g., measuring tumor size at a first timepoint and measuring tumor size at one or more additional timepoints.
- increased inhibition of tumor growth in the subject indicates the subject as responsive to the cancer treatment.
- the inhibition of growth of at least one of the one or more tumors in the subject can be, can be about, can be at least, or can be at least about 1.1 times greater, 1.2 times greater, 1.3 times greater, 1.4 times greater, 1.5 times greater, 1.6 times greater, 1.7 times greater, 1.8 times greater, 1.9 times greater, 2 times greater, or a number or a range between any two of these values, or more, than the inhibition of growth caused by onvansertib alone or the PARP inhibitor alone, following one or more cycles of treatment.
- the inhibition of growth of at least one of the one or more tumors in the subject can be increased by, by about, by at least, or by at least about 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or a number or a range between any two of these values, relative to a subject treated with onvansertib alone or the PARP inhibitor alone, following one or more cycles of treatment.
- the growth of at least one of the one or more tumors in the subject can be inhibited by, by about, by at least, or by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or a number or a range between any two of these values relative to an untreated subject, following one or more cycles of treatment.
- the growth of at least one of the one or more tumors in the subject can be inhibited by, by about, by at least, or by at least about 70%, 75%, 80%, 85%, 90%, 95%, 100% or a number or a range between any two of these values relative to an untreated subject, following one or more cycles of treatment.
- the subject can be tumor-free following one or more cycles of treatment.
- the method comprises measuring expression of one or more markers in the subject (e.g., in a sample obtained from the subject).
- the method can comprise: measuring expression of one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof in the subject before and/or after the subject is administered with onvansertib and/or the PARP inhibitor.
- the one or more markers can comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof
- a method of determining responsiveness of a subject to a combination treatment comprising a PARP inhibitor and a PLK1 inhibitor of the disclosure can comprise, for example, analyzing a sample (e.g., a biopsy sample) obtained from a subject with cancer, wherein the subject is undergoing a treatment and/or has received the combination treatment, thereby determining the responsiveness of the subject to the combination treatment.
- determining the responsiveness of the subject comprises determining if the subject is a responder of the treatment, e.g., by measuring expression of one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof in the subject.
- measuring the one or more markers can comprise measuring cleaved-caspase3 in a first sample obtained from the subject at a first time point, detecting cleaved-caspase3 in the sample obtained from the subject at one or more additional time points in one or more additional samples, and determining the difference of the levels of cleaved-caspase3 between the first and at least one of the one or more additional samples.
- an increase in levels of cleaved-caspase3 e.g., increased apoptosis
- in at least one of the additional samples relative to the first sample indicates the subject as responsive to the cancer treatment.
- the first time point is prior or immediately prior to the combination treatment, and at least one of the one or more additional time points are at the end of or after at least one cycle of the combination treatment.
- the cycle of the combination treatment is the first cycle of the combination treatment.
- the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment.
- the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
- the method comprises continuing the combination treatment to the subject if the subject is indicated as responsive to the combination treatment.
- the method comprises discontinuing the combination treatment to the subject and/or starting a different combination treatment to the subject if the subject is not indicated as responsive to the combination treatment.
- the first time point is prior or immediately prior to the combination treatment, and the one or more additional time points are at the end of or after at least a cycle of the combination treatment, optionally the cycle of the combination treatment is the first cycle of the combination treatment.
- the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment, optionally the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
- the method comprises starting an additional treatment to the subject if the subject is indicated as in cancer relapse.
- the additional treatment can be the same or different from the current or prior combination treatment.
- analyzing the sample comprises measuring expression of one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof.
- the method comprises measuring expression of at least one of the one or more markers in the subject at a first time point in a first sample, measuring expression of at least one of the one or more markers in the subject at one or more additional time points in one or more additional samples, and determining the difference in expression between the first and at least one of the one or more additional samples.
- Samples for measurement of the one or more markers can be obtained by any method known in the art.
- the biological sample is obtained from an animal subject, such as a human subject.
- a biological sample is any solid or fluid sample obtained from, excreted by or secreted by any living organism, (including samples from a healthy or apparently healthy human subject or a human patient affected by cancer).
- a biological sample can be a biological fluid obtained from, for example, blood, plasma, serum, urine, bile, ascites, saliva, cerebrospinal fluid, aqueous or vitreous humor, or any bodily secretion, a transudate, an exudate (for example, fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (for example, a normal joint or a joint affected by disease, such as a rheumatoid arthritis, osteoarthritis, gout or septic arthritis).
- a sample can also be obtained from any organ or tissue (including a biopsy, such as a tumor biopsy) or can include a cell (whether a primary cell or cultured cell) or medium conditioned by any cell, tissue or organ.
- exemplary samples include, without limitation, cells, cell lysates, blood smears, cytocentrifuge preparations, cytology smears, bodily fluids (e.g., blood, plasma, serum, saliva, sputum, urine, bronchoalveolar lavage, semen, etc.), tissue biopsies (e.g., tumor biopsies), fine-needle aspirates, and/or tissue sections (e.g., cryostat tissue sections and/or paraffin-embedded tissue sections).
- the sample includes circulating tumor cells (which can be identified by cell surface markers).
- samples are used directly (e.g., fresh or frozen), or can be manipulated prior to use, for example, by fixation (e.g., using formalin) and/or embedding in wax (such as formalin- fixed paraffin-embedded (FFPE) tissue samples).
- fixation e.g., using formalin
- FFPE formalin- fixed paraffin-embedded
- the levels of the one or more markers in the subject can be measured by any method known in the art.
- the one or more markers are detected by immunofluorescence, mass cytometry (CyTOF), FACS, drop-seq, RNA-seq, single cell qPCR, MERFISH (multiplex (in situ) RNA FISH), microarray and/or by in situ hybridization.
- Other methods including absorbance assays and colorimetric assays are known in the art and may be used herein.
- measuring expression of the one or more markers comprises measuring protein expression levels.
- Protein expression levels may be measured, for example, by performing a Western blot, an ELISA, immunohistochemistry or binding to an antibody array.
- measuring expression of the one or more markers comprises measuring RNA expression levels.
- RNA expression levels may be measured by performing RT-PCR, Northern blot, an array hybridization, or RNA sequencing methods.
- An enzyme-linked immunosorbent assay may be used to measure the differential expression of a plurality of markers.
- an ELISA assay There are many variations of an ELISA assay. All are based on the immobilization of an antigen or antibody on a solid surface, generally a microtiter plate.
- the original ELISA method comprises preparing a sample containing the biomarker proteins of interest, coating the wells of a microtiter plate with the sample, incubating each well with a primary antibody that recognizes a specific antigen, washing away the unbound antibody, and then detecting the antibody- antigen complexes. The antibody-antibody complexes may be detected directly.
- the primary antibodies are conjugated to a detection system, such as an enzyme that produces a detectable product.
- the antibody-antibody complexes may be detected indirectly.
- the primary antibody is detected by a secondary antibody that is conjugated to a detection system, as described above.
- the microtiter plate is then scanned and the raw intensity data may be converted into expression values using means known in the art.
- Detection of the one or more markers can be by FACS.
- FACS fluorescent activated cell sorting
- a beam of light (usually laser light) of a single wavelength is directed onto a hydro-dynamically focused stream of fluid.
- a number of detectors are aimed at the point where the stream passes through the light beam; one in line with the light beam (Forward Scatter, correlates to cell volume) and several perpendicular to the beam, (Side Scatter, correlates to the inner complexity of the particle and/or surface roughness) and one or more fluorescent detectors.
- Each suspended particle passing through the beam scatters the light in some way, and fluorescent chemicals found in the particle or attached to the particle may be excited into emitting light at a lower frequency than the light source.
- Detection of the one or more markers may involve a cell sorting step to enrich for cells of interest and thus facilitate or enhance their sensitive and specific detection.
- Cell sorting techniques are commonly based on tagging the cell with antibody against the cell membrane antigen specific to the target subpopulation of cells.
- the antibody is conjugated to a magnetic bead and/or fluorophore or other label to enable cell sorting and detection.
- Such methods may include affinity chromatography, particle magnetic separation, centrifugation, or filtration, and flow cytometry (including fluorescence activated cell sorting; FACS).
- RNA can be isolated from the cancer cells and can be sequenced by any method known in the art for determining expression of one or more markers. Methods of preparing cDNA are known in the art. Single cells may be sequenced for detection of at least one of the one or more markers. Single cells of the present invention may be divided into single droplets using a microfluidic device. The single cells in such droplets may be further labeled with a barcode.
- Markers for apoptosis, DNA damage, and cell cycle are known in the art.
- the one or more markers can comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof.
- proteins that can serve as markers for DNA damage and repair.
- Exemplary proteins mediating NHEJ include, but are not limited to, Ligase4, XRCC4, H2AX, DNAPKcs (DNA-PK), Ku70, Ku80, Artemis, Cemunnos/XLF, MRE11, NBS1, and RAD50.
- Exemplary homologous recombination proteins include RAD51, RAD52, RAD54, XRCC3, RAD51C, BRCA1, BRCA2 (FANCD1), FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ (BRIP1/BACH1), FANCL, FANCM, Chkl, Chk2, ATM, and ATR.
- Exemplary proteins mediating BER include, but are not limited to, UNG, SMUG1, MBD4, TDG, OFF1, MYH, NTH1, MPG, APE1, APE2, LIG3, XRCC1, ADPRT, ADPRTL2 AND ADPRTL3.
- Exemplary proteins mediating MER include, but are not limited to, MSH2, MSH3, MSH4, MSH5, MSH6, PMS1, PMS3, MLH1, MLH3, PMS213 and PMS214.
- Exemplary DNA repair helicases include BLM and WRN.
- Exemplary proteins mediating NER include, but are not limited to, XPA, XPB, XPC, XPD, XPF, XPG, XPV, RAD23B, USP7, RPA, CAK, ERCC1, RFC, LIG1, LIG3, CSA, CSB, PARP1, NEIL1, and APE1.
- Markers for apoptosis include caspases-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.
- the marker for apoptosis is cleaved-caspase3, and elevated levels of cleaved-caspase3 are indicative of increased apoptosis.
- a TUNEL assay can be used.
- the TUNEL assay is a method for detecting apoptotic DNA fragmentation, and is a fluorescence based assay that detects 3 ’-hydroxyl termini of DNA double stranded breaks.
- Mitochondrial damage can also serve as a measure for apoptosis.
- release of cytochrome c into the cytosol is associated with mitochondrial permeability.
- Annexin V assay can detect lipids associated with the inner leaflet of the plasma membrane, which are exposed during apoptosis.
- Cell cycle (e.g., proliferation) can be assessed, e.g., by DAPI or other DNA stain.
- Exemplary cell replication protein markers include, but are not limited to, phosphorylated histone H3 (pH3), Ki-67 protein, phosphorylated MPM-2 antigen, Proliferating Cell Nuclear Antigen (PCNA, a protein that is expressed in the nuclei of cells during the DNA synthesis phase of the cell cycle), phospho-S780-Rb epitope, Cenp-F (mitosin), class III -Tubulin, spindle checkpoint protein hMad2, phosphorylated myosin light chain kinase, topoisomerase II, Check point kinase 1 (Chkl), Vesicular Monoamine Transporter 2 (VMAT2), loss of cyclin-dependent kinase 1 (Cdkl) kinase activity.
- Histone H3 can be phosphorylated at Ser28 or SerlO.
- the expression of at least one of the one or more markers in the subject can be increased by, by about, by at least, or by at least about 1.25 fold (e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10-fold or a number or a range between any two of these values, or more) after being administered with both the onvansertib and the PARP inhibitor relative to the expression in the subject before being administered with both the onvansertib and the PARP inhibitor.
- 1.25 fold e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10-fold or a number or a range between any two of these values, or more
- the expression of at least one of the one or more markers in the subject can be increased by, by about, by at least, or by at least about 1.25 fold (e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10-fold or a number or a range between any two of these values, or more) after being administered with both the onvansertib and the PARP inhibitor relative to the expression in a subject being administered with onvansertib alone and/or the expression in a subject being administered with the PARP inhibitor alone.
- 1.25 fold e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10-fold or a number or a range between any two
- ctDNA can be analyzed to predict/determine clinical outcome for cancer treatment using a combination of a PARP inhibitor and onvansertib, monitor the combination treatment, predict/determine responsiveness of a subject to the combination treatment, determine cancer status in a subject, improve combination treatment outcome, guide combination treatment, provide combination treatment recommendations, and/or to reduce or avoid ineffective combination treatment.
- ctDNA can be analyzed to predict/determine clinical outcome for cancer treatment, monitor cancer treatment, predict/determine responsiveness of a subject to a cancer treatment, determine cancer status in a subject, improve cancer treatment outcome, guide cancer treatment, provide treatment recommendations, and/or to reduce or avoid ineffective cancer treatment.
- Such analysis of ctDNA has been described in PCT Application published as WO2021146322, the content of which is incorporated herein by reference in its entirety.
- a method of determining responsiveness of a subject to a combination treatment comprising a PARP inhibitor and onvansertib can comprise, for example, analyzing circulating tumor DNA (ctDNA) of a subject with cancer, the subject is undergoing a treatment and/or has received the combination treatment, thereby determining the responsiveness of the subject to the combination treatment.
- 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 CR, or if the subject is or is going to be in partial remission (PR).
- analyzing ctDNA can comprise detecting variant allele frequency in the ctDNA in a first sample obtained from the subject at a first time point, detecting variant allele frequency in the ctDNA obtained from the subject at one or more additional time points in one or more additional samples, and determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, a decrease in the variant allele frequency in at least one of the additional samples relative to the first sample indicates the subject as responsive to the cancer treatment.
- the first time point is prior or immediately prior to the combination treatment, and at least one of the one or more additional time points are at the end of or after at least a cycle of the combination treatment.
- the cycle of the combination treatment is the first cycle of the combination treatment.
- the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment.
- the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
- the method comprises continuing the combination treatment to the subject if the subject is indicated as responsive to the combination treatment.
- the method comprises discontinuing the combination treatment to the subject and/or starting a different combination treatment to the subject if the subject is not indicated as responsive to the combination treatment.
- the method comprises analyzing circulating tumor DNA (ctDNA) of a subject, thereby determining cancer status of the subject.
- the subject can be a subject undergoing a current combination treatment comprising a PARP inhibitor and onvansertib, a subject that has received a prior combination treatment of the present disclosure, and/or a subject that is in remission for the cancer.
- the subject in remission for cancer can be in complete remission (CR), or in partial remission (PR).
- analyzing the ctDNA comprises detecting variant allele frequency in the ctDNA. In some embodiments, analyzing the ctDNA comprises detecting variant allele frequency in the ctDNA obtained from the subject at a first time point in a first sample, detecting variant allele frequency in the ctDNA obtained from the subject at one or more additional time points in one or more additional samples, and determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, an increase in the variant allele frequency at the additional sample(s) relative to the first sample indicates that the subject is at risk of cancer relapse or is in cancer relapse.
- the first time point is prior or immediately prior to the combination treatment, and the one or more additional time points are at the end of or after at least a cycle of the combination treatment, optionally the cycle of the combination treatment is the first cycle of the combination treatment.
- the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment, optionally the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
- the method comprises starting an additional treatment to the subject if the subject is indicated as in cancer relapse.
- the additional treatment can be the same or different from the current or prior combination treatment.
- the variant allele frequency in ctDNA can be determined, for example, by total mutation count in the ctDNA in each of the first sample and one or more additional samples, or by the mean variant allele frequency in each of the first sample and one or more additional samples.
- the variant allele frequency is mutant allelic frequency (MAF) for a driver mutation of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof).
- the variant allele frequency is MAF for one or more driver mutations of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof).
- Log2(Ci/Co) ⁇ a MAF threshold indicates a decrease in ctDNA MAF Co is ctDNA MAF in the first sample and Ci is ctDNA MAF in one of the additional samples.
- the MAF threshold is, or is about, 0.01 to -0.10. In some embodiments, the MAF threshold is, or is about, 0.06. In some embodiments, the MAF threshold is, or is about, 0.05.
- the first sample comprises ctDNA from the subject before treatment
- the one of additional samples comprises ctDNA from the subject after treatment.
- the driver mutation is a mutation in one of the below 75 genes: ABL1, ANKRD26, ASXL1, ATRX, BCOR, BCORL1, BRAF, BTK, CALR, CBL, CBLB, CBLC, CCND2, CDC25C, CDKN2A, CEBPA, CSF3R, CUX1, CXCR4, DCK, DDX41, DHX15, DNMT3A, ETNK1, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, IAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, LUC7L2, MAP2K1, MPL, MYC, MYD88, NF1, NOTCH1, NPM1, NRAS,
- the driver mutation or at least one of the one or more driver mutations can be in a gene selected from the group consisting of TP53, ASXL1, DNMT3A, NRAS, SRSF2, TET2, SF3B1, FLT3, FLT3 ITD, IDH2, NPM1, RUNX1, CDKN2A, KRAS, STAG2, CALR, CBL, CSF3R, DDX41, GATA2, JAK2, PHF6, and SETBP1.
- the driver mutation or at least one of the one or more driver mutations is in a gene selected from the group consisting of DNMT3A, TET2, NPM1, SRSF2, NRAS, CDKN2A, SF3B1, FLT3, ASXL1, SRSF2, IDH2, NRAS, and SF3B1.
- the method further comprises determining variant allele frequency in one or more of the ctDNA, PBMCs and BMMCs of the subject.
- the ctDNA can be analyzed using, for example, polymerase chain reaction (PCR), next generation sequencing (NGS), and/or droplet digital PCR (ddPCR).
- PCR polymerase chain reaction
- NGS next generation sequencing
- ddPCR droplet digital PCR
- the sample disclosed herein can be derived from, for example, whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
- the ctDNA is from whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
- the method comprises analyzing ctDNA of the subject before the treatment.
- the treatment comprises one or more cycles, and the ctDNA is analyzed before, during and after each cycle of the treatment.
- Each cycle of treatment can be at least 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days. In some embodiments, the subject is human.
- the method can comprise: detecting variant allele frequency in circulating tumor DNA (ctDNA) obtained from a subject at a first time point in a first sample before the subject undergoes a combination treatment comprising a PARP inhibitor and onvansertib; detecting variant allele frequency in ctDNA obtained from the subject at one or more additional time points in one or more additional samples after the subject undergoes the combination treatment; determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, a decrease in the variant allele frequency in at least one of the additional samples relative to the first sample indicates the subject as responsive to the combination treatment; and continuing the combination treatment to the subject if the subject is indicated as responsive to the combination treatment, or discontinuing the combination treatment to the subject and/or starting a different cancer treatment to the subject if the subject is not indicated as responsive to the combination treatment.
- ctDNA circulating tumor DNA
- Also disclosed herein include methods of treating cancer
- the method can comprise: administering a combination treatment comprising a PARP inhibitor and a PLK1 inhibitor of the present disclosure to a subject in need thereof; determining a decrease, relative to a variant allele frequency in a first sample of the subject obtained at a first time point before the subject receives the combination treatment, in a variant allele frequency in a second sample of the subject obtained at a second time point after the subject receives the combination treatment; and continuing with the combination treatment.
- the subject is a subject newly diagnosed with cancer, for example a subject that has not received any prior cancer treatment before the combination treatment.
- the subject has received prior cancer treatment and was in remission for the cancer, for example a subject in complete remission (CR), or in partial remission (PR) after receiving the prior combination treatment.
- the first time point can be, for example, prior or immediately prior to the combination treatment.
- the at least one of the one or more additional time points can be, for example, at the end of or after at least a cycle of the combination treatment.
- the cycle of the combination treatment is the first cycle of the combination treatment.
- the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment.
- the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
- the variant allele frequency in ctDNA can be determined, for example, by total mutation count in the ctDNA in each of the first sample and one or more additional samples, and/or by the mean variant allele frequency in each of the first sample and one or more additional samples.
- the variant allele frequency is mutant allelic frequency (MAF) for a driver mutation of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, or a combination thereof).
- the variant allele frequency is mutant allelic frequency (MAF) for one or more driver mutations of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, or a combination thereof).
- Log2(Ci/Co) ⁇ a MAF threshold indicates a decrease in ctDNA MAF Co is ctDNA MAF in the first sample and Ci is ctDNA MAF in one of the additional samples.
- the MAF threshold is -0.05.
- At least one of the one or more the driver mutations is a mutation in one of the below 75 genes: ABL1, ANKRD26, ASXL1, ATRX, BCOR, BCORL1, BRAF, BTK, CALR, CBL, CBLB, CBLC, CCND2, CDC25C, CDKN2A, CEBPA, CSF3R, CUX1, CXCR4, DCK, DDX41, DHX15, DNMT3A, ETNK1, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, LUC7L2, MAP2K1, MPL, MYC, MYD88, NF1, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PPM1D, PTEN, PTPN11, RAD21, RBBP6, RPS14,
- the driver mutation or at least one of the one or more driver mutations is in a gene selected from the group consisting of TP53, ASXL1, DNMT3A, NRAS, SRSF2, TET2, SF3B1, FLT3, FLT3 ITD, IDH2, NPM1, RUNX1, CDKN2A, KRAS, STAG2, CALR, CBL, CSF3R, DDX41, GATA2, IAK2, PHF6, and SETBP1.
- the driver mutation or at least one of the one or more driver mutations is in a gene selected from the group consisting of DNMT3A, TET2, NPM1, SRSF2, NRAS, CDKN2A, SF3B1, FLT3, ASXL1, SRSF2, IDH2, NRAS, and SF3B1.
- the method further comprises determining variant allele frequency in one or more of the ctDNA, PBMCs and BMMCs of the subject.
- the variant allele frequency in ctDNA can be detected, for example, using polymerase chain reaction (PCR) or next generation sequencing (NGS).
- PCR polymerase chain reaction
- NGS next generation sequencing
- the variant allele frequency in ctDNA is detected using droplet digital PCR (ddPCR).
- At least one of the first sample, the one or more additional samples, and the second sample can be derived from whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
- the ctDNA is from whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
- the subject whose sample (e.g., tumor biopsy, ctDNA) is analyzed is undergoing or will be undergoing treatment for the cancer.
- the method can comprise analyzing the sample of the subject before the treatment.
- the treatment can comprise one or more cycles, and the sample is analyzed before, during and after one or more cycles of the treatment.
- the sample can be analyzed before, during and after two or more cycle of the treatment, three or more cycle of the treatment, or each cycle of the treatment.
- Each cycle of treatment can be at least 21 days, for example, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or more, or a range between any two of these values.
- each cycle of treatment is from about 21 days to about 28 days.
- each cycle of treatment is from 21 days to 28 days.
- the subject is human.
- kits for treating cancer comprises: a Polo-like kinase 1 (PLK1) inhibitor (e.g., onvansertib); and a manual providing instructions for co-administrating onvansertib with a PARP inhibitor to a subject for treating cancer.
- the kit comprises the PARP inhibitor (e.g., olaparib, niraparib, and/or AZD5305).
- the cancer can be, for example, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
- the cancer can be a homologous recombination (HR)-deficient cancer.
- the cancer can be a BRCAl-homozygous mutant cancer, a BRCA2 -homozygous mutant cancer, a BRCA1 -heterozygous mutant cancer, a BRCA2 -heterozygous mutant cancer or any combination thereof.
- the cancer can be homozygous wild type for BRCA1, BRCA2, or both.
- the instructions comprise instructions for coadministrating onvansertib and the PARP inhibitor simultaneously. In some embodiments, the instructions comprise instructions for co-administrating onvansertib and the PARP inhibitor sequentially. In some embodiments, the instructions comprise instructions for administering of onvansertib orally. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor orally.
- the instructions comprise instructions the subject has received a prior PARP inhibitor treatment. In some embodiments, the instructions comprise instructions the subject did not respond to treatment with the PARP inhibitor alone. In some embodiments, the instructions comprise instructions the subject is known to be resistant to a PARP inhibitor therapy.
- the instructions comprise instructions the subject has received at least one prior treatment for the cancer.
- the prior treatment does not comprise the use of a PARP inhibitor, a PLK inhibitor, or both.
- the instructions comprise instructions the subject was in remission for the cancer.
- the subject in remission for cancer was in complete remission (CR), or in partial remission (PR).
- the instructions comprise instructions for administering each of the PARP inhibitor and onvansertib to the subject in a cycle of at least twice within a week. In some embodiments, the instructions comprise instructions for administering each of the PARP inhibitor and onvansertib to the subject in a cycle of at least five times within a week In some embodiments, the instructions comprise instructions for administering the PARP inhibitor, onvansertib, or both are in a cycle of at least 7 days. In some embodiments, each cycle of treatment is at least about 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days, for example 28 days.
- the instructions can comprise instructions for administering onvansertib on at least four days, at least 14 days, or at least 21 days in the cycle. In some embodiments, the instructions comprise instructions for administering onvansertib on at least four days in the cycle. The instructions can comprise instructions for not administering onvansertib on at least one day, at least 7 days, at least 14 days, or at least 21 days in the cycle. In some embodiments, the instructions comprise instructions for not administering onvansertib on at least one day in the cycle. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor daily. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor and onvansertib for at least two cycles.
- the PARP inhibitor is selective and/or specific for PARP inhibition (e.g., PARP1 inhibitor, PARP2 inhibition, or both).
- the PARP inhibitor is iniparib (BSI 201), talazoparib (BMN-673), AZD5305, olaparib (AZD-2281), rucaparib (AG014699, PF-01367338), ABT-888, veliparib (ABT-888), niraparib, CEP 9722, MK 4827, BGB-290 (pamiparib), BSI-201, CEP-8983, E7016, 3-aminobenzamide, or a combination thereof.
- the PARP inhibitor is olaparib. In some embodiments, the PARP inhibitor is or NMS-293. In some embodiments, the PARP inhibitor is selected from olaparib, niraparib, and AZD5305.
- the kit can comprise the PARP inhibitor.
- the instructions comprise instructions for administering onvansertib at 6 mg/m 2 - 90 mg/m 2 . In some embodiments, the instructions comprise instructions for administering the PARP inhibitor at 20 mg - 1200 mg. [0169]
- the methods, compositions and kits disclosed herein can also be used to sensitize cancer cells to one or more PARP inhibitors.
- the method can comprise contacting cancer cells with a composition comprising a PLK1 inhibitor (e.g., onvansertib), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, thereby sensitizing the cancer cells to the one or more PARP inhibitors (e.g., olaparib, niraparib, or AZD5305).
- a PLK1 inhibitor e.g., onvansertib
- a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof thereby sensitizing the cancer cells to the one or more PARP inhibitors (e.g., olaparib, niraparib, or AZD5305).
- Contacting cancer cells with the composition can occur in vitro, ex vivo, in vivo, or in any combination.
- contacting cancer cells with the composition is in a subject’s body.
- cancer cells are contacted with the composition in a cell culture.
- the sensitization of the cancer cells can increase the responsiveness of the cancer cells to the one or more PARP inhibitors by, or by about, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or a range between any two of these values.
- the sensitization of the cancer cells can increase the responsiveness of the cancer cells to the one or more PARP inhibitors by at least, or by at least about, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or a range between any two of these values.
- the increase of the responsiveness of the cancer cells is, in some embodiments, relative to the untreated cancer cells.
- the sensitization of the cancer cells can increase the responsiveness of the subject having the cancer cells to one or more PARP inhibitors by, or by about, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or a range between any two of these values.
- the sensitization of the cancer cells can increase the responsiveness of the subject having the cancer cells to the one or more PARP inhibitors by at least, or by at least about, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or a range between any two of these values.
- the increase of the responsiveness of the subject having the cancer cells is, in some embodiments, relative to the subjects untreated with the composition.
- the method can comprise determining sensitization of the cancer cells to the one or more PARP inhibitors after being contacted with the PLK1 inhibitor (e.g., onvansertib).
- the method can comprise contacting the cancer cells with the one or more PARP inhibitors concurrently and/or after being contacted with onvansertib.
- contacting the cancer cells with the one or more PARP inhibitors occurs in the body of a subject.
- the subject can be a mammal, for example human.
- the subject can be, for example, a subject that did not respond to, or is known to be resistant to, PARP inhibitors alone.
- the subject can be, for example, a subject that had prior treatment with one of the one or more PARP inhibitors.
- the method comprises determining the response of the subject to the one or more PARP inhibitors.
- onvansertib and the PARP inhibitor produce an in vitro synergistic effect.
- Synergy may be measured by various methods, including, for example, the Bliss synergy method.
- the Bliss value can be defined as the difference between the experimental response and the calculated Bliss Independence value.
- the Bliss value indicates whether the effect of two compounds in combination is merely additive or is synergistic.
- a Bliss value of zero is considered additive, wherein the term “additive” means that the result of the combination of the two compounds is the sum of each compound individually, and the compounds are not considered synergistic.
- a negative Bliss value indicates antagonism, wherein one of the compounds acts to inhibit the effect of the other.
- a positive Bliss value indicates synergy, wherein the combined effect of the two compounds is greater than their sum. The higher the positive Bliss value, the greater the synergy of the two compounds.
- the in vitro synergistic effect has a synergy score of, of about, of at least, or of at least about 10 to 80 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
- the in vitro synergistic effect has a synergy score of, of about, of at least, or of at least about 1 to about 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 or a number or a range between any two of these values).
- the in vitro synergistic effect has a synergy score of, of about, of at least, or of at least about 10 to 80 in two or more cancer cell lines (e.g., OVCAR3 cell line, DU4475 cell line, PSN1 cell line).
- cancer cell lines e.g., OVCAR3 cell line, DU4475 cell line, PSN1 cell line.
- Synergy scores can be assessed over a wide range of concentrations (e.g., over a dilution or concentration series).
- the each of the concentrations of onvansertib used for assessment of synergy can be any value from about 1 nM to about 2000 nM (e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
- each of the concentrations of the PARP inhibitor used for assessment of synergy can be any value from about 0.25 nM to about 10000 nM (e.g., about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
- the cancer cells can be provided from any subject (e.g., a mammal).
- the cancer cells comprise a sample from a patient (e.g., a biopsy sample).
- the method can comprise: determining sensitization of the cancer cells to the PARP inhibitor after being contacted with the composition.
- Determining sensitization of the cancer cells to the PARP inhibitor can comprise measuring the proportion of cancer cells expressing one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof after the cancer cells are contacted with the composition and/or the PARP inhibitor.
- Markers for apoptosis, DNA damage, and cell cycle are known in the art.
- the one or more markers can comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof.
- the proportion of cells expressing the one or more markers can be measured by any method known in the art.
- the one or more markers are detected by immunofluorescence, mass cytometry (CyTOF), FACS, drop-seq, RNA-seq, single cell qPCR, MERFISH (multiplex (in situ) RNA FISH), microarray and/or by in situ hybridization. Other methods including absorbance assays and colorimetric assays are known in the art and may be used herein.
- measuring proportion of cells expressing the one or more markers comprises measuring protein expression levels. Protein expression levels may be measured, for example, by performing a Western blot, an ELISA, immunohistochemistry or binding to an antibody array.
- measuring expression of the one or more markers comprises measuring RNA expression levels. RNA expression levels may be measured by performing RT- PCR, Northern blot, an array hybridization, or RNA sequencing methods.
- proteins that can serve as markers for DNA damage and repair include, but are not limited to, Ligase4, XRCC4, H2AX, DNAPKcs (DNA-PK), Ku70, Ku80, Artemis, Cernunnos/XLF, MRE11, NBS1, and RAD50.
- Exemplary homologous recombination proteins include RAD51, RAD52, RAD54, XRCC3, RAD51C, BRCA1, BRCA2 (FANCD1), FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ (BRIP1/BACH1), FANCL, FANCM, Chkl, Chk2, ATM, and ATR.
- Exemplary proteins mediating BER include, but are not limited to, UNG, SMUG1, MBD4, TDG, OFF1, MYH, NTH1, MPG, APE1, APE2, LIG3, XRCC1, ADPRT, ADPRTL2 and ADPRTL3.
- Exemplary proteins mediating MER include, but are not limited to, MSH2, MSH3, MSH4, MSH5, MSH6, PMS1, PMS3, MLH1, MLH3, PMS213 and PMS214.
- Exemplary DNA repair helicases include BLM and WRN.
- Exemplary proteins mediating NER include, but are not limited to, XPA, XPB, XPC, XPD, XPF, XPG, XPV, RAD23B, USP7, RPA, CAK, ERCC1, RFC, LIG1, LIG3, CSA, CSB, PARP1, NEIL1, and APE1.
- Markers for apoptosis include caspases-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.
- the marker for apoptosis is cleaved-caspase3, and elevated levels of cleaved-caspase3 are indicative of increased apoptosis.
- a TUNEL assay can be used.
- the TUNEL assay is a method for detecting apoptotic DNA fragmentation, and is a fluorescence based assay that detects 3 ’-hydroxyl termini of DNA double stranded breaks.
- Mitochondrial damage can also serve as a measure for apoptosis.
- release of cytochrome c into the cytosol is associated with mitochondrial permeability.
- Annexin V assay can detect lipids associated with the inner leaflet of the plasma membrane, which is exposed during apoptosis.
- Cell cycle (e.g., proliferation) can be assessed, e.g., by DAPI or other DNA stain.
- Exemplary cell replication protein markers include, but are not limited to, phosphorylated histone H3 (pH3), Ki-67 protein, phosphorylated MPM-2 antigen, Proliferating Cell Nuclear Antigen (PCNA, a protein that is expressed in the nuclei of cells during the DNA synthesis phase of the cell cycle), phospho-S780-Rb epitope, Cenp-F (mitosin), class III [1-Tubulin, spindle checkpoint protein hMad2, phosphorylated myosin light chain kinase, topoisomerase II, Check point kinase 1 (Chkl), Vesicular Monoamine Transporter 2 (VMAT2), loss of cyclin-dependent kinase 1 (Cdkl) kinase activity.
- Histone H3 can be phosphorylated at Ser28 or SerlO.
- the proportion of cancer cells expressing at least one of the one or more markers can be increased by, by about, by at least, or by at least about 1.25 fold (e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10- fold or a number or a range between any two of these values, or more) after being contacted with the composition relative to cancer cells not contacted with the composition.
- 1.25 fold e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10- fold or a number or a range between any two of these values, or more
- the proportion of cancer cells expressing at least one of the one or more markers can be increased by, by about, by at least, or by at least about 1.25 fold (e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10-fold or a number or a range between any two of these values, or more) after being contacted with the composition and the PARP inhibitor relative to cancer cells contacted with the composition alone or the PARP inhibitor alone.
- an increase in the proportion of cancer cells expressing at least one of the one or more markers indicates sensitization of the cancer cells to the PARP inhibitor.
- onvansertib in combination with olaparib was tested in 2 intraperitoneal BRCAl-mutant high grade serous ovarian cancer (HGSOC) patient derived xenograft (PDX) models resistant to olaparib (MNH022 and MNHOC266). Treatment was tolerated, with no body weight loss exceeding 20%.
- the combination of onvansertib and olaparib was highly effective, inducing significant increase in survival in comparison to vehicle and single agent treatments in the 2 models (FIG. 4A-FIG. 4B).
- tumor cells (#MNHOC22 and #MNHOC266) were intraperitoneally transplanted and mice were treated for 4 weeks with vehicle, onvansertib (50mg/kg, 5d/week), olaparib (80 mg/kg for MNHOC266 and lOOmg/kg for MNHOC22, 5days/week), or the combination of onvansertib + olaparib.
- onvansertib 50mg/kg, 5d/week
- olaparib 80 mg/kg for MNHOC266 and lOOmg/kg for MNHOC22, 5days/week
- onvansertib in combination with olaparib was tested in an intraperitoneal BRCAl-wild type (wt) HGSOC PDX model resistant to olaparib and cisplatin (MNHO316DDP).
- the treatment was well tolerated, as indicated in FIG. 6A.
- FIG. 6B the combination of onvansertib and olaparib was effective, inducing significant increase in survival in comparison to cisplatin and single agent treatments.
- Tumor cells #MNHOC316DDP were intraperitoneally transplanted and mice were treated for 4 weeks with cisplatin (5mg/kg, weekly for 3 weeks), onvansertib (50mg/kg, 5d/week), olaparib (100 mg/kg, 5days/week), or the combination of onvansertib + olaparib.
- MNHOC124 and MNHOC239 tumor fragments were subcutaneously transplanted and mice were treated for 4 weeks with vehicle, onvansertib (50mg/kg for #124 and 40mg/kg for #239, 5d/week), olaparib (100 mg/kg for #124 and 80mg/kg for #239, 5days/week), or the combination of onvansertib + olaparib.
- onvansertib in combination with olaparib was tested in 2 BRCA2-mutated (mono-allelic loss) prostate cancer models: CWR22-RH (androgen receptor positive, AR+) and LgCAP-CR (androgen receptor negative and neuroendocrine marks negative, AR-NE-).
- CWR22-RH androgen receptor positive, AR+
- LgCAP-CR androgen receptor negative and neuroendocrine marks negative, AR-NE-
- FIG. 10A-FIG. 10B onvansertib but not olaparib induced significant tumor growth inhibition in the 2 models, and, in this model, the combination of onvansertib and olaparib showed similar activity as onvansertib single agent. Tumor fragments were subcutaneously transplanted in castrated NGS male mice.
- mice were treated for 3 to 4 weeks with vehicle, onvansertib (50mg/kg, 5d/week), olaparib (75mg/kg, 5days/week), or the combination of onvansertib + olaparib.
- One-way ANOVA and Dunnett’s multiple comparison test were used to compare mean tumor volumes on Day 27 (CW22-RH) or Day 21 (LgCAP-CR), *p ⁇ 0.05, *** p ⁇ 0.001.
- FIG. 10C tumor growth data from LuCaP86.2 (BRCA2-mutated (bi-allelic loss) CRPC model). The combination, but not the single agent, induced a significant tumor growth inhibition (83% at Day 24).
- FIG. 10D is data related to the BCAP-CR (BRCA-WT CRPC model).
- onvansertib and combination treatments induced significant tumor growth inhibition (TGI) compared to vehicle (62% and 80% respectively).
- TGI tumor growth inhibition
- Tumor fragments were subcutaneously transplanted in castrated NSG (immunodeficient) male mice.
- mice were treated for with vehicle, onvansertib (50mg/kg, 5d/week) or olaparib (75mg/kg, 5days/week), or the combination of onvansertib + olaparib.
- LuCAP86.2 combination group was treated for 3 weeks, the other groups for 5 weeks.
- vehicle group was treated for 2 weeks, the other groups for 4 weeks.
- Kruskal-Wallis multiple comparison test were used to compare mean tumor volumes on Day 28 (LuCaP86.2) or Day 15 (BCaP-CR), *p ⁇ 0.05; ** p ⁇ 0.01; ****p ⁇ 0.0001.
- FIG. 11 shows results from a screen in which the combination of onvansertib + olaparib was tested in a panel of 63 cell lines.
- the triple-negative breast cancer (TNBC) cell lines DU-4475 and HMC- 1-8 both BRCAwt) showed high synergy score.
- TNBC triple-negative breast cancer
- FIG. 12A- FIG. 12C the synergy was tested and confirmed in the DU4475 cell line and onvansertib synergizes with several PARP inhibitors in the DU4475 cell line.
- y-H2AX is a marker of double strand DNA breaks (DSBs). The levels of this marker were measured in DU4475 cells following treatment as shown in FIG. 14A-FIG. 14C.
- the combination of onvansertib and olaparib induced a time-dependent increase in y-H2AX+ cells (WB and FACS).
- the increase in y-H2AX+ cells in the combination group was observed primarily in the G1 and S populations.
- DU4475 were treated with DMSO, onvansertib 50nM, olaparib 800nM or the combination during the indicated times.
- CHK1 and CHK2 are proteins that are involved in the DNA damage response, and are phosphorylated in response to DNA damage.
- An increase in pCHKl and pCHK2 at 48h was observed in the combination group vs olaparib alone as assessed by western blot (FIG. 15).
- pancreatic cancer cell lines KP-4 and PSN1 both BRACwt
- Onvansertib synergizes with several PARP inhibitors in the PSN 1 cell line (FIG. 18A-FIG. 18C).
- PDAC pancreatic ductal adenocarcinoma
- ovarian cancer PDX models PDX#154 Intrinsic resistance to olaparib
- CTG-0253 BRCA2-mut, olaparib-resistant, platinum-resistant model
- the combination on patient-derived lines, in vivo on xenografts are tested.
- In vivo anti-tumor activity of onvansertib + olaparib are tested in syngeneic orthotopic models of PDAC: KPC (KRASm, p53m) BRCA WT and BRCA KO cell lines KMC (KRASm, MYC overexpressing) cell lines.
- Additional models include TNBC BRCA2m Olaparib-resistant PDX model.
Abstract
Disclosed herein include methods, compositions, and kits suitable for use in treating cancer in a subject. In some embodiments, the method comprises administration of onvansertib and a PART inhibitor (e.g., olaparib, niraparib, and AZD53O5) to the subject in a manner sufficient to inhibit progression of the cancer.
Description
ONVANSERTIB AND PARP INHIBITOR COMBINATION
RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63/404,895, filed September 8, 2022, the content of which is herein expressly incorporated by reference in its entirety.
BACKGROUND
Field
[0002] The present application generally relates to treatment for cancer. More specifically, combination therapies for treating cancer using PARP inhibitors in combination with the polo-like kinase 1 (PLK1) inhibitor onvansertib are provided.
Description of the Related Art
[0003] Poly (ADP-ribose) polymerase (PARP) proteins mediate post-translational PARylation (covalent addition of poly (ADP-ribose) chains) to substrate proteins. PARP1 is important for the repair of single- stranded DNA breaks (SSBs) through base excision repair. It is recruited at SSBs, and catalyzes the formation of PAR chains on itself and other proteins such as histones. PARP1 activity opens chromatin and facilitates recruitment of downstream DNA repair factors. PARP inhibitors (PARPi) can block PARP1 enzymatic activity and trap PARP1 protein to the damaged DNA. Therefore, SSB repair is inhibited resulting in stalled replication forks and double-stranded breaks (DSBs). Cells require functional homologous recombination (HR) to resume cell-cycle progression, therefore HR-deficient cells will eventually die. Non-limiting examples of PARPi include: Talazoparib, Niraparib, Olaparib, Rucaparib and Veliparib. They all block PARP enzymatic activity but differ in their PARP-trapping capacity.
[0004] PARP inhibitors in a BRCA1/2 loss of function cell can result in synthetic lethality. Breast Cancer 1 and 2 proteins (BRCA1/2) are essential factors of HR and can be inactivated by mutation or promoter hypermethylation. BRCA1/2 deficiency induces increased sensitivity to PARP inhibitors due to inhibition of HR. Upon DNA damage by agents such as Topoisomerase I inhibitors, PARP inhibitors, or radiation, PLK1 is recruited at DSBs, where it promotes DNA repair by homologous recombination.
[0005] PLKl-mediated RAD51 phosphorylation stimulates phosphorylation of RAD51 by the DNA-damage response regulators checkpoint kinase 1 (CHK1) and casein kinase 2 (CK2). This results in recruitment of RAD51 to the site of DNA damage and DNA repair by HR. PLK1 also phosphorylates BRCA1 and promotes its recruitment at DSBs and DNA repair. Upon Topoisomerase I inhibitor-induced DNA damage, ataxia telangiectasia mutated protein
(ATM) and PLK1 counteract the non-homologous end joining (NHEJ) by suppressing RNF168- dependent H2A ubiquitination and BRCA1-A recruitment and thereby promoting replication fork breakage repair by HR. PLK1 inhibition sensitizes tumor cells to DNA damage through inhibition of DNA repair by homologous recombination.
[0006] Some PARP inhibitors have been approved for treating certain cancer types, but patients can be resistant or develop resistance to PARP inhibitor treatment. There is a need to find effective treatment for cancer patients, including the patients resistant to PARP inhibitor treatment.
SUMMARY
[0007] Disclosed herein include methods for treating cancer. In some embodiments, the method comprises: administrating onvansertib and a PARP inhibitor selected from olaparib, niraparib, and AZD5305 to a subject with cancer, thereby inhibiting progression of the cancer, wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
[0008] In some embodiments, the cancer is a homologous recombination-deficient cancer. In some embodiments, the cancer is a B RCA 1 -homozygous mutant cancer, a BRCA2- homozygous mutant cancer, a BRC Al -heterozygous mutant cancer, a BRCA2-heterozygous mutant cancer, or any combination thereof. In some embodiments, the cancer is homozygous wild type for BRCA1, BRCA2, or both.
[0009] In some embodiments, the inhibition of cancer progression is greater than the combined inhibition of progression caused by the PARP inhibitor alone plus onvansertib alone. In some embodiments, inhibiting progression of the cancer comprises inhibition of growth of one or more tumors in the subject. In some embodiments, the inhibition of growth of at least one of the one or more tumors in the subject is about 1.1 times greater, about 1.2 times greater, about 1.3 times greater, about 1.4 times greater, about 1.5 times greater, about 1.6 times greater, about 1.7 times greater, about 1.8 times greater, about 1.9 times greater, about 2 times greater, or more, than the inhibition of growth caused by onvansertib alone or the PARP inhibitor alone, following one or more cycles of treatment. In some embodiments, the inhibition of growth of at least one of the one or more tumors in the subject is increased by about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% relative to a subject treated with onvansertib alone or the PARP inhibitor alone, following one or more cycles of treatment. In some embodiments, the growth of at least one of the one or more tumors in the subject is inhibited by about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% relative to an untreated subject, following one or more cycles of treatment. In some embodiments, the subject is tumor-
free following one or more cycles of treatment.
[0010] In some embodiments, onvansertib and the PARP inhibitor are co- administered simultaneously. In some embodiments, onvansertib and the PARP inhibitor are administered sequentially. In some embodiments, onvansertib is administered prior to the administration of the PARP inhibitor. In some embodiments, onvansertib is administered prior to the administration of the PARP inhibitor every day on which the subject is administered with onvansertib and the PARP inhibitor. In some embodiments, onvansertib is administered about 30 minutes to about 5 hours prior to the administration of the PARP inhibitor on a given day.
[0011] In some embodiments, the administration of onvansertib is oral administration, the administration of the PARP inhibitor is oral administration, or both. In some embodiments, the subject achieves a complete response. In some embodiments, the subject has received a prior PARP inhibitor treatment. In some embodiments, the subject did not respond to treatment with the PARP inhibitor alone. In some embodiments, the subject is known to be resistant to a PARP inhibitor therapy.
[0012] In some embodiments, onvansertib and the PARP inhibitor are each administered to the subject in a cycle of at least twice or at least five times within a week. In some embodiments, onvansertib, the PARP inhibitor, or both are administered in a cycle of at least 7 days. In some embodiments, each cycle of treatment is at least about 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days. In some embodiments, onvansertib is administered on at least four days, at least 14 days, or at least 21 days in the cycle. In some embodiments, onvansertib is not administered on at least one day, at least 7 days, at least 14 days, or at least 21 days in the cycle. In some embodiments, the PARP inhibitor is administered daily. In some embodiments, the subject undergoes at least two cycles of the administration of onvansertib and the PARP inhibitor.
[0013] In some embodiments, the PARP inhibitor is selective and/or specific for PARP inhibition. In some embodiments, onvansertib is administered at 6 mg/m2 - 90 mg/m2. In some embodiments, a maximum concentration (Cmax) of onvansertib in a blood of the subject is from about 100 nmol/L to about 1500 nmol/L. In some embodiments, an area under curve (AUC) of a plot of a concentration of onvansertib in a blood of the subject over time is from about 1000 nmol/L.hour to about 400000 nmol/L.hour. In some embodiments, a time (Tmax) to reach a maximum concentration of onvansertib in a blood of the subject is from about 1 hour to about 5 hours. In some embodiments, an elimination half-life (T1/2) of onvansertib in a blood of the subject is from about 10 hours to about 60 hours.
[0014] In some embodiments, the subject has received at least one prior cancer treatment. In some embodiments, the prior treatment does not comprise the use of a PARP
inhibitor, onvansertib, or both. In some embodiments, the subject was in remission for cancer. In some embodiments, the subject in remission for cancer was in complete remission (CR) or in partial remission (PR).
[0015] The method can comprise one or more of (1) determining cancer status of the subject, (2) determining responsiveness of the subject to onvansertib treatment, and (3) administering one or more cancer therapeutics or therapies for the cancer. In some embodiments, the subject is human. The method can comprise: measuring expression of one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof in the subject before and/or after the subject is administered with onvansertib and/or the PARP inhibitor. In some embodiments, the one or more markers comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof. In some embodiments, the expression of at least one of the one or more markers in the subject is increased by at least about 1.25 fold after being administered with both the onvansertib and the PARP inhibitor relative to the expression in the subject before being administered with both the onvansertib and the PARP inhibitor. In some embodiments, the expression of at least one of the one or more markers in the subject is increased by at least about 1.25 fold after being administered with both the onvansertib and the PARP inhibitor relative to the expression in a subject being administered with onvansertib alone and/or the expression in a subject being administered with the PARP inhibitor alone.
[0016] Disclosed herein include methods for sensitizing cancer cells to a PARP inhibitor. In some embodiments, the method comprises: contacting cancer cells with a composition comprising onvansertib, thereby sensitizing the cancer cells to the PARP inhibitor, wherein the PARP inhibitor is olaparib, niraparib, AZD53O5, or a combination thereof.
[0017] In some embodiments, onvansertib and the PARP inhibitor produce an in vitro synergistic effect. In some embodiments, the in vitro synergistic effect has a synergy score of about 10 to about 80. In some embodiments, contacting cancer cells with the composition occurs in vitro, ex vivo, and/or in vivo. In some embodiments, contacting cancer cells with the composition is in a subject. In some embodiments, the subject did not respond to, or is known to be resistant to, the PARP inhibitor. In some embodiments, the subject had prior treatment with the PARP inhibitor or a different PARP inhibitor. In some embodiments, the subject is a mammal. In some embodiments, the mammal is human.
[0018] The method can comprise: determining sensitization of the cancer cells to the PARP inhibitor after being contacted with the composition. In some embodiments, determining sensitization of the cancer cells to the PARP inhibitor comprises measuring the proportion of cancer cells expressing one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof after the cancer cells are contacted with the composition and/or the PARP
inhibitor. In some embodiments, the one or more markers comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof. In some embodiments, the proportion of cancer cells expressing at least one of the one or more markers is increased by at least about 1.25 fold after being contacted with the composition relative to cancer cells not contacted with the composition. In some embodiments, the proportion of cancer cells expressing at least one of the one or more markers is increased by at least about 1.25 fold after being contacted with the composition and the PARP inhibitor relative to cancer cells contacted with the composition alone or the PARP inhibitor alone.
[0019] The method can comprise: contacting the cancer cells with the PARP inhibitor. In some embodiments, contacting the cancer cells with the PARP inhibitor occurs in the subject. The method can comprise: determining the response of the subject to the PARP inhibitor. In some embodiments, contacting the cancer cells with the PARP inhibitor is concurrent with the contacting the cancer cells with the composition, or after the contacting the cancer cells with the composition.
[0020] Disclosed herein include kits. The kit can comprise: onvansertib: and a manual providing instructions for co-administrating onvansertib with a Poly-(ADP-ribose) polymerase (PARP) inhibitor to a subject for treating cancer, wherein the PARP inhibitor is olaparib, niraparib, or AZD5305, and wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
[0021] In some embodiments, the cancer is a homologous recombination (HR)- deficient cancer. In some embodiments, the cancer is a B RCA 1 -homozygous mutant cancer, a BRCA2-homozygous mutant cancer, a BRCA1 -heterozygous mutant cancer, a BRCA2- heterozygous mutant cancer or any combination thereof. In some embodiments, the cancer is homozygous wild type for BRCA1, BRCA2, or both.
[0022] In some embodiments, the instructions comprise instructions for coadministrating onvansertib and the PARP inhibitor simultaneously. In some embodiments, the instructions comprise instructions for co-administrating onvansertib and the PARP inhibitor sequentially. In some embodiments, the instructions comprise (1) instructions for administering of onvansertib orally, (2) instructions for administrating the PARP inhibitor orally, or both. In some embodiments, the instructions comprise instructions the subject has received a prior PARP inhibitor treatment. In some embodiments, the instructions comprise instructions the subject did not respond to treatment with the PARP inhibitor alone. In some embodiments, the instructions comprise instructions the subject is known to be resistant to a PARP inhibitor therapy. In some embodiments, the instructions comprise instructions for administering each of the PARP inhibitor and onvansertib to the subject in a cycle of at least twice or at least five times within a week. In
some embodiments, the instructions comprise instructions for administering the PARP inhibitor, onvansertib, or both in a cycle of at least 7 days. In some embodiments, each cycle of treatment is at least about 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days. In some embodiments, the instructions comprise instructions for administering onvansertib on at least four days, at least 14 days, or at least 21 days in the cycle. In some embodiments, the instructions comprise instructions for not administering onvansertib on at least one day, at least 7 days, at least 14 days, or at least 21 days in the cycle. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor daily. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor and onvansertib for at least two cycles.
[0023] In some embodiments, the PARP inhibitor is selective and/or specific for PARP1 and/or PARP2 inhibition. In some embodiments, the instructions comprise instructions for administering onvansertib at 6 mg/m2 - 90 mg/m2. In some embodiments, the instructions comprise instructions the subject has received at least one prior treatment for the cancer. In some embodiments, the prior treatment does not comprise the use of a PARP inhibitor, onvansertib, or both. In some embodiments, the instructions comprise instructions the subject was in remission for cancer. In some embodiments, the subject in remission for cancer was in complete remission (CR) or in partial remission (PR). The kit can comprise the PARP inhibitor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 depicts an illustration of the mechanisms of action of some PARP Inhibitors.
[0025] FIG. 2 depicts an non-limiting exemplary illustration of how PLK1 promotes DNA repair by homologous recombination.
[0026] FIG. 3 depicts an exemplary embodiment of how PLK1 inhibition can resensitize tumor cells to PARP inhibitors. PARP is essential for repair of single strand DNA breaks (SSBs). Failure to repair SSBs through PARP inhibition results in double strand DNA breaks (DSBs).
[0027] FIG. 4A-FIG. 4B display data related to Onvansertib + Olaparib efficacy in BRCAl-mutated and Olaparib-resistant HGSOC PDX models.
[0028] FIG. 5A-FIG. 5B depict data related to Onvansertib + Olaparib efficacy in BRCAl-mutated and Olaparib-resistant HGSOC PDX model PDX#218ola.
[0029] FIG. 6A-FIG. 6B display data related to body weight of animals and efficacy of Onvansertib + Olaparib in BRCAl-wildtype Olaparib-resistant HGSOC PDX models MNHOC316DDP.
[0030] FIG. 7 depicts data related to Onvansertib + Olaparib efficacy in BRCA1-
wildtype Olaparib-resistant HGSOC PDX model MNHOC124.
[0031] FIG. 8A-FIG. 8B depict data related to body weight of animals and efficacy of Onvansertib + Olaparib in BRCA1 -wildtype Olaparib-resistant HGSOC PDX model MNHOC239.
[0032] FIG. 9A-FIG. 9C depict synergy scores for Onvansertib and three different PARP inhibitors in the indicated Ovarian Cancer cell line, OVCAR3.
[0033] FIG. 10A-FIG. 10D display data related to Onvansertib + Olaparib efficacy in Prostate Cancer PDX models CWR22-RH, LgCaP-CR, LuCaP86.2, and BCAP.
[0034] FIG. 11 shows results from a synergy screen for the combination of Onvansertib and Olaparib in breast, ovarian, prostate and pancreatic cancer cell lines.
[0035] FIG. 12A-FIG. 12C depict synergy score data for Onvansertib and three different PARP inhibitors in the indicated Breast Cancer cell line, DU4475.
[0036] FIG. 13A-FIG. 13C display data showing Onvansertib + Olaparib induces an increase in apoptosis.
[0037] FIG. 14A-FIG. 14C depict data showing that Onvansertib + Olaparib induces an increase in cells expressing the DNA Damage/ Apoptotic Marker y-H2AX.
[0038] FIG. 15 depicts exemplary western blot analysis showing that ATR-CHK1 and ATM-CHK2 pathways are activated by Olaparib and Olaparib+Onvansertib treatments.
[0039] FIG. 16A-FIG. 16C depict exemplary data showing that Onvansertib + Olaparib induces an increase in G2/M and S Phase.
[0040] FIG. 17A-FIG. 17B depict data related to in vivo studies in a Breast Cancer model.
[0041] FIG. 18 A- FIG. 18C show synergy score data for Onvansertib and three different PARP inhibitors in indicated Pancreatic Cancer Cell Lines.
[0042] FIG. 19A-FIG. 19D display exemplary data related to Onvansertib and Olaparib Synergy in Pancreatic Cancer cell lines.
DETAILED DESCRIPTION
[0043] 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.
[0044] 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.
[0045] Provided herein include methods, compositions, and kits for treating cancer. Some embodiments provide a method of treating cancer comprising administrating a Poly-(ADP- ribose) polymerase (PARP) inhibitor and a Polo-like kinase 1 (PLK1) inhibitor to a subject. In some embodiments, the compositions and kits provided herein comprise a PARP inhibitor and a PLK1 inhibitor.
[0046] In some embodiments, the method comprises: administrating onvansertib and a PARP inhibitor selected from the group consisting of olaparib, niraparib, and AZD5305 to a subject with cancer, thereby inhibiting progression of the cancer, wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
[0047] Also disclosed herein include methods and compositions for sensitizing cancer cells to a PARP inhibitor. In some embodiments, the method comprises: contacting cancer cells with a composition comprising onvansertib, thereby sensitizing the cancer cells to the PARP inhibitor, wherein the PARP inhibitor is olaparib, niraparib, AZD53O5, or a combination thereof.
[0048] In some embodiments, the kit comprises: onvansertib; and a manual providing instructions for co-administrating onvansertib with a PARP inhibitor to a subject for treating cancer, wherein the PARP inhibitor is olaparib, niraparib, or AZD5305, and wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof. Definitions
[0049] 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.
[0050] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animals” include cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
[0051] 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.
[0052] As used herein, “administration” or “administering” refers to a method of giving a dosage of a pharmaceutically active ingredient to a vertebrate.
[0053] As used herein, a “dosage” refers to the combined amount of the active ingredients (e.g., PLK1 inhibitor (e.g., onvansertib) or PARP inhibitor (e.g., olaparib)).
[0054] As used herein, a “unit dosage” refers to an amount of therapeutic agent administered to a patient in a single dose.
[0055] As used herein, the term “daily dose” or “daily dosage” refers to a total amount of a pharmaceutical composition or a therapeutic agent that is to be taken within 24 hours.
[0056] 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.
[0057] 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.
[0058] 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 sterile.
[0059] 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 carriers 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.
[0060] 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, quinates, 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.
[0061] 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,A-di methyl formamide, tetrahydrofuran, dimethylsulfoxide, and water.
[0062] 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.
[0063] 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 self-administered patient questionnaire).
[0064] As used herein, the term “prophylaxis,” “prevent,” “preventing,” “prevention,” and grammatical variations thereof as used herein refers the preventive treatment of a subclinical disease-state in a subject, e.g., a mammal (including a human), for reducing the probability of the occurrence of a clinical disease-state. The method can partially or completely delay or preclude the onset or recurrence of a disorder or condition and/or one or more of its attendant symptoms or barring a subject from acquiring or reacquiring a disorder or condition or reducing a subject’s risk of acquiring or requiring a disorder or condition or one or more of its attendant symptoms. The subject is selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. “Prophylaxis” therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
[0065] As used herein, each of the terms “partial response” and “partial remission”
refers to the amelioration of a cancerous state, as measured by, for example, tumor size and/or cancer marker levels, in response to a treatment. In some embodiments, a “partial response” means that a tumor or tumor-indicating blood marker has decreased in size or level by about 50% in response to a treatment. The treatment can be any treatment directed against cancer, including but not limited to, chemotherapy, radiation therapy, hormone therapy, surgery, cell or bone marrow transplantation, and immunotherapy. The size of a tumor can be detected by clinical or by radiological means. Tumor-indicating markers can be detected by means well known to those of skill, e.g., ELISA, FACS, or other antibody-based tests.
[0066] As used herein, each of the terms “complete response” or “complete remission” means that a cancerous state, as measured by, for example, tumor size and/or cancer marker levels, has disappeared following a treatment, including but are not limited to, chemotherapy, radiation therapy, hormone therapy, surgery, cell or bone marrow transplantation, and immunotherapy. The presence of a tumor can be detected by clinical or by radiological means. Tumor-indicating markers can be detected by means well known to those of skill, e.g., ELISA, FACS or other antibody-based tests. A “complete response” does not necessarily indicate that the cancer has been cured, however, as a complete response can be followed by a relapse.
Cancer
[0067] Methods, compositions and kits disclosed herein can be used for treating cancer. In some embodiments, the method comprises: administrating onvansertib or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof and a Poly-(ADP- ribose) polymerase (PARP) inhibitor selected from olaparib, niraparib, and AZD53O5 or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof to a subject (e.g., a patient) with cancer, thereby inhibiting progression of the cancer. The cancer can be ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
[0068] The methods, compositions and kits disclosed herein can be used for various types of cancer, including but not limited to, melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), pancreatic adenocarcinoma, breast cancer, colon cancer, lung cancer (e.g., nonsmall cell lung cancer (NSCLC) and small-cell lung cancer (SCLC)), esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and other neoplastic malignancies. Additionally, the disease or condition provided herein includes refractory or recurrent malignancies whose growth may be inhibited using the methods and compositions disclosed herein. In some embodiments, the cancer is carcinoma, squamous carcinoma, adenocarcinoma,
sarcomata, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, hematological cancer, leukemia, lymphoma, neuroma, or a combination thereof. In some embodiments, the cancer is carcinoma, squamous carcinoma (e.g., cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and adenocarcinoma (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary). In some embodiments, the cancer is sarcomata (e.g., myogenic sarcoma), leukosis, neuroma, melanoma, and lymphoma.
[0069] The cancer can be a solid tumor, a liquid tumor, or a combination thereof. In some embodiments, the cancer is a solid tumor, including but not limited to, 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. In some embodiments, the cancer is a liquid tumor. In some embodiments, the cancer is a hematological cancer. Non-limiting examples of hematological cancer include Diffuse large B cell lymphoma (“DLBCL”), Hodgkin's lymphoma (“HL”), NonHodgkin's lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), and Multiple myeloma (“MM”).
[0070] The cancer can be, for example, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof. The cancer can be pancreatic ductal carcinoma, pancreatic adenocarcinoma, ovary serous adenocarcinoma, breast ductal carcinoma, a high-grade serous ovarian adenocarcinoma, or a combination thereof. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer.
[0071] The cancer can be a homologous recombination-deficient cancer. The cancer can be a BRCA1 mutant cancer, a BRCA2 mutant cancer, or both. The cancer can be a BRCA1- homozygous mutant cancer, a BRCA2 -homozygous mutant cancer, a BRCA1 -heterozygous mutant cancer, a BRCA2-heterozygous mutant cancer, or any combination thereof. The cancer can be homozygous wild type for BRCA1, BRCA2, or both. In some embodiments, the cancer is a BRCA2-mutant prostate cancer. In some embodiments, the cancer is a BRCAl-mutant ovarian
cancer. The cancer can be a BRCA wild type cancer with wildtype BRCA1 and/or BRCA2 sequence, such as BRCA1 wild type ovarian cancer and/or BRCA2 wild type ovarian cancer. In some embodiments, the cancer is a BRCAl-wild type prostate cancer.
[0072] In some embodiments, the cancer is sensitive to a PARP inhibitor treatment. In some embodiments, the cancer is characterized by deficiencies in DNA repair. The cancer can be a homologous recombination (HR) -deficient cancer with impaired HR-mediated DNA repair functionality. In some embodiments, the subject having the cancer has one or more pathogenic variants of one or more genes involved in the HR-mediated DNA repair mechanism including but not limited to, BRCA1, BRCA2, 53BP1, ATM, ATR, ATRIP, BARD1, BLM, BRIP1, DMC1, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RIF1, RMI1, RMI2, RPA1, TOP3A, TOPBP1, XRCC2, and XRCC3.
[0073] In some embodiments, the cancer is BRCA1- and/or BRCA2-deficient. In some embodiments, HRDetect score can be calculated for a cancer or tumor to detect BRACAl/BRCA2-deficient tumors. HRDetect is a whole-genome sequencing based classifier designed to predict BRCA1 and BRCA2 deficiency based on six mutational signatures. Details about the HRDetect method are described in Davies H et al., Nat Med. 2017; 23:517-25, the content of which is incorporated herein by reference in its entirety. In some embodiments, a HRDetect score equal to or greater than about 0.7 suggest a HR deficiency, while less than about 0.7 indicates HR proficiency. In some embodiments, a cancer has a HRDetect score equal to or greater than 0.7. In some embodiments, a cancer has a HRDetect score less than 0.7.
[0074] The cancer can be a PARP inhibitor resistant cancer or has developed resistance to a PARP inhibitor. The cancer can be a PARP inhibitor resistant (e.g., olaparib resistant) breast cancer, a PARP inhibitor resistant (e.g., olaparib resistant) ovarian cancer, a PARP inhibitor resistant (e.g., olaparib resistant) pancreatic cancer, or a PARP inhibitor resistant (e.g., olaparib resistant) prostate cancer. In some embodiments, the combinatorial inhibition of PLK1 and PARP can effectively treat PARP inhibitor resistant cancer by significantly reducing the tumor size, increasing survival rate of a subject with cancer, and prolonging survival duration of a subject with cancer in comparison with a single agent treatment (a PARP inhibitor or a PLK1 inhibitor).
[0075] In some embodiments, RAD51 foci assay is conducted to discriminate between PARP inhibitor- sensitive and PARP inhibitor-resistant cancer. RAD51 refers to a homologous recombination DNA repair protein forming nuclear foci after DNA damage and can be used as an indicator of homologous recombination DNA repair functionality. RAD51 foci can be quantified using an immunofluorescence-based method in formalin-fixed paraffin-embedded tumor samples treated with vehicle or a PARP inhibitor. Low RAD51 score can be associated with PARP inhibitor (e.g., olaparib, niraparib, and AZD5305) sensitivity, while high RAD51 score can be
associated with PARP inhibitor (e.g., olaparib, niraparib, and AZD5305) resistance. Details about the RAD51 foci assay can be found, for example, in Guffanti F et al., Br J Cancer, 2022 Jan; 126(1): 120- 128, the content of which is incorporated by reference herein. In some embodiments, the cancer has a RAD51 foci level equal to or greater than 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%. In some embodiments, the cancer has a RAD51 foci level less than 30%, 25%, 20%, 155, 10%, 5%, 2%, or 1%.
PARP Inhibitors and PLK Inhibitors
[0076] Methods, compositions and kits disclosed herein can be used for treating cancer, for example ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof. In some embodiments, a method for treating cancer comprises administrating a PARP inhibitor (e.g., olaparib, niraparib, and AZD5305), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and a PLK1 inhibitor (e.g., onvansertib), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, to a subject (e.g., a patient) in need thereof. The method can comprise administering a pharmaceutically effective amount of the PARP inhibitor and a pharmaceutically effective amount of the PLK1 inhibitor.
TABLE I: EXEMPLARY FDA APPROVALS FOR PARPI
[0077] Table 1 shows several PARPi that are FDA- approved for cancer treatment. However, resistance to PARPi can occur in cancer patients. In some embodiments, initial response rate to PARPi is high but patients will eventually develop mechanisms of resistance and relapse (progression free survival ~8 months). In some embodiments, mechanisms of resistance include restoration of HR, decreased PARP trapping, stabilization of stalled forks, and increased drug efflux. As disclosed herein, combination therapies have the potential to prolong the effect of PARPi and/or overcome resistance.
PARP Inhibitors
[0078] Poly-(ADP-ribose) polymerase (PARP) plays a key role in the DNA damage response and either directly or indirectly affects numerous DNA damage repair (DDR) pathways, including base excision repair (BER), homologous recombination (HR), nucleotide excision repair (NER), non-homologus end joining (NHEJ) and DNA mismatch repair (MMR). PARP inhibitors are inhibitors of PARP, which are developed for multiple indications, including treatment of cancer. PARP is essential for repair of single strand DNA breaks (SSBs). Failure to repair SSBs through PARP inhibition results in double strand DNA breaks (DSBs). In cells with functional homologous recombination (HR) pathway, the DSB are repaired. In cells with a dysfunctional HR pathway, such as BRCA1 and/or BRCA2 mutant cells, the lesions cannot be adequately repaired resulting in cell death.
[0079] Several forms of cancer are more dependent on PARP than regular cells, making PARP an attractive target for cancer therapy. In addition to their use in cancer therapy, PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction, as well as for long-term neurodegenerative diseases. DNA is damaged thousands of times during each cell cycle, and that damage must be repaired. BRCA1, BRCA2 and PALB2 are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombination repair, or HRR, pathway. When the gene for either protein is mutated, the change can lead to errors in DNA repair that can eventually cause breast cancer. When subjected to enough damage at one time, the altered gene can cause the death of the cells. PARPI is a protein that is important for repairing single-strand breaks (“nicks” in the DNA). If such nicks persist unrepaired until DNA is replicated (which must precede cell division), then the replication itself can cause double strand breaks to form. Drugs that inhibit PARPI cause multiple double strand breaks to form in this way, and in tumors with BRCA1, BRCA2 or PALB2 mutations these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that don't replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2, still have homologous repair operating, which allows them to survive the
inhibition of PARP. Some cancer cells that lack the tumor suppressor PTEN may be sensitive to PARP inhibitors because of down-regulation of Rad51, a critical homologous recombination component, although other data suggest PTEN may not regulate Rad51. In some embodiments, PARP inhibitors are PARP inhibitors effective against one or more PTEN-defective tumors (e.g. some aggressive prostate cancers). Cancer cells that are low in oxygen (e.g. in fast growing tumors) are sensitive to PARP inhibitors. PARP inhibitors were originally thought to work primarily by blocking PARP enzyme activity, thus preventing the repair of DNA damage and ultimately causing cell death. PARP inhibitors have an additional mode of action: localizing PARP proteins at sites of DNA damage, which has relevance to their anti-tumor activity. The trapped PARP protein-DNA complexes are highly toxic to cells because they block DNA replication. The PARP family of proteins in humans includes PARP1 and PARP2, which are DNA binding and repair proteins. When activated by DNA damage, these proteins recruit other proteins that do the actual work of repairing DNA. Under normal conditions, PARP1 and PARP2 are released from DNA once the repair process is underway. But when they are bound to PARP inhibitors, PARP1 and PARP2 become trapped on DNA. It was shown that trapped PARP-DNA complexes are more toxic to cells than the unrepaired single-strand DNA breaks that accumulate in the absence of PARP activity, indicating that PARP inhibitors act as PARP poisons. As described herein, there are two classes of PARP inhibitors: (1) catalytic inhibitors that act mainly to inhibit PARP enzyme activity and do not trap PARP proteins on DNA, and (2) dual inhibitors that both block PARP enzyme activity and act as PARP poison. Non-limiting examples of PARP inhibitors include: Iniparib (BSI 201) (for example, for breast cancer and squamous cell lung cancer); Olaparib (AZD-2281) (for example, for breast, ovarian and colorectal cancer); Rucaparib (AG014699, PF- 01367338, for example, for metastatic breast and ovarian cancer); Veliparib (ABT-888) (for example, for metastatic melanoma and breast cancer); CEP 9722 (for example, for non-small-cell lung cancer (NSCLC)); MK 4827 which inhibits both PARP1 and PARP2; BMN-673 (for example, for advanced hematological malignancies and for advanced or recurrent solid tumors); and 3-aminobenzamide. The PARP inhibitor can be a PARP1 inhibitor or a PARP2 inhibitor. In some embodiments, the PARP inhibitor can inhibit PARP1 and PARP2. The PARP inhibitor can be a selective inhibitor for PARP1, PARP2, or both.
[0080] The methods and compositions for treating cancer in combination with one or more PLK1 inhibitors disclosed herein can include one or more PARP inhibitors (including but not limited to, olaparib, talazoparib (BMN-673), AZD5305, rucaparib, veliparib, niraparib, CEP 9722, MK 4827, BGB-290 (pamiparib), ABT-888, AG014699, BSI-201, CEP-8983, E7016, NMS-P293, and 3-aminobenzamide). PARP inhibitors are known to exhibit synthetic lethality, for example in tumors with mutations in BRCA1/2. Olaparib has received FDA approval for
treatment of ovarian cancer patients with mutations in BRCA1 or BRCA2. In addition to olaparib, other FDA-approved PARP inhibitors for ovarian cancer include nirapirib and rucaparib. Talazoparib was recently approved for treatment of breast cancer with germline BRCA mutations and is in phase III trials for hematological malignancies and solid tumors and has reported efficacy in SCLC, ovarian, breast, and prostate cancers. Veliparib is in phase III trials for advanced ovarian cancer, TNBC and NSCLC. Not all PARP inhibitors are dependent on BRCA mutation status and niraparib has been approved for maintenance therapy of recurrent platinum sensitive ovarian, fallopian tube or primary peritoneal cancer, independent of BRCA status. NMS-P293 was described in, for example, Abstract 4843: NMS-P293, a PARP-1 selective inhibitor with no trapping activity and high CNS penetration, possesses potent in vivo efficacy and represents a novel therapeutic option for brain localized metastases and glioblastoma, Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL.
[0081] Some PARP inhibitors have been approved for BRCA1/2 mutant ovarian, breast, prostate and pancreatic cancer patients. Although initial response to PARP inhibitors is high, patients will eventually develop resistance. Mechanisms of resistance to PARP inhibitors include restoration of homologous recombination (HR).
[0082] The PARP inhibitor can be, for example, Iniparib (BSI 201), Talazoparib (BMN-673), AZD5305, Olaparib (AZD-2281), Rucaparib (AG014699, PF-01367338), ABT-888, Veliparib (ABT-888), niraparib, CEP 9722, MK 4827, BGB-290 (pamiparib), BSI-201, CEP- 8983, E7016, 3-aminobenzamide, or a combination thereof.
Niraparib
Olaparib
PLK1 Inhibitors
[0086] Polo-like kinases (PLK) are a family of five highly conserved serine/threonine protein kinases. PLK1 is a master regulator of mitosis and is involved in several steps of the cell cycle, including mitosis entry, centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 has been shown to be overexpressed in solid tumors and hematologic malignancies, including AML. PLK1 inhibition induces G2-M-phase arrest with subsequent apoptosis in cancer cells, and has emerged as a promising targeted therapy. Several PLK inhibitors have been studied in clinical trials. In a randomized phase 11 study of patients with AML who were treatment naive yet unsuitable for induction therapy, the pan-PLK inhibitor, volasertib (BI6727), administered intravenously in combination with LDAC showed a significant increase in OS when compared with LDAC alone. A subsequent randomized phase III study identified no benefit of the combination and described an increased risk of severe infections. PLK1 facilitates HR during Double Strand DNA Break (DSB) Repair. PLK1 phosphorylates Rad51 and BRCA1, facilitating their recruitment to DSB sites and thereby HR-mediated DNA repair.
[0087] Onvansertib (also known as PCM-075, NMS-1286937, NMS-937, “compound of formula (I)” in US Patent No. 8,927,530, IUPAC name l-(2-hydroxyethyl)-8-{ [5-(4- methylpiperazin-l-yl)-2-(trifhioromethoxy) phenyl] amino }-4,5-dihydro-lH-pyrazolo[4,3-h] quinazoline-3 -carboxamide) is a selective ATP-competitive PLK1 inhibitor. Biochemical assays demonstrated high specificity of onvansertib for PLK1 among a panel of 296 kinases, including other PLK members. Onvansertib has potent in vitro and in vivo antitumor activity in models of both solid and hematologic malignancies. Onvansertib is the first PLK1 specific ATP competitive inhibitor administered by oral route to enter clinical trials with proven antitumor activity in different preclinical models. Onvansertib inhibited cell proliferation at nanomolar concentrations in AML cell lines and tumor growth in xenograft models of AML. Onvansertib also significantly increased cytarabine antitumor activity in disseminated models of AML.
Onvansertib
[0088] Onvansertib shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid as well as hematologic tumors. Onvansertib potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with a clear PLK1 -related mechanism of action at well tolerated doses in mice after oral administration. In addition, onvansertib shows activity in combination therapy with approved cytotoxic drugs, such as irinotecan, in which there is enhanced tumor regression in HT29 human colon adenocarcinoma xenografts compared to each agent alone, and shows prolonged survival of animals in a disseminated model of AML in combination therapy with cytarabine. Onvansertib has favorable pharmacologic parameters and good oral bioavailability in rodent and nonrodent species, as well as proven antitumor activity in different nonclinical models using a variety of dosing regimens, which can provide a high degree of flexibility in dosing schedules, warranting investigation in clinical settings. Onvansertib has several advantages over volasertib (BI6727, another PLK1 inhibitor), including a higher degree of potency and specificity for the PLK1 isozyme, and oral bioavailability.
[0089] A phase I, first-in-human, dose-escalation study of onvansertib in patients with advanced/metastatic solid tumors identified neutropenia and thrombocytopenia as the primary dose-limiting toxicities. These hematologic toxicities were anticipated on the basis of the mechanism of action of the drug and were reversible, with recovery occurring within 3 weeks. The half-life of onvansertib was established between 20 and 30 hours. The oral bioavailability of onvansertib plus its short half-life provide the opportunity for convenient, controlled, and flexible dosing schedules with the potential to minimize toxicities and improve the therapeutic window. Pharmacodynamics and biomarker studies, including baseline genomic profiling, serial monitoring of mutant allele fractions in plasma, and the extent of PLK1 inhibition in circulating blasts, have been performed to identify biomarkers associated with clinical response and are
described in WO 2021/146322, the content of which is incorporated herein by reference in its entirety.
[0090] As disclosed herein, a combination therapy of a PARP inhibitor and onvansertib can result in significantly enhanced efficacy against cancer (e.g., ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof), causing tumor regression and cancer survival. The resulted tumor regression and cancer survival rate/duration by the combination can be surprisingly synergistic (i.e., more than additive, superior to the cumulated anti-tumor efficacy caused by the PARP inhibitor and the PLK1 inhibitor separately). Provided herein include methods, compositions and kits for treating cancer in a subject (e.g., a human patient suffering from cancer). The method comprises administrating a PARP inhibitor and onvansertib to the patient in a manner sufficient to inhibit or reduce progression of the cancer. For example, the PARP inhibitor and onvansertib can be administrated to a subject with cancer simultaneously, separately, or sequentially. Surprisingly, the resulted tumor regression and cancer survival rate/duration by the combination is more than additive, i.e., superior to the cumulated anti-tumor efficacy caused by the PARP inhibitor and onvansertib separately. Provided herein include methods, compositions and kits for treating cancer in a subject (for example, a human patient suffering from cancer ). The method comprises administrating a PARP inhibitor and onvansertib to the patient in a manner sufficient to inhibit progression of the cancer. For example, the PARP inhibitor and onvansertib can be administrated to a subject with cancer simultaneously, separately, or sequentially.
[0091] 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 PARP inhibitor alone plus onvansertib alone). The enhanced or synergistic efficacy or inhibition of any combination of a PARP inhibitor and onvansertib 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 PARP inhibitor and onvansertib 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 the PARP inhibitor alone plus onvansertib alone.
[0092] The molar ratio of the PLK1 inhibitor (e.g., onvansertib) to the PARP inhibitor (e.g., olaparib, niraparib, and AZD53O5) 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 the PARP inhibitor and onvansertib 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 the PARP inhibitor alone plus onvansertib alone. For example, a combination of the PARP inhibitor and onvansertib 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 PARP inhibitor alone plus 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 the PARP inhibitor and the PLK1 inhibitor can be, for example, 50%, 60%, 70%, 80%, 90%, 100%, or more higher than the combined inhibition of progression caused by the PARP inhibitor alone plus onvansertib alone. In some embodiments, the PARP inhibitor is olaparib.
[0093] The method described herein using the combination of the PARP inhibitor and the PLK1 inhibitor (e.g., onvansertib) is expected to be effective with various cancers, for example head and neck cancer, non-small cell lung cancer, intrahepatic cholangiocarcinoma, gastric cancer, urothelial cancer, small cell lung cancer, breast cancer, endometrial cancer, cervical cancer, rhabdomyosarcoma, cholangiocarcinoma, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, prostate cancer, or a combination thereof.
[0094] As described herein, the patient can achieve complete response or partial response after treatment with the PARP inhibitor and onvansertib. In some embodiments, the patient achieves a complete response. In some embodiments, the patient achieves a partial response. In some embodiments, the subject has received a prior PARP inhibitor treatment. In some embodiments, the patient did not respond to treatment with only PARP inhibitor(s). In some embodiments, the patient did not respond to treatment with the PARP inhibitor alone. In some embodiments, the subject is known to be resistant to a PARP inhibitor therapy. In some embodiments, the subject has received at least one prior cancer treatment. In some embodiments, the prior treatment does not comprise the use of a PARP inhibitor, onvansertib, or both. In some embodiments, the subject was in remission for cancer. In some embodiments, the subject in remission for cancer was in complete remission (CR) or in partial remission (PR).
[0095] The PARP inhibitor and the PLK1 inhibitor (e.g., onvansertib) can be administered to the patient in any manner deemed effective to treat the cancer. The PARP inhibitor can be administered together with, or separately from, onvansertib. When administered separately,
the PARP inhibitor can be administered before or after onvansertib, or in different administration cycles.
[0096] Onvansertib and the PARP inhibitor can be co-administered (i.e., simultaneously) or sequentially. In some embodiments, it can be advantageous to administer the PLK1 inhibitor (e.g., onvansertib) to the subject before the PARP inhibitor (e.g., olaparib, niraparib, or AZD5305), e.g., on one or more days, or each day, of the days on which onvansertib and the PARP inhibitor are administered to the subject, such that onvansertib can sensitize cells (e.g., cancer cells) to the PARP inhibitor (e.g., through impairment of HR) to achieve effective treatment. The time interval between the administration of onvansertib and the administration of the PARP inhibitor 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, a range between any two of these values, or any value between 30 minutes and 12 hours. In some embodiments, onvansertib and the PARP inhibitor (e.g., olaparib) 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 onvansertib is administered to the subject prior to the PARP inhibitor 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 the PARP inhibitor.
[0097] The PARP inhibitor 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 PARP inhibitor and onvansertib are each administered to the patient in a cycle of at least twice within a week. In other embodiments, the PARP inhibitor and onvansertib are each administered to the patient in a cycle of at least five times within a week. In further embodiments, the patient undergoes at least two cycles of administration. 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, i.e., an interval between the last day of the first cycle and the first day of the second cycle. The break (i.e., 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 PARP inhibitor 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 PARP inhibitor in a four-week period.
[0098] The PARP inhibitor (e.g., olaparib, niraparib, and AZD5305) can be administered to the patient at any appropriate dosage, e.g., a dosage of about, at least or at most 0.1 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 200 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, 1000 mg/kg, 1500 mg/kg, 2000 mg/kg, or a number between any two of these values. The dosage unit based on the body weight (mg/kg) can be converted to another unit (e.g., 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. In some embodiments, the PARP inhibitor is olaparib, niraparib, or AZD5305, which is administered at a dosage of about, at least or at most 1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 200 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, 1000 mg/kg, or a number between any two of these values.
[0099] The PARP inhibitor (e.g., olaparib, niraparib, or AZD5305) can be administrated to the patient once daily, twice daily, or three times daily. In some embodiments, the PARP inhibitor is administered in a cycle of 7-56 days of daily administration. In some embodiments, the PARP inhibitor 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 PARP inhibitor 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 PARP inhibitor 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 PARP inhibitor 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 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. For example, olaparib, niraparib, or AZD5305 can be administered in a cycle of 5, 6, 7, 8, 9, or 10 days. Olaparib can be administrated daily on each day or on selected days of the administration cycle. In some embodiments, olaparib is administered in a cycle of 7 days with a daily administration for 5 days (e.g., days 1-5) and no administration for two days (e.g., days 6-7).
[0100] Any PARP inhibitor, now known or later discovered, can be used in these methods, including PARP inhibitors that are selective for PARP (e.g., PARP1, PARP2 or both), and PARP inhibitors that also inhibit the activity of other proteins. Nonlimiting examples of PARP inhibitors include Iniparib (BSI 201), Talazoparib (BMN-673), AZD5305, Olaparib (AZD-2281), Rucaparib (AG014699, PF-01367338), ABT-888, Veliparib (ABT-888), niraparib, CEP 9722, MK 4827, BGB-290 (pamiparib), BSI-201, CEP-8983, E7016, 3 -aminobenzamide, and combinations thereof. In some embodiments, the PARP inhibitor is 2X 121, ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib (ZEJULA) (MK-4827), NMS-P293, NOV- 140101, NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), 0N02231, pamiparib, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699, PF-01367338), SBP 101, SC 101914, simmiparib, talazoparib (BMN- 673), AZD53O5, veliparib (ABT-888), WW 46, 2-(4-(trifhioromethyl)phenyl)-7,8-dihydro-5H- thiopyrano[4,3-d]pyrimidin-4-ol, or combinations thereof. In some embodiments, the PARP inhibitor is olaparib.
[0101] 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 dihydropteridinone, a pyridopyrimidine, a aminopyrimidine, a substituted thiazolidinone, 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.
[0102] In some embodiments, the PLK1 inhibitor is onvansertib. In these embodiments, the onvansertib is administered to the patient at any appropriate dosage, e.g., 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 daily. In additional 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.
[0103] In some embodiments, a PLK1 inhibitor alone (e.g., onvansertib) or in combination with a PARP inhibitor 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 a PARP inhibitor. 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.
[0104] As can be appreciated by one of skill in the art, the amount of co-administration of the PARP inhibitor and onvansertib, and the timing of co-administration, 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 PARP inhibitor and onvansertib can 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.
[0105] 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. The cancer can be ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof. The cancer can be a BRCA mutant cancer, for example a BRCA1 homozygous mutant cancer, a BRAC2 homozygous mutant cancer, or a BRAC1 and BRAC2 homozygous mutant cancer. The cancer can be a BRCA wild type cancer (e.g., no BRCA mutation), for example a BRCA1 wild type cancer or a BRCA2 wild type cancer. The cancer can be a BRCAl-heterozygous mutant cancer or a BRCA2 -heterozygous mutant
cancer, or both. The cancer can be heterozygous mutant for BRCA1 and/or 2 and/or homozygous mutant for BRCA 1 and/or 2. The methods can further comprise administering an additional therapeutic intervention to the subject. The additional therapeutic intervention can comprise a different therapeutic intervention than administering onvansertib and the PARP inhibitor, an antibody, an adoptive T cell therapy, a chimeric antigen receptor (CAR) T cell therapy, an antibody-drug conjugate, a cytokine therapy, a cancer vaccine, a checkpoint inhibitor, a radiation therapy, surgery, a chemotherapeutic agent, or any combination thereof. The therapeutic intervention can be administered at any time of the treatment, for example at a time when the subject has an early-stage cancer, and wherein the therapeutic intervention is more effective that if the therapeutic intervention were to be administered to the subject at a later time.
[0106] Without being bound to any particular theory, it is believed that the PLK1 inhibitor (e.g., onvansertib) can sensitize cells (e.g., cancer cells) to PARP inhibitor treatment (e.g., through impairment of HR) to achieve effective cancer treatment.
Dosing and Pharmacokinetics
[0107] The treatment of the present disclosure can comprise administration of a PLK1 inhibitor (e.g., onvansertib) for a desired duration in one or more cycles of treatment, and administration of a PARP inhibitor. The administration of onvansertib can be oral administration. The administration of the PARP inhibitor can be oral administration. Both onvansertib and the PARP inhibitor can be administered orally.
[0108] The treatment can, for example, comprise daily administration of a PARP inhibitor (e.g., olaparib) at, or at about, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 5mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, or a number or a range between any two of these values. In some embodiments, the daily dose of the PARP inhibitor (e.g., olaparib) can be adjusted (e.g., increased or decreased with the range) during the treatment of the subject. The daily administration of the PARP inhibitor can be at different amounts on different days or during different weeks. For example, the treatment can comprise daily administration of the PARP inhibitor (e.g., olaparib) at 0.1 mg to 20 mg during week 1, 0.25 mg to 50 mg during week 2, 0.5 mg to 100 mg during week 3, 1 mg to 200 mg during week 4, and 2 mg to 400 mg during week 5 and beyond. For example, the treatment can comprise daily administration of the PARP inhibitor (e.g., olaparib) at 300 mg on day 1, 450 mg on day 2, 600 mg on day 3, and 750 mg or 600 mg on day 4 and beyond. In some embodiments, the PARP inhibitor (e.g., olaparib) is administered to the subject orally twice daily (two 150 mg tablets each
time), with or without food, for a total daily dose of 600 mg. In some embodiments, the PARP inhibitor (e.g., olaparib) is administered to the subject orally twice daily (one 100 mg tablet and one 150 mg tablets each time), with or without food, for a total daily dose of 500 mg. In some embodiments, the PARP inhibitor (e.g., olaparib) is administered to the subject orally twice daily (two 100 mg tablets each time), with or without food, for a total daily dose of 400 mg.
[0109] A maximum concentration (Cmax) of the PARP inhibitor (e.g., olaparib) in a blood of the subject (during the treatment and/or after the treatment) when the PARP inhibitor is administered alone or in combination with onvansertib can be from about 0.1 pg/mL (picogram per mL) to about 10 pg/mL (microgram per mL). For example, the Cmax of the PARP inhibitor (e.g., olaparib) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib can be, or be about, 0.1 pg/mL, 0.2 pg/mL, 0.3 pg/mL, 0.4 pg/mL, 0.5 pg/mL, 0.6 pg/mL, 0.7 pg/mL, 0.8 pg/mL, 0.9 pg/mL, 1 pg/mL, 1.1 pg/mL, 1.2 pg/mL, 1.3 pg/mL, 1.4 pg/mL, 1.5 pg/mL, 1.6 pg/mL, 1.7 pg/mL, 1.8 pg/mL, 1.9 pg/mL, 2 pg/mL, 2.1 pg/mL, 2.2 pg/mL, 2.3 pg/mL, 2.4 pg/mL, 2.5 pg/mL, 2.6 pg/mL, 2.7 pg/mL, 2.8 pg/mL, 2.9 pg/mL, 3 pg/mL, 3.1 pg/mL, 3.2 pg/mL, 3.3 pg/mL, 3.4 pg/mL, 3.5 pg/mL, 3.6 pg/mL, 3.7 pg/mL, 3.8 pg/mL, 3.9 pg/mL, 4 pg/mL, 4.1 pg/mL, 4.2 pg/mL, 4.3 pg/mL, 4.4 pg/mL, 4.5 pg/mL, 4.6 pg/mL, 4.7 pg/mL, 4.8 pg/mL, 4.9 pg/mL, 5 pg/mL, 5.1 pg/mL, 5.2 pg/mL, 5.3 pg/mL, 5.4 pg/mL, 5.5 pg/mL, 5.6 pg/mL, 5.7 pg/mL, 5.8 pg/mL, 5.9 pg/mL, 6 pg/mL, 6.1 pg/mL, 6.2 pg/mL, 6.3 pg/mL, 6.4 pg/mL, 6.5 pg/mL, 6.6 pg/mL, 6.7 pg/mL, 6.8 pg/mL, 6.9 pg/mL, 7 pg/mL, 7.1 pg/mL, 7.2 pg/mL, 7.3 pg/mL, 7.4 pg/mL, 7.5 pg/mL, 7.6 pg/mL, 7.7 pg/mL, 7.8 pg/mL, 7.9 pg/mL, 8 pg/mL, 8.1 pg/mL, 8.2 pg/mL, 8.3 pg/mL, 8.4 pg/mL, 8.5 pg/mL, 8.6 pg/mL, 8.7 pg/mL, 8.8 pg/mL, 8.9 pg/mL, 9 pg/mL, 9.1 pg/mL, 9.2 pg/mL, 9.3 pg/mL, 9.4 pg/mL, 9.5 pg/mL, 9.6 pg/mL, 9.7 pg/mL, 9.8 pg/mL, 9.9 pg/mL, 10 pg/mL, a range between any two of these values, or any value between 0.1 pg/mL to 10 pg/mL.
[0110] An area under curve (AUC) of a plot of a concentration of the PARP inhibitor (e.g., olaparib) in a blood of the subject over time (e.g., AUC0-24 for the first 24 hours after administration) when the PARP inhibitor is administered alone or in combination with onvansertib can be from about 1 pg.h/mL to about 100 pg.h/mL. For example, the AUC of a plot of a concentration of the PARP inhibitor (e.g., olaparib) in a blood of the subject overtime (e.g., AUCo- 24 for the first 24 hours after administration) when the PARP inhibitor is administered alone or in combination with onvansertib can be, or be about, 1 pg.h/mL, 5 pg.h/mL, 10 pg.h/mL, 20 pg.h/mL, 30 pg.h/mL, 40 pg.h/mL, 50 pg.h/mL, 60 pg.h/mL, 70 pg.h/mL, 80 pg.h/mL, 90 pg.h/mL, 100 pg.h/mL, 200 pg.h/mL, 300 pg.h/mL, 400 pg.h/mL, 500 pg.h/mL, 600 pg.h/mL, 700 pg.h/mL, 800 pg.h/mL, 900 pg.h/mL, 1000 pg.h/mL, 2000 pg.h/mL, 3000 pg.h/mL, 4000 pg.h/mL, 5000 pg.h/mL, 6000 pg.h/mL, 7000 pg.h/mL, 8000 pg.h/mL, 9000 pg.h/mL, 10000 pg.h/mL, 50000
pg.h/mL, 100000 pg.h/mL, 500000 pg.h/mL, 1000000 pg.h/mL(l pg.h/mL), 2 pg.h/mL, 3 pg.h/mL, 4 pg.h/mL, 5 pg.h/mL, 6 pg.h/mL, 7 pg.h/mL, 8 pg.h/mL, 9 pg.h/mL, 10 pg.h/mL, 11 pg.h/mL, 12 pg.h/mL, 13 pg.h/mL, 14 ug.h/mL, 15 pg.h/mL, 16 pg.h/mL, 17 pg.h/mL, 18
|jg.h/mL, 19 pg.li/niL, 20 pg.h/mL, 21 pg.h/mL, 22 pg.h/mL, 23 pg.h/mL, 24 pg.h/mL, 25 pg.h/mL, 26 pg.h/mL, 27 pg.h/mL, 28 ug.h/mL, 29 pg.h/mL, 30 pg.h/mL, 31 pg.h/mL, 32 pg.h/mL, 33 pg.h/mL, 34 pg.h/mL, 35 pg.h/mL, 36 pg.h/mL, 37 pg.h/mL, 38 pg.h/mL, 39 pg.h/mL, 40 pg.h/mL, 41 pg.h/mL, 42 pg.h/mL, 43 pg.h/mL, 44 pg.h/mL, 45 pg.h/mL, 46 pg.h/mL, 47 pg.h/mL, 48 pg.h/mL, 49 pg.h/mL, 50 pg.h/mL, 51 pg.h/mL, 52 pg.h/mL, 53
|jg.h/mL, 54 pg.h/mL, 55 pg.h/mL, 56 pg.h/mL, 57 pg.h/mL, 58 pg.h/mL, 59 pg.h/mL, 60 pg.h/mL, 61 pg.h/mL, 62 pg.h/mL, 63 pg.h/mL, 64 pg.h/mL, 65 pg.h/mL, 66 pg.h/mL, 67 pg.h/mL, 68 pg.h/mL, 69 pg.h/mL, 70 ug.h/mL, 71 pg.h/mL, 72 pg.h/mL, 73 pg.h/mL, 74 pg.h/mL, 75 pg.h/mL, 76 pg.h/mL, 77 ug.h/mL, 78 pg.h/mL, 79 pg.h/mL, 80 pg.h/mL, 81 |jg.h/mL, 82 pg.h/mL, 83 pg.h/mL, 84 pg.h/mL, 85 pg.h/mL, 86 pg.h/mL, 87 pg.h/mL, 88 pg.h/mL, 89 pg.h/mL, 90 pg.h/mL, 91 ug.h/mL, 92 pg.h/mL, 93 pg.h/mL, 94 pg.h/mL, 95 pg.h/mL, 96 pg.h/mL, 97 pg.h/mL, 98 pg.h/mL, 99 pg.h/mL, 100 pg.h/mL, a range between any two of these values, or any value between 10 pg.h/mL and 100 pg.h/mL. For example, the PARP inhibitor is olaparib, and the AUC of a plot of a concentration of olaparib in a blood of the subject over time (e.g., AUCo-ioh for the first 10 hours after administration) when olaparib is administered alone or in combination with onvansertib can be, or be about, 0.5 pg.h/mL, 1 pg.h/mL, 1.5 pg.h/mL, 2 pg.h/mL, 2.5 pg.h/mL, 3 pg.h/mL, 3.5 pg.h/mL, 4 pg.h/mL, 4.5 pg.h/mL, 5 pg.h/mL, 5.5 pg.h/mL, 6 pg.h/mL, 6.5 pg.h/mL, 7 pg.h/mL, 8 pg.h/mL, 9 pg.h/mL, 10 pg.h/mL, 20 pg.h/mL, 30 pg.h/mL, 40 pg.h/mL, 50 pg.h/mL, 100 pg.h/mL, or a number or a range between any two of these values.
[0111] A time (Tmax) to reach a maximum concentration of the PARP inhibitor (e.g., olaparib, niraparib, or AZD5305) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib can be from about 3 hours to 10 hours. For example, the time (Tinas) to reach a maximum concentration of the PARP inhibitor (e.g., olaparib) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib can be, or be about, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, a range between any two of these values, or any value between 2 hours and 24 hours. For example, the PARP inhibitor is olaparib, and the time (Tmax) to reach a maximum concentration of olaparib in a blood of the subject when olaparib is administered alone or in combination with onvansertib can be, or be about 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, or a number or a range between any two of these values.
[0112] An elimination half-life (T1/2) of the PARP inhibitor (e.g., olaparib, niraparib, or AZD5305) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib can be from about 10 hours to about 100 hours. For example, the elimination half-life (T1/2) of the PARP inhibitor (e.g., olaparib) in a blood of the subject when the PARP inhibitor is administered alone or in combination with onvansertib 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, 65 hours, 70 hours, 75 hours, 80 hours, 85 hours, 90 hours, 95 hours, 100 hours, a range between any two of these values, or any value between 10 hours and 100 hours. For example, the PARP inhibitor is olaparib, and the elimination half-life (T 1/2) of olaparib in a blood of the subject when olaparib is administered alone or in combination with onvansertib can be, or be about, 40 hours, 50 hours, 60 hours, 70 hours, 80 hours, 90 hours, 100 hours, or a number or a range between any two of these values.
[0113] 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 the onvansertib (and/or the one or more chemotherapeutic agents) 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 the one or more chemotherapeutic agents) 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 the one or more chemotherapeutic agents 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 onvansertib and/or the one or more chemotherapeutic agents 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 onvansertib and/or the one or more chemotherapeutic agents 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.
[0114] 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, 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 PARP inhibitor and onvansertib can be the same or different. For combination treatment, the administration cycle, dosing schedule, and/or dosage amount of the PARP inhibitor can be adjusted according to the administration cycle, dosing schedule, and/or dosage amount of onvansertib. For example, the PARP inhibitor (e.g., olaparib, niraparib, or AZD5305) 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).
[0115] 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 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 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, 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, 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, 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 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, onvansertib is administered at or at about 12 mg/m2. In some embodiments, onvansertib is administered at or at about 15 mg/m2. In some embodiments, onvansertib is administered at or at about 18 mg/m2.
[0116] 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 PARP inhibitor can be from about 100 nmol/L to about 1500 nmol/L. For example, the Cmax of onvansertib in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor 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.
[0117] An area under curve (AUC) of a plot of a concentration of the PLK1 inhibitor (e.g., onvanserib) 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 PARP inhibitor 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 onvansertib in a blood of the subject over time (e.g., AUC0-24 for the first 24 hours after administration) when onvansertib is administered alone or in combination with the PARP inhibitor 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.
[0118] A time (Tmax) to reach a maximum concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor can be from about 1 hour to about 5 hours. For example, the time (Tmax) to reach a maximum concentration of onvansertib in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor 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.
[0119] An elimination half-life (T1/2) of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor can be from about 10 hours to about 60 hours. For example, the elimination half-life (T1/2) of onvansertib in a blood of the subject when onvansertib is administered alone or in combination with the PARP inhibitor 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.
Additional Cancer Therapeutics or Therapy
[0120] Methods, compositions and kits disclosed herein can be used for treating cancer. In some embodiments, a method for treating cancer comprises administrating a PARP inhibitor (e.g., olaparib, niraparib, or AZD53O5) and a PLK1 inhibitor (e.g., onvansertib) to a subject (e.g., a patient) in need thereof. The method can comprise administering a therapeutically effective amount of the PARP inhibitor and a therapeutically effective amount of onvansertib. The treatment can comprise administration of at least one additional cancer therapeutics or cancer therapy. The treatment can comprise administration of a therapeutically effective amount of at least one additional cancer therapeutics or cancer therapy. The PARP inhibitor and the cancer therapeutics or cancer therapy can, for example, co-administered simultaneously or sequentially. The PLK1 inhibitor (e.g., onvansertib) and the cancer therapeutics or cancer therapy can, for example, be co-administered simultaneously or sequentially. In some embodiments, the additional cancer therapeutics is cytarabine, low-dose cytarabine (LDAC) and/or decitabine. The safety, pharmacokinetics, and preliminary clinical activity of onvansertib in combination with either LDAC or decitabine have been determined in patients with R/R AML and are described in PCT Application published as WO2021146322, the content of which is incorporated herein by reference in its entirety. In some embodiments, the treatment comprises administration of LDAC at, or at about, 20 mg/m2 subcutaneous (SC) once a day (qd) for seven, eight, night, ten, eleven, twelve, or thirteen days in a cycle. In some embodiments, the treatment comprises administration of decitabine at, or at about, 20 mg/m2 intravenous (IV) qd for three, four, five, six, or seven days in a cycle. In some embodiments, the treatment comprises administration of LDAC at, or at about, 20 mg/m2 subcutaneous (SC) once a day (qd) for ten days in a cycle, and administration of decitabine at 20 mg/m2 intravenous (IV) qd for five days in a cycle.
Methods for Predicting/Determining Treatment Efficacy and Status for Cancer
[0121] Also disclosed herein include methods, compositions, kits, and systems for
predicting/determining clinical outcome for a combination treatment of cancer of the present disclosure, monitoring of the combination treatment, predicting/determining responsiveness of a subject to the combination treatment, determining the status of the cancer in a subject, and improving combination treatment outcome. The methods, compositions, kits and systems can be used to guide the combination treatment, provide combination treatment recommendations, and/or reduce or avoid unnecessary ineffective combination treatment for patients.
[0122] In some embodiments, predicting/determining clinical outcome for a combination treatment of cancer of the present disclosure, monitoring of the combination treatment, predicting/determining responsiveness of a subject to the combination treatment, and/or determining the status of the cancer in a subject comprises measure tumor size and/or inhibition of tumor growth. Inhibiting progression of the cancer can comprise inhibition of growth of one or more tumors in the subject. The term “inhibition of tumor growth” can refer to causing a reduction in or complete cessation of tumor growth and/or causing a regression in tumor size (e.g., volume). The term “tumor volume” or “tumor size” can refer to the total size of the tumor, which can include the tumor itself plus affected lymph nodes if applicable. Tumor size can be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of the tumor using calipers, computed tomography (CT) or magnetic resonance imaging (MRI) scans, mammography, and X- ray; and calculating the volume using equations based on, for example, the z-axis diameter, or on standard shapes such as the sphere, ellipsoid, or cube. Tumor size may be assessed at any time before, during or following at least one cycle of treatment with onvansertib and/or a PARP inhibitor. Tumor size can be assessed at a first timepoint, and at one or more additional timepoints. In some embodiments, tumor size can be assessed in the subject and, e.g., an untreated subject at equivalent timepoints (e.g., at a first timepoint, and at one or more additional timepoints). Tumor growth can be determined by, e.g., measuring tumor size at a first timepoint and measuring tumor size at one or more additional timepoints. In some embodiments, increased inhibition of tumor growth in the subject indicates the subject as responsive to the cancer treatment.
[0123] The inhibition of growth of at least one of the one or more tumors in the subject can be, can be about, can be at least, or can be at least about 1.1 times greater, 1.2 times greater, 1.3 times greater, 1.4 times greater, 1.5 times greater, 1.6 times greater, 1.7 times greater, 1.8 times greater, 1.9 times greater, 2 times greater, or a number or a range between any two of these values, or more, than the inhibition of growth caused by onvansertib alone or the PARP inhibitor alone, following one or more cycles of treatment. The inhibition of growth of at least one of the one or more tumors in the subject can be increased by, by about, by at least, or by at least about 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or a number or a range between any two of these values, relative to a subject treated with onvansertib alone or the
PARP inhibitor alone, following one or more cycles of treatment. The growth of at least one of the one or more tumors in the subject can be inhibited by, by about, by at least, or by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or a number or a range between any two of these values relative to an untreated subject, following one or more cycles of treatment. The growth of at least one of the one or more tumors in the subject can be inhibited by, by about, by at least, or by at least about 70%, 75%, 80%, 85%, 90%, 95%, 100% or a number or a range between any two of these values relative to an untreated subject, following one or more cycles of treatment. The subject can be tumor-free following one or more cycles of treatment.
[0124] In some embodiments, the method comprises measuring expression of one or more markers in the subject (e.g., in a sample obtained from the subject). The method can comprise: measuring expression of one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof in the subject before and/or after the subject is administered with onvansertib and/or the PARP inhibitor. The one or more markers can comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof
[0125] A method of determining responsiveness of a subject to a combination treatment comprising a PARP inhibitor and a PLK1 inhibitor of the disclosure can comprise, for example, analyzing a sample (e.g., a biopsy sample) obtained from a subject with cancer, wherein the subject is undergoing a treatment and/or has received the combination treatment, thereby determining the responsiveness of the subject to the combination treatment. In some embodiments, determining the responsiveness of the subject comprises determining if the subject is a responder of the treatment, e.g., by measuring expression of one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof in the subject. For example, measuring the one or more markers can comprise measuring cleaved-caspase3 in a first sample obtained from the subject at a first time point, detecting cleaved-caspase3 in the sample obtained from the subject at one or more additional time points in one or more additional samples, and determining the difference of the levels of cleaved-caspase3 between the first and at least one of the one or more additional samples. In some embodiments, an increase in levels of cleaved-caspase3 (e.g., increased apoptosis) in at least one of the additional samples relative to the first sample indicates the subject as responsive to the cancer treatment.
[0126] In some embodiments, the first time point is prior or immediately prior to the combination treatment, and at least one of the one or more additional time points are at the end of or after at least one cycle of the combination treatment. In some embodiments, the cycle of the combination treatment is the first cycle of the combination treatment. In some embodiments, the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination
treatment.
[0127] In some embodiments, the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment. In some embodiments, the method comprises continuing the combination treatment to the subject if the subject is indicated as responsive to the combination treatment. In some embodiments, the method comprises discontinuing the combination treatment to the subject and/or starting a different combination treatment to the subject if the subject is not indicated as responsive to the combination treatment.
[0128] In some embodiments, the first time point is prior or immediately prior to the combination treatment, and the one or more additional time points are at the end of or after at least a cycle of the combination treatment, optionally the cycle of the combination treatment is the first cycle of the combination treatment. In some embodiments, the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment, optionally the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
[0129] In some embodiments, the method comprises starting an additional treatment to the subject if the subject is indicated as in cancer relapse. The additional treatment can be the same or different from the current or prior combination treatment.
[0130] In some embodiments, analyzing the sample comprises measuring expression of one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof. In some embodiments, the method comprises measuring expression of at least one of the one or more markers in the subject at a first time point in a first sample, measuring expression of at least one of the one or more markers in the subject at one or more additional time points in one or more additional samples, and determining the difference in expression between the first and at least one of the one or more additional samples.
[0131] Samples for measurement of the one or more markers (e.g., at least one of the first sample, the one or more additional samples, or the second sample) can be obtained by any method known in the art. In some embodiments, the biological sample is obtained from an animal subject, such as a human subject. A biological sample is any solid or fluid sample obtained from, excreted by or secreted by any living organism, (including samples from a healthy or apparently healthy human subject or a human patient affected by cancer). A biological sample can be a biological fluid obtained from, for example, blood, plasma, serum, urine, bile, ascites, saliva, cerebrospinal fluid, aqueous or vitreous humor, or any bodily secretion, a transudate, an exudate (for example, fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (for example, a normal joint or a joint affected by disease, such as a
rheumatoid arthritis, osteoarthritis, gout or septic arthritis). A sample can also be obtained from any organ or tissue (including a biopsy, such as a tumor biopsy) or can include a cell (whether a primary cell or cultured cell) or medium conditioned by any cell, tissue or organ. Exemplary samples include, without limitation, cells, cell lysates, blood smears, cytocentrifuge preparations, cytology smears, bodily fluids (e.g., blood, plasma, serum, saliva, sputum, urine, bronchoalveolar lavage, semen, etc.), tissue biopsies (e.g., tumor biopsies), fine-needle aspirates, and/or tissue sections (e.g., cryostat tissue sections and/or paraffin-embedded tissue sections). In other examples, the sample includes circulating tumor cells (which can be identified by cell surface markers). In some embodiments, samples are used directly (e.g., fresh or frozen), or can be manipulated prior to use, for example, by fixation (e.g., using formalin) and/or embedding in wax (such as formalin- fixed paraffin-embedded (FFPE) tissue samples). It will be appreciated that any method of obtaining tissue from a subject can be utilized, and that the selection of the method used will depend upon various factors such as the type of tissue, age of the subject, or procedures available to the practitioner.
[0132] The levels of the one or more markers in the subject (e.g., in a biopsy sample obtained from the subject) can be measured by any method known in the art. In some embodiments, the one or more markers are detected by immunofluorescence, mass cytometry (CyTOF), FACS, drop-seq, RNA-seq, single cell qPCR, MERFISH (multiplex (in situ) RNA FISH), microarray and/or by in situ hybridization. Other methods including absorbance assays and colorimetric assays are known in the art and may be used herein. In some aspects, measuring expression of the one or more markers comprises measuring protein expression levels. Protein expression levels may be measured, for example, by performing a Western blot, an ELISA, immunohistochemistry or binding to an antibody array. In another aspect, measuring expression of the one or more markers comprises measuring RNA expression levels. RNA expression levels may be measured by performing RT-PCR, Northern blot, an array hybridization, or RNA sequencing methods.
[0133] An enzyme-linked immunosorbent assay, or ELISA, may be used to measure the differential expression of a plurality of markers. There are many variations of an ELISA assay. All are based on the immobilization of an antigen or antibody on a solid surface, generally a microtiter plate. The original ELISA method comprises preparing a sample containing the biomarker proteins of interest, coating the wells of a microtiter plate with the sample, incubating each well with a primary antibody that recognizes a specific antigen, washing away the unbound antibody, and then detecting the antibody- antigen complexes. The antibody-antibody complexes may be detected directly. For this, the primary antibodies are conjugated to a detection system, such as an enzyme that produces a detectable product. The antibody-antibody complexes may be
detected indirectly. For this, the primary antibody is detected by a secondary antibody that is conjugated to a detection system, as described above. The microtiter plate is then scanned and the raw intensity data may be converted into expression values using means known in the art.
[0134] Detection of the one or more markers can be by FACS. The term “fluorescent activated cell sorting” or “FACS”, as used herein, refers to a technique for counting, examining, and sorting microscopic particles suspended in a stream of fluid. It allows simultaneous multiparametric analysis of the physical and/or chemical characteristics of single cells flowing through an optical and/or electronic detection apparatus. Generally, a beam of light (usually laser light) of a single wavelength is directed onto a hydro-dynamically focused stream of fluid. A number of detectors are aimed at the point where the stream passes through the light beam; one in line with the light beam (Forward Scatter, correlates to cell volume) and several perpendicular to the beam, (Side Scatter, correlates to the inner complexity of the particle and/or surface roughness) and one or more fluorescent detectors. Each suspended particle passing through the beam scatters the light in some way, and fluorescent chemicals found in the particle or attached to the particle may be excited into emitting light at a lower frequency than the light source. By analyzing the combinations of scattered and fluorescent light picked up by the detectors it is then possible to derive information about the physical and chemical structure of each individual particle.
[0135] Detection of the one or more markers may involve a cell sorting step to enrich for cells of interest and thus facilitate or enhance their sensitive and specific detection. Cell sorting techniques are commonly based on tagging the cell with antibody against the cell membrane antigen specific to the target subpopulation of cells. The antibody is conjugated to a magnetic bead and/or fluorophore or other label to enable cell sorting and detection. Such methods may include affinity chromatography, particle magnetic separation, centrifugation, or filtration, and flow cytometry (including fluorescence activated cell sorting; FACS).
[0136] RNA can be isolated from the cancer cells and can be sequenced by any method known in the art for determining expression of one or more markers. Methods of preparing cDNA are known in the art. Single cells may be sequenced for detection of at least one of the one or more markers. Single cells of the present invention may be divided into single droplets using a microfluidic device. The single cells in such droplets may be further labeled with a barcode.
[0137] Markers for apoptosis, DNA damage, and cell cycle are known in the art. The one or more markers can comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof. Below include non-limiting examples of proteins that can serve as markers for DNA damage and repair. Exemplary proteins mediating NHEJ include, but are not limited to, Ligase4, XRCC4, H2AX, DNAPKcs (DNA-PK), Ku70, Ku80, Artemis, Cemunnos/XLF, MRE11, NBS1, and RAD50. Exemplary homologous
recombination proteins include RAD51, RAD52, RAD54, XRCC3, RAD51C, BRCA1, BRCA2 (FANCD1), FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ (BRIP1/BACH1), FANCL, FANCM, Chkl, Chk2, ATM, and ATR. Exemplary proteins mediating BER include, but are not limited to, UNG, SMUG1, MBD4, TDG, OFF1, MYH, NTH1, MPG, APE1, APE2, LIG3, XRCC1, ADPRT, ADPRTL2 AND ADPRTL3. Exemplary proteins mediating MER include, but are not limited to, MSH2, MSH3, MSH4, MSH5, MSH6, PMS1, PMS3, MLH1, MLH3, PMS213 and PMS214. Exemplary DNA repair helicases include BLM and WRN. Exemplary proteins mediating NER include, but are not limited to, XPA, XPB, XPC, XPD, XPF, XPG, XPV, RAD23B, USP7, RPA, CAK, ERCC1, RFC, LIG1, LIG3, CSA, CSB, PARP1, NEIL1, and APE1.
[0138] Methods for measuring apoptosis are also known in the art, and non-limiting examples of methods for measuring apoptosis are described below. Markers for apoptosis include caspases-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. In some embodiments, the marker for apoptosis is cleaved-caspase3, and elevated levels of cleaved-caspase3 are indicative of increased apoptosis. A TUNEL assay can be used. The TUNEL assay is a method for detecting apoptotic DNA fragmentation, and is a fluorescence based assay that detects 3 ’-hydroxyl termini of DNA double stranded breaks. Mitochondrial damage can also serve as a measure for apoptosis. For example, release of cytochrome c into the cytosol is associated with mitochondrial permeability. Annexin V assay can detect lipids associated with the inner leaflet of the plasma membrane, which are exposed during apoptosis.
[0139] Cell cycle (e.g., proliferation) can be assessed, e.g., by DAPI or other DNA stain. Exemplary cell replication protein markers include, but are not limited to, phosphorylated histone H3 (pH3), Ki-67 protein, phosphorylated MPM-2 antigen, Proliferating Cell Nuclear Antigen (PCNA, a protein that is expressed in the nuclei of cells during the DNA synthesis phase of the cell cycle), phospho-S780-Rb epitope, Cenp-F (mitosin), class III -Tubulin, spindle checkpoint protein hMad2, phosphorylated myosin light chain kinase, topoisomerase II, Check point kinase 1 (Chkl), Vesicular Monoamine Transporter 2 (VMAT2), loss of cyclin-dependent kinase 1 (Cdkl) kinase activity. Histone H3 can be phosphorylated at Ser28 or SerlO.
[0140] The expression of at least one of the one or more markers in the subject can be increased by, by about, by at least, or by at least about 1.25 fold (e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10-fold or a number or a range between any two of these values, or more) after being administered with both the onvansertib and the PARP inhibitor relative to the expression in the subject before being administered with both the onvansertib and the PARP inhibitor. The expression of at least one of the one or more markers in the subject can be increased by, by about, by at least, or by at least
about 1.25 fold (e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10-fold or a number or a range between any two of these values, or more) after being administered with both the onvansertib and the PARP inhibitor relative to the expression in a subject being administered with onvansertib alone and/or the expression in a subject being administered with the PARP inhibitor alone.
[0141] ctDNA can be analyzed to predict/determine clinical outcome for cancer treatment using a combination of a PARP inhibitor and onvansertib, monitor the combination treatment, predict/determine responsiveness of a subject to the combination treatment, determine cancer status in a subject, improve combination treatment outcome, guide combination treatment, provide combination treatment recommendations, and/or to reduce or avoid ineffective combination treatment. ctDNA can be analyzed to predict/determine clinical outcome for cancer treatment, monitor cancer treatment, predict/determine responsiveness of a subject to a cancer treatment, determine cancer status in a subject, improve cancer treatment outcome, guide cancer treatment, provide treatment recommendations, and/or to reduce or avoid ineffective cancer treatment. Such analysis of ctDNA has been described in PCT Application published as WO2021146322, the content of which is incorporated herein by reference in its entirety.
[0142] A method of determining responsiveness of a subject to a combination treatment comprising a PARP inhibitor and onvansertib can comprise, for example, analyzing circulating tumor DNA (ctDNA) of a subject with cancer, the subject is undergoing a treatment and/or has received the combination treatment, thereby determining the responsiveness of the subject to the combination treatment. 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 CR, or if the subject is or is going to be in partial remission (PR). For example, analyzing ctDNA can comprise detecting variant allele frequency in the ctDNA in a first sample obtained from the subject at a first time point, detecting variant allele frequency in the ctDNA obtained from the subject at one or more additional time points in one or more additional samples, and determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, a decrease in the variant allele frequency in at least one of the additional samples relative to the first sample indicates the subject as responsive to the cancer treatment.
[0143] In some embodiments, the first time point is prior or immediately prior to the combination treatment, and at least one of the one or more additional time points are at the end of or after at least a cycle of the combination treatment. In some embodiments, the cycle of the combination treatment is the first cycle of the combination treatment. In some embodiments, the first time point is prior or immediately prior to a first cycle of the combination treatment, and the
one or more additional time points are at the end of or after a second cycle of the combination treatment.
[0144] In some embodiments, the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment. In some embodiments, the method comprises continuing the combination treatment to the subject if the subject is indicated as responsive to the combination treatment. In some embodiments, the method comprises discontinuing the combination treatment to the subject and/or starting a different combination treatment to the subject if the subject is not indicated as responsive to the combination treatment.
[0145] Disclosed herein include methods of determining cancer status of a subject. In some embodiments, the method comprises analyzing circulating tumor DNA (ctDNA) of a subject, thereby determining cancer status of the subject. The subject can be a subject undergoing a current combination treatment comprising a PARP inhibitor and onvansertib, a subject that has received a prior combination treatment of the present disclosure, and/or a subject that is in remission for the cancer. The subject in remission for cancer can be in complete remission (CR), or in partial remission (PR).
[0146] In some embodiments, analyzing the ctDNA comprises detecting variant allele frequency in the ctDNA. In some embodiments, analyzing the ctDNA comprises detecting variant allele frequency in the ctDNA obtained from the subject at a first time point in a first sample, detecting variant allele frequency in the ctDNA obtained from the subject at one or more additional time points in one or more additional samples, and determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, an increase in the variant allele frequency at the additional sample(s) relative to the first sample indicates that the subject is at risk of cancer relapse or is in cancer relapse.
[0147] In some embodiments, the first time point is prior or immediately prior to the combination treatment, and the one or more additional time points are at the end of or after at least a cycle of the combination treatment, optionally the cycle of the combination treatment is the first cycle of the combination treatment. In some embodiments, the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment, optionally the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
[0148] In some embodiments, the method comprises starting an additional treatment to the subject if the subject is indicated as in cancer relapse. The additional treatment can be the same or different from the current or prior combination treatment.
[0149] The variant allele frequency in ctDNA can be determined, for example, by total
mutation count in the ctDNA in each of the first sample and one or more additional samples, or by the mean variant allele frequency in each of the first sample and one or more additional samples. In some embodiments, the variant allele frequency is mutant allelic frequency (MAF) for a driver mutation of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof). In some embodiments, the variant allele frequency is MAF for one or more driver mutations of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof). In some embodiments, Log2(Ci/Co) < a MAF threshold indicates a decrease in ctDNA MAF Co is ctDNA MAF in the first sample and Ci is ctDNA MAF in one of the additional samples. In some embodiments, the MAF threshold is, or is about, 0.01 to -0.10. In some embodiments, the MAF threshold is, or is about, 0.06. In some embodiments, the MAF threshold is, or is about, 0.05.
[0150] In some embodiments, the first sample comprises ctDNA from the subject before treatment, and the one of additional samples comprises ctDNA from the subject after treatment. In some embodiments, the driver mutation is a mutation in one of the below 75 genes: ABL1, ANKRD26, ASXL1, ATRX, BCOR, BCORL1, BRAF, BTK, CALR, CBL, CBLB, CBLC, CCND2, CDC25C, CDKN2A, CEBPA, CSF3R, CUX1, CXCR4, DCK, DDX41, DHX15, DNMT3A, ETNK1, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, IAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, LUC7L2, MAP2K1, MPL, MYC, MYD88, NF1, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PPM1D, PTEN, PTPN11, RAD21, RBBP6, RPS14, RUNX1, SETBP1, SF3B1, SH2B3, SLC29A1, SMC1A, SMC3, SRSF2, STAG2, STAT3, TET2, TP53, U2AF1, U2AF2, WT1, XPO1, andZRSR2. In some embodiments, at least one of the one or more the driver mutations is a mutation in the 75 genes. In some embodiments, one or more the driver mutations are mutations in the 75 genes.
[0151] The driver mutation or at least one of the one or more driver mutations can be in a gene selected from the group consisting of TP53, ASXL1, DNMT3A, NRAS, SRSF2, TET2, SF3B1, FLT3, FLT3 ITD, IDH2, NPM1, RUNX1, CDKN2A, KRAS, STAG2, CALR, CBL, CSF3R, DDX41, GATA2, JAK2, PHF6, and SETBP1. In some embodiments, the driver mutation or at least one of the one or more driver mutations is in a gene selected from the group consisting of DNMT3A, TET2, NPM1, SRSF2, NRAS, CDKN2A, SF3B1, FLT3, ASXL1, SRSF2, IDH2, NRAS, and SF3B1. In some embodiments, the method further comprises determining variant allele frequency in one or more of the ctDNA, PBMCs and BMMCs of the subject.
[0152] The ctDNA can be analyzed using, for example, polymerase chain reaction (PCR), next generation sequencing (NGS), and/or droplet digital PCR (ddPCR). The sample disclosed herein can be derived from, for example, whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof. In some embodiments, the ctDNA is from
whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
[0153] In some embodiments, the method comprises analyzing ctDNA of the subject before the treatment. In some embodiments, the treatment comprises one or more cycles, and the ctDNA is analyzed before, during and after each cycle of the treatment. Each cycle of treatment can be at least 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days. In some embodiments, the subject is human.
[0154] Disclosed herein include methods of improving treatment outcome for the cancer. The method can comprise: detecting variant allele frequency in circulating tumor DNA (ctDNA) obtained from a subject at a first time point in a first sample before the subject undergoes a combination treatment comprising a PARP inhibitor and onvansertib; detecting variant allele frequency in ctDNA obtained from the subject at one or more additional time points in one or more additional samples after the subject undergoes the combination treatment; determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, a decrease in the variant allele frequency in at least one of the additional samples relative to the first sample indicates the subject as responsive to the combination treatment; and continuing the combination treatment to the subject if the subject is indicated as responsive to the combination treatment, or discontinuing the combination treatment to the subject and/or starting a different cancer treatment to the subject if the subject is not indicated as responsive to the combination treatment.
[0155] Also disclosed herein include methods of treating cancer The method can comprise: administering a combination treatment comprising a PARP inhibitor and a PLK1 inhibitor of the present disclosure to a subject in need thereof; determining a decrease, relative to a variant allele frequency in a first sample of the subject obtained at a first time point before the subject receives the combination treatment, in a variant allele frequency in a second sample of the subject obtained at a second time point after the subject receives the combination treatment; and continuing with the combination treatment. In some embodiments, the subject is a subject newly diagnosed with cancer, for example a subject that has not received any prior cancer treatment before the combination treatment. In some embodiments, the subject has received prior cancer treatment and was in remission for the cancer, for example a subject in complete remission (CR), or in partial remission (PR) after receiving the prior combination treatment.
[0156] The first time point can be, for example, prior or immediately prior to the combination treatment. The at least one of the one or more additional time points can be, for example, at the end of or after at least a cycle of the combination treatment. In some embodiments, the cycle of the combination treatment is the first cycle of the combination treatment. In some embodiments, the first time point is prior or immediately prior to a first cycle of the combination
treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment. In some embodiments, the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
[0157] The variant allele frequency in ctDNA can be determined, for example, by total mutation count in the ctDNA in each of the first sample and one or more additional samples, and/or by the mean variant allele frequency in each of the first sample and one or more additional samples. In some embodiments, the variant allele frequency is mutant allelic frequency (MAF) for a driver mutation of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, or a combination thereof). In some embodiments, the variant allele frequency is mutant allelic frequency (MAF) for one or more driver mutations of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, or a combination thereof). In some embodiments, Log2(Ci/Co) < a MAF threshold indicates a decrease in ctDNA MAF Co is ctDNA MAF in the first sample and Ci is ctDNA MAF in one of the additional samples. In some embodiments, the MAF threshold is -0.05.
[0158] At least one of the one or more the driver mutations is a mutation in one of the below 75 genes: ABL1, ANKRD26, ASXL1, ATRX, BCOR, BCORL1, BRAF, BTK, CALR, CBL, CBLB, CBLC, CCND2, CDC25C, CDKN2A, CEBPA, CSF3R, CUX1, CXCR4, DCK, DDX41, DHX15, DNMT3A, ETNK1, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, LUC7L2, MAP2K1, MPL, MYC, MYD88, NF1, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PPM1D, PTEN, PTPN11, RAD21, RBBP6, RPS14, RUNX1, SETBP1, SF3B1, SH2B3, SLC29A1, SMC1A, SMC3, SRSF2, STAG2, STAT3, TET2, TP53, U2AF1, U2AF2, WT1, XPO1, and ZRSR2, and/or one or more the driver mutations are mutations in the 75 genes. In some embodiments, the driver mutation or at least one of the one or more driver mutations is in a gene selected from the group consisting of TP53, ASXL1, DNMT3A, NRAS, SRSF2, TET2, SF3B1, FLT3, FLT3 ITD, IDH2, NPM1, RUNX1, CDKN2A, KRAS, STAG2, CALR, CBL, CSF3R, DDX41, GATA2, IAK2, PHF6, and SETBP1. In some embodiments, the driver mutation or at least one of the one or more driver mutations is in a gene selected from the group consisting of DNMT3A, TET2, NPM1, SRSF2, NRAS, CDKN2A, SF3B1, FLT3, ASXL1, SRSF2, IDH2, NRAS, and SF3B1.
[0159] In some embodiments, the method further comprises determining variant allele frequency in one or more of the ctDNA, PBMCs and BMMCs of the subject. The variant allele frequency in ctDNA can be detected, for example, using polymerase chain reaction (PCR) or next generation sequencing (NGS). In some embodiments, the variant allele frequency in ctDNA is detected using droplet digital PCR (ddPCR).
[0160] At least one of the first sample, the one or more additional samples, and the
second sample can be derived from whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof. In some embodiments, the ctDNA is from whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
[0161] In some embodiments, the subject whose sample (e.g., tumor biopsy, ctDNA) is analyzed is undergoing or will be undergoing treatment for the cancer. The method can comprise analyzing the sample of the subject before the treatment. The treatment can comprise one or more cycles, and the sample is analyzed before, during and after one or more cycles of the treatment. For example, the sample can be analyzed before, during and after two or more cycle of the treatment, three or more cycle of the treatment, or each cycle of the treatment. Each cycle of treatment can be at least 21 days, for example, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or more, or a range between any two of these values. In some embodiments, each cycle of treatment is from about 21 days to about 28 days. In some embodiments, each cycle of treatment is from 21 days to 28 days. In some embodiments, the subject is human.
Compositions and Kits
[0162] Disclosed herein include compositions and kits for treating cancer. In some embodiments, a kit comprises: a Polo-like kinase 1 (PLK1) inhibitor (e.g., onvansertib); and a manual providing instructions for co-administrating onvansertib with a PARP inhibitor to a subject for treating cancer. In some embodiments, the kit comprises the PARP inhibitor (e.g., olaparib, niraparib, and/or AZD5305). The cancer can be, for example, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof. The cancer can be a homologous recombination (HR)-deficient cancer. The cancer can be a BRCAl-homozygous mutant cancer, a BRCA2 -homozygous mutant cancer, a BRCA1 -heterozygous mutant cancer, a BRCA2 -heterozygous mutant cancer or any combination thereof. The cancer can be homozygous wild type for BRCA1, BRCA2, or both.
[0163] In some embodiments, the instructions comprise instructions for coadministrating onvansertib and the PARP inhibitor simultaneously. In some embodiments, the instructions comprise instructions for co-administrating onvansertib and the PARP inhibitor sequentially. In some embodiments, the instructions comprise instructions for administering of onvansertib orally. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor orally.
[0164] In some embodiments, the instructions comprise instructions the subject has received a prior PARP inhibitor treatment. In some embodiments, the instructions comprise instructions the subject did not respond to treatment with the PARP inhibitor alone. In some
embodiments, the instructions comprise instructions the subject is known to be resistant to a PARP inhibitor therapy.
[0165] In some embodiments, the instructions comprise instructions the subject has received at least one prior treatment for the cancer. In some embodiments, the prior treatment does not comprise the use of a PARP inhibitor, a PLK inhibitor, or both. In some embodiments, the instructions comprise instructions the subject was in remission for the cancer. In some embodiments, the subject in remission for cancer was in complete remission (CR), or in partial remission (PR).
[0166] In some embodiments, the instructions comprise instructions for administering each of the PARP inhibitor and onvansertib to the subject in a cycle of at least twice within a week. In some embodiments, the instructions comprise instructions for administering each of the PARP inhibitor and onvansertib to the subject in a cycle of at least five times within a week In some embodiments, the instructions comprise instructions for administering the PARP inhibitor, onvansertib, or both are in a cycle of at least 7 days. In some embodiments, each cycle of treatment is at least about 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days, for example 28 days. The instructions can comprise instructions for administering onvansertib on at least four days, at least 14 days, or at least 21 days in the cycle. In some embodiments, the instructions comprise instructions for administering onvansertib on at least four days in the cycle. The instructions can comprise instructions for not administering onvansertib on at least one day, at least 7 days, at least 14 days, or at least 21 days in the cycle. In some embodiments, the instructions comprise instructions for not administering onvansertib on at least one day in the cycle. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor daily. In some embodiments, the instructions comprise instructions for administrating the PARP inhibitor and onvansertib for at least two cycles.
[0167] In some embodiments, the PARP inhibitor is selective and/or specific for PARP inhibition (e.g., PARP1 inhibitor, PARP2 inhibition, or both). In some embodiments, the PARP inhibitor is iniparib (BSI 201), talazoparib (BMN-673), AZD5305, olaparib (AZD-2281), rucaparib (AG014699, PF-01367338), ABT-888, veliparib (ABT-888), niraparib, CEP 9722, MK 4827, BGB-290 (pamiparib), BSI-201, CEP-8983, E7016, 3-aminobenzamide, or a combination thereof. In some embodiments, the PARP inhibitor is olaparib. In some embodiments, the PARP inhibitor is or NMS-293. In some embodiments, the PARP inhibitor is selected from olaparib, niraparib, and AZD5305. The kit can comprise the PARP inhibitor.
[0168] In some embodiments, the instructions comprise instructions for administering onvansertib at 6 mg/m2 - 90 mg/m2. In some embodiments, the instructions comprise instructions for administering the PARP inhibitor at 20 mg - 1200 mg.
[0169] The methods, compositions and kits disclosed herein can also be used to sensitize cancer cells to one or more PARP inhibitors. The method can comprise contacting cancer cells with a composition comprising a PLK1 inhibitor (e.g., onvansertib), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, thereby sensitizing the cancer cells to the one or more PARP inhibitors (e.g., olaparib, niraparib, or AZD5305). Contacting cancer cells with the composition can occur in vitro, ex vivo, in vivo, or in any combination. In some embodiments, contacting cancer cells with the composition is in a subject’s body. In some embodiments, cancer cells are contacted with the composition in a cell culture. The subject can be a mammal, for example a human. The sensitization of the cancer cells can increase the responsiveness of the cancer cells to the one or more PARP inhibitors by, or by about, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or a range between any two of these values. The sensitization of the cancer cells can increase the responsiveness of the cancer cells to the one or more PARP inhibitors by at least, or by at least about, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or a range between any two of these values. The increase of the responsiveness of the cancer cells is, in some embodiments, relative to the untreated cancer cells. The sensitization of the cancer cells can increase the responsiveness of the subject having the cancer cells to one or more PARP inhibitors by, or by about, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or a range between any two of these values. The sensitization of the cancer cells can increase the responsiveness of the subject having the cancer cells to the one or more PARP inhibitors by at least, or by at least about, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or a range between any two of these values. The increase of the responsiveness of the subject having the cancer cells is, in some embodiments, relative to the subjects untreated with the composition.
[0170] The method can comprise determining sensitization of the cancer cells to the one or more PARP inhibitors after being contacted with the PLK1 inhibitor (e.g., onvansertib). The method can comprise contacting the cancer cells with the one or more PARP inhibitors concurrently and/or after being contacted with onvansertib. In some embodiments, contacting the cancer cells with the one or more PARP inhibitors occurs in the body of a subject. The subject can be a mammal, for example human. The subject can be, for example, a subject that did not respond to, or is known to be resistant to, PARP inhibitors alone. The subject can be, for example, a subject that had prior treatment with one of the one or more PARP inhibitors. In some embodiments, the method comprises determining the response of the subject to the one or more PARP inhibitors.
[0171] In some embodiments, onvansertib and the PARP inhibitor produce an in vitro
synergistic effect. Synergy may be measured by various methods, including, for example, the Bliss synergy method. The Bliss value can be defined as the difference between the experimental response and the calculated Bliss Independence value. The Bliss value indicates whether the effect of two compounds in combination is merely additive or is synergistic. In some embodiments, a Bliss value of zero is considered additive, wherein the term “additive” means that the result of the combination of the two compounds is the sum of each compound individually, and the compounds are not considered synergistic. In some embodiments, a negative Bliss value indicates antagonism, wherein one of the compounds acts to inhibit the effect of the other. In some embodiments, a positive Bliss value indicates synergy, wherein the combined effect of the two compounds is greater than their sum. The higher the positive Bliss value, the greater the synergy of the two compounds. In some embodiments, the in vitro synergistic effect has a synergy score of, of about, of at least, or of at least about 10 to 80 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, 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 or a number or a range between any two of these values). In some embodiments, the in vitro synergistic effect has a synergy score of, of about, of at least, or of at least about 1 to about 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 or a number or a range between any two of these values). In some embodiments, the in vitro synergistic effect has a synergy score of, of about, of at least, or of at least about 10 to 80 in two or more cancer cell lines (e.g., OVCAR3 cell line, DU4475 cell line, PSN1 cell line).
[0172] Synergy scores can be assessed over a wide range of concentrations (e.g., over a dilution or concentration series). In some embodiments, the each of the concentrations of onvansertib used for assessment of synergy can be any value from about 1 nM to about 2000 nM (e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 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, 200, 300, 400,
500, 600, 700, 800, 900, 1000, 1500, 2000 nM, or a number between any two of these values).
[0173] In some embodiments, each of the concentrations of the PARP inhibitor (e.g., olaparib, niraparib, or AZD53O5) used for assessment of synergy can be any value from about 0.25 nM to about 10000 nM (e.g., about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 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, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 10000 nM, or a number between any two of these values).
[0174] Any of the methods, reagents, protocols and devices known in the art can be used in determining sensitization of the cancer cells to one or more PARP inhibitors. The cancer cells can be provided from any subject (e.g., a mammal). In some embodiments, the cancer cells comprise a sample from a patient (e.g., a biopsy sample). The method can comprise: determining sensitization of the cancer cells to the PARP inhibitor after being contacted with the composition.
[0175] Determining sensitization of the cancer cells to the PARP inhibitor can comprise measuring the proportion of cancer cells expressing one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof after the cancer cells are contacted with the composition and/or the PARP inhibitor. Markers for apoptosis, DNA damage, and cell cycle are known in the art. The one or more markers can comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof.
[0176] The proportion of cells expressing the one or more markers can be measured by any method known in the art. In one embodiment, the one or more markers are detected by immunofluorescence, mass cytometry (CyTOF), FACS, drop-seq, RNA-seq, single cell qPCR, MERFISH (multiplex (in situ) RNA FISH), microarray and/or by in situ hybridization. Other methods including absorbance assays and colorimetric assays are known in the art and may be used herein. In some aspects, measuring proportion of cells expressing the one or more markers comprises measuring protein expression levels. Protein expression levels may be measured, for example, by performing a Western blot, an ELISA, immunohistochemistry or binding to an antibody array. In another aspect, measuring expression of the one or more markers comprises measuring RNA expression levels. RNA expression levels may be measured by performing RT- PCR, Northern blot, an array hybridization, or RNA sequencing methods.
[0177] Below include non-limiting examples of proteins that can serve as markers for DNA damage and repair. Exemplary proteins mediating DNA repair include, but are not limited to, Ligase4, XRCC4, H2AX, DNAPKcs (DNA-PK), Ku70, Ku80, Artemis, Cernunnos/XLF, MRE11, NBS1, and RAD50. Exemplary homologous recombination proteins include RAD51, RAD52, RAD54, XRCC3, RAD51C, BRCA1, BRCA2 (FANCD1), FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ (BRIP1/BACH1), FANCL, FANCM, Chkl, Chk2, ATM, and ATR. Exemplary proteins mediating BER include, but are not limited to, UNG, SMUG1, MBD4, TDG, OFF1, MYH, NTH1, MPG, APE1, APE2, LIG3, XRCC1, ADPRT, ADPRTL2 and ADPRTL3. Exemplary proteins mediating MER include, but are not limited to, MSH2, MSH3, MSH4, MSH5, MSH6, PMS1, PMS3, MLH1, MLH3, PMS213 and PMS214. Exemplary DNA repair helicases include BLM and WRN. Exemplary proteins mediating NER
include, but are not limited to, XPA, XPB, XPC, XPD, XPF, XPG, XPV, RAD23B, USP7, RPA, CAK, ERCC1, RFC, LIG1, LIG3, CSA, CSB, PARP1, NEIL1, and APE1.
[0178] Methods for measuring apoptosis are also known in the art, and non-limiting examples of methods for measuring apoptosis are described below. Markers for apoptosis include caspases-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. In some embodiments, the marker for apoptosis is cleaved-caspase3, and elevated levels of cleaved-caspase3 are indicative of increased apoptosis. A TUNEL assay can be used. The TUNEL assay is a method for detecting apoptotic DNA fragmentation, and is a fluorescence based assay that detects 3 ’-hydroxyl termini of DNA double stranded breaks. Mitochondrial damage can also serve as a measure for apoptosis. For example, release of cytochrome c into the cytosol is associated with mitochondrial permeability. Annexin V assay can detect lipids associated with the inner leaflet of the plasma membrane, which is exposed during apoptosis.
[0179] Cell cycle (e.g., proliferation) can be assessed, e.g., by DAPI or other DNA stain. Exemplary cell replication protein markers include, but are not limited to, phosphorylated histone H3 (pH3), Ki-67 protein, phosphorylated MPM-2 antigen, Proliferating Cell Nuclear Antigen (PCNA, a protein that is expressed in the nuclei of cells during the DNA synthesis phase of the cell cycle), phospho-S780-Rb epitope, Cenp-F (mitosin), class III [1-Tubulin, spindle checkpoint protein hMad2, phosphorylated myosin light chain kinase, topoisomerase II, Check point kinase 1 (Chkl), Vesicular Monoamine Transporter 2 (VMAT2), loss of cyclin-dependent kinase 1 (Cdkl) kinase activity. Histone H3 can be phosphorylated at Ser28 or SerlO.
[0180] The proportion of cancer cells expressing at least one of the one or more markers can be increased by, by about, by at least, or by at least about 1.25 fold (e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10- fold or a number or a range between any two of these values, or more) after being contacted with the composition relative to cancer cells not contacted with the composition. The proportion of cancer cells expressing at least one of the one or more markers can be increased by, by about, by at least, or by at least about 1.25 fold (e.g., 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10-fold or a number or a range between any two of these values, or more) after being contacted with the composition and the PARP inhibitor relative to cancer cells contacted with the composition alone or the PARP inhibitor alone. In some embodiments, an increase in the proportion of cancer cells expressing at least one of the one or more markers indicates sensitization of the cancer cells to the PARP inhibitor.
EXAMPLES
[0181] 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
Onvansertib - PARPi Combination
[0182] This example demonstrates use of onvansertib - PARP inhibitor combination provided herein in treating various cancers.
Ovarian Cancer
[0183] The efficacy of onvansertib in combination with olaparib was tested in 2 intraperitoneal BRCAl-mutant high grade serous ovarian cancer (HGSOC) patient derived xenograft (PDX) models resistant to olaparib (MNH022 and MNHOC266). Treatment was tolerated, with no body weight loss exceeding 20%. The combination of onvansertib and olaparib was highly effective, inducing significant increase in survival in comparison to vehicle and single agent treatments in the 2 models (FIG. 4A-FIG. 4B).
[0184] For the experiments shown in FIG. 4A-FIG. 4B, tumor cells (#MNHOC22 and #MNHOC266) were intraperitoneally transplanted and mice were treated for 4 weeks with vehicle, onvansertib (50mg/kg, 5d/week), olaparib (80 mg/kg for MNHOC266 and lOOmg/kg for MNHOC22, 5days/week), or the combination of onvansertib + olaparib. For data in FIG. 4B, at day 295, 2 mice were still alive in the combination group and were sacrificed, and 1 mouse was tumor-free.
[0185] The efficacy of the PARP inhibitor and PLK1 combination was also tested in a PDX#218ola model (subcutaneous BRCA1 -mutated, induced olaparib resistance). Mice were treated with vehicle, olaparib (80 mg/kg), onvansertib (30 or 45 mg/kg) or the combination for 5 weeks. Body weight loss >20% was observed in 3/8 mice treated with the combination (onvansertib (onv) 45mg/kg), but no mice died of toxicity, and treatment was completed. As shown in FIG. 5A-FIG. 5B, combination treatments induced significant dose-dependent tumor growth inhibition compared to vehicle and single agents.
[0186] Next, the efficacy of onvansertib in combination with olaparib was tested in an intraperitoneal BRCAl-wild type (wt) HGSOC PDX model resistant to olaparib and cisplatin (MNHO316DDP). The treatment was well tolerated, as indicated in FIG. 6A. As shown in FIG. 6B, the combination of onvansertib and olaparib was effective, inducing significant increase in survival in comparison to cisplatin and single agent treatments. Tumor cells #MNHOC316DDP were intraperitoneally transplanted and mice were treated for 4 weeks with cisplatin (5mg/kg, weekly for 3 weeks), onvansertib (50mg/kg, 5d/week), olaparib (100 mg/kg, 5days/week), or the combination of onvansertib + olaparib.
[0187] The efficacy of onvansertib + olaparib was also tested in two subcutaneous BRCAl-wt HGSOC PDXs (#124 and #239). The combination showed toxicity: 2 mice died while
on treatment in the #124 model and 3 in #239model. The combination of onvansertib and olaparib showed limited activity in these 2 models (FIG. 7 and FIG. 8B). MNHOC124 and MNHOC239 tumor fragments were subcutaneously transplanted and mice were treated for 4 weeks with vehicle, onvansertib (50mg/kg for #124 and 40mg/kg for #239, 5d/week), olaparib (100 mg/kg for #124 and 80mg/kg for #239, 5days/week), or the combination of onvansertib + olaparib.
[0188] in vitro synergy analysis showed that onvansertib synergizes with PARP inhibitors in the OVCAR3 cell line (FIG. 9A-FIG. 9C).
Prostate Cancer
[0189] The efficacy of onvansertib in combination with olaparib was tested in 2 BRCA2-mutated (mono-allelic loss) prostate cancer models: CWR22-RH (androgen receptor positive, AR+) and LgCAP-CR (androgen receptor negative and neuroendocrine marks negative, AR-NE-). As shown in FIG. 10A-FIG. 10B, onvansertib but not olaparib induced significant tumor growth inhibition in the 2 models, and, in this model, the combination of onvansertib and olaparib showed similar activity as onvansertib single agent. Tumor fragments were subcutaneously transplanted in castrated NGS male mice. Mice were treated for 3 to 4 weeks with vehicle, onvansertib (50mg/kg, 5d/week), olaparib (75mg/kg, 5days/week), or the combination of onvansertib + olaparib. One-way ANOVA and Dunnett’s multiple comparison test were used to compare mean tumor volumes on Day 27 (CW22-RH) or Day 21 (LgCAP-CR), *p<0.05, *** p<0.001.
[0190] Two additional models were tested. Shown in FIG. 10C is tumor growth data from LuCaP86.2 (BRCA2-mutated (bi-allelic loss) CRPC model). The combination, but not the single agent, induced a significant tumor growth inhibition (83% at Day 24). Shown in FIG. 10D is data related to the BCAP-CR (BRCA-WT CRPC model). At Day 15, onvansertib and combination treatments induced significant tumor growth inhibition (TGI) compared to vehicle (62% and 80% respectively). At Day 26, the combination treatment induced significant superior TGI compared to single agents. Tumor fragments were subcutaneously transplanted in castrated NSG (immunodeficient) male mice. Mice were treated for with vehicle, onvansertib (50mg/kg, 5d/week) or olaparib (75mg/kg, 5days/week), or the combination of onvansertib + olaparib. For the LuCAP86.2 combination group was treated for 3 weeks, the other groups for 5 weeks. For the BCAP model, vehicle group was treated for 2 weeks, the other groups for 4 weeks. Kruskal-Wallis multiple comparison test were used to compare mean tumor volumes on Day 28 (LuCaP86.2) or Day 15 (BCaP-CR), *p<0.05; ** p<0.01; ****p<0.0001.
Breast Cancer
[0191] FIG. 11 shows results from a screen in which the combination of onvansertib + olaparib was tested in a panel of 63 cell lines. The triple-negative breast cancer (TNBC) cell
lines DU-4475 and HMC- 1-8 (both BRCAwt) showed high synergy score. As shown in FIG. 12A- FIG. 12C, the synergy was tested and confirmed in the DU4475 cell line and onvansertib synergizes with several PARP inhibitors in the DU4475 cell line.
[0192] Effects of the combination on apoptosis and DNA damage response was next tested in the DU4475 cell line (FIG. 13A-FIG. 13C). The combination of onvansertib and olaparib induced a time-dependent increase in cleaved-caspase3+ cells. The increase in cl-caspase3+ cells in the combination group was observed primarily in the subGl, G1 and S populations. Similarly, an increase in the apoptotic marker cleaved-PARP was observed by western blot in the combination group. DU4475 were treated with DMSO, onvansertib 50nM, olaparib 800nM or the combination during the indicated times.
[0193] y-H2AX is a marker of double strand DNA breaks (DSBs). The levels of this marker were measured in DU4475 cells following treatment as shown in FIG. 14A-FIG. 14C. The combination of onvansertib and olaparib induced a time-dependent increase in y-H2AX+ cells (WB and FACS). The increase in y-H2AX+ cells in the combination group was observed primarily in the G1 and S populations. DU4475 were treated with DMSO, onvansertib 50nM, olaparib 800nM or the combination during the indicated times. CHK1 and CHK2 are proteins that are involved in the DNA damage response, and are phosphorylated in response to DNA damage. An increase in pCHKl and pCHK2 at 48h was observed in the combination group vs olaparib alone as assessed by western blot (FIG. 15).
[0194] Analysis of cancer cells by DAPI stain found that at 24h, an increase in S phase was observed in the combination group (similarly to olaparib single agent). At 48h, the combination induced a G2/M increase similar to onvansertib single agent. At 72h, a marked increase in S Phase was observed in the combination group compared to the control and single agents (FIG. 16A-FIG. 16C). Shown in FIG. 17A-FIG. 17B are studies using DU4475 CDX. Onvansertib was administered at 40mg/kg, 5d/week; olaparib at 75mg/kg 5d/week for 4 weeks, 4mice/group.
Pancreatic Cancer
[0195] Results from the screen shown in FIG. 11 found that the pancreatic cancer cell lines KP-4 and PSN1 (both BRACwt) had the highest synergy scores of all cell lines tested. Further experiments found that Onvansertib synergizes with several PARP inhibitors in the PSN 1 cell line (FIG. 18A-FIG. 18C). The combination of onvansertib and olaparib in 2 pancreatic ductal adenocarcinoma (PDAC) cell lines (Panc-1 and MiaPaCa-2, both BRCAWT) was also tested. Onvansertib and olaparib had synergistic effect in both cell lines (FIG. 19A-FIG. 19D).
Example 2
Studies of olaparib and onvansertib combination in in vivo models
[0196] This prophetic example provides additional studies of olaparib and onvansertib combination in in vivo models.
[0197] The ovarian cancer PDX models PDX#154 (intrinsic resistance to olaparib) and CTG-0253 (BRCA2-mut, olaparib-resistant, platinum-resistant model) are tested. Additionally, the combination on patient-derived lines, in vivo on xenografts are tested. In vivo anti-tumor activity of onvansertib + olaparib are tested in syngeneic orthotopic models of PDAC: KPC (KRASm, p53m) BRCA WT and BRCA KO cell lines KMC (KRASm, MYC overexpressing) cell lines. Additional models include TNBC BRCA2m Olaparib-resistant PDX model.
[0198] 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.
[0199] 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 various 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.
[0200] 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.
[0201] 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.
[0202] 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.
[0203] 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
1. A method of treating cancer, the method comprising: administrating onvansertib and a Poly-(ADP-ribose) polymerase (PARP) inhibitor selected from the group consisting of olaparib, niraparib, and AZD5305 to a subject with cancer, thereby inhibiting progression of the cancer, wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
2. The method of claim I, wherein the cancer is a homologous recombinationdeficient cancer.
3. The method of any one of claims 1-2, wherein the cancer is a BRCAl-homozygous mutant cancer, a BRCA2 -homozygous mutant cancer, a B RCA 1 -heterozygous mutant cancer, a BRCA2 -heterozygous mutant cancer, or any combination thereof.
4. The method of any one of claims 1-3, wherein the cancer is homozygous wild type for BRCAl, BRCA2, or both.
5. The method of any one of claims 1-4, wherein the inhibition of cancer progression is greater than the combined inhibition of progression caused by the PARP inhibitor alone plus onvansertib alone.
6. The method of any one of claims 1-5, wherein inhibiting progression of the cancer comprises inhibition of growth of one or more tumors in the subject.
7. The method of claim 6, wherein the inhibition of growth of at least one of the one or more tumors in the subject is about 1.1 times greater, about 1.2 times greater, about 1.3 times greater, about 1.4 times greater, about 1.5 times greater, about 1.6 times greater, about 1.7 times greater, about 1.8 times greater, about 1.9 times greater, about 2 times greater, or more, than the inhibition of growth caused by onvansertib alone or the PARP inhibitor alone, following one or more cycles of treatment.
8. The method of claim 6, wherein the inhibition of growth of at least one of the one or more tumors in the subject is increased by about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% relative to a subject treated with onvansertib alone or the PARP inhibitor alone, following one or more cycles of treatment.
9. The method of claim 6, wherein the growth of at least one of the one or more tumors in the subject is inhibited by about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% relative to an untreated subject, following one or more cycles of treatment.
10. The method of claim 6, wherein the subject is tumor-free following one or more cycles of treatment.
11. The method of any one of claims 1-10, wherein onvansertib and the PARP inhibitor are co-administered simultaneously.
12. The method of any one of claims 1-10, wherein onvansertib and the PARP inhibitor are administered sequentially.
13. The method of claim 12, wherein onvansertib is administered prior to the administration of the PARP inhibitor, and optionally wherein onvansertib is administered prior to the administration of the PARP inhibitor every day on which the subject is administered with onvansertib and the PARP inhibitor; optionally wherein onvansertib is administered about 30 minutes to about 5 hours prior to the administration of the PARP inhibitor on a given day.
14. The method of any one of claims 1-13, wherein the administration of onvansertib is oral administration, the administration of the PARP inhibitor is oral administration, or both.
15. The method of any one of claims 1-14, wherein the subject achieves a complete response.
16. The method of any one of claims 1-15, wherein the subject has received a prior PARP inhibitor treatment.
17. The method of any one of claims 1-16, wherein the subject did not respond to treatment with the PARP inhibitor alone.
18. The method of any one of claims 1-17, wherein the subject is known to be resistant to a PARP inhibitor therapy.
19. The method of any one of claims 1-18, wherein onvansertib and the PARP inhibitor are each administered to the subject in a cycle of at least twice or at least five times within a week.
20. The method of any one of claims 1-19, wherein onvansertib, the PARP inhibitor, or both are administered in a cycle of at least 7 days; optionally each cycle of treatment is at least about 21 days; and further optionally each cycle of treatment is from about 21 days to about 28 days.
21. The method of any one of claims 19-20, wherein onvansertib is administered on at least four days, at least 14 days, or at least 21 days in the cycle.
22. The method of any one of claims 20-21, wherein onvansertib is not administered on at least one day, at least 7 days, at least 14 days, or at least 21 days in the cycle.
23. The method of any one of claims 1-22, wherein the PARP inhibitor is administered daily.
24. The method of any one of claims 1-23, wherein the subject undergoes at least two cycles of the administration of onvansertib and the PARP inhibitor.
25. The method of any one of claims 1-24, wherein the PARP inhibitor is selective and/or specific for PARP inhibition.
26. The method of any one of claims 1-25, wherein onvansertib is administered at 6 mg/m2 - 90 mg/m2.
27. The method of any one of claims 1-26, wherein a maximum concentration (Cmax) of onvansertib in a blood of the subject is from about 100 nmol/L to about 1500 nmol/L.
28. The method of any one of claims 1-27, wherein an area under curve (AUC) of a plot of a concentration of onvansertib in a blood of the subject over time is from about 1000 nmol/L.hour to about 400000 nmol/L.hour.
29. The method of any one of claims 1-28, wherein a time (Tmax) to reach a maximum concentration of onvansertib in a blood of the subject is from about 1 hour to about 5 hours.
30. The method of any one of claims 1-29, wherein an elimination half-life (T1/2) of onvansertib in a blood of the subject is from about 10 hours to about 60 hours.
31. The method of any one of claims 1-30, wherein the subject has received at least one prior cancer treatment, and optionally wherein the prior treatment does not comprise the use of a PARP inhibitor, onvansertib, or both.
32. The method of any one of claims 1-31, wherein the subject was in remission for cancer, optionally wherein the subject in remission for cancer was in complete remission (CR) or in partial remission (PR).
33. The method of any one of claims 1-32, further comprising one or more of (1) determining cancer status of the subject, (2) determining responsiveness of the subject to onvansertib treatment, and (3) administering one or more cancer therapeutics or therapies for the cancer.
34. The method of any one of claims 1-33, wherein the subject is human.
35. The method of any one of claims 1-34, further comprising measuring expression of one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof in the subject before and/or after the subject is administered with onvansertib and/or the PARP inhibitor; optionally wherein the one or more markers comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof.
36. The method of claim 35, wherein the expression of at least one of the one or more markers in the subject is increased by at least about 1.25 fold after being administered with both the onvansertib and the PARP inhibitor relative to the expression in the subject before being administered with both the onvansertib and the PARP inhibitor.
37. The method of claim 35, wherein the expression of at least one of the one or more markers in the subject is increased by at least about 1.25 fold after being administered with both the onvansertib and the PARP inhibitor relative to the expression in a subject being administered with onvansertib alone and/or the expression in a subject being administered with the PARP
inhibitor alone.
38. A method of sensitizing cancer cells to a PARP inhibitor, the method comprising: contacting cancer cells with a composition comprising onvansertib, thereby sensitizing the cancer cells to the PARP inhibitor, wherein the PARP inhibitor is selected from the group consisting of olaparib, niraparib, and AZD5305.
39. The method of claim 38, wherein onvansertib and the PARP inhibitor produce an in vitro synergistic effect, optionally wherein the in vitro synergistic effect has a synergy score of about 10 to about 80.
40. The method of any one of claims 38-39, wherein contacting cancer cells with the composition occurs in vitro, ex vivo, and/or in vivo.
41. The method of any one of claims 38-40, wherein contacting cancer cells with the composition is in a subject, and optionally wherein the subject did not respond to, or is known to be resistant to, the PARP inhibitor; optionally wherein the subject had prior treatment with the PARP inhibitor or a different PARP inhibitor; and further optionally wherein the subject is a mammal, and optionally the mammal is human.
42. The method of any one of claims 38-41, comprising determining sensitization of the cancer cells to the PARP inhibitor after being contacted with the composition.
43. The method of claim 42, wherein determining sensitization of the cancer cells to the PARP inhibitor comprises measuring the proportion of cancer cells expressing one or more markers for apoptosis, DNA damage, cell cycle or any combination thereof after the cancer cells are contacted with the composition and/or the PARP inhibitor; optionally wherein the one or more markers comprise cleaved-caspase3, y-H2AX, phosphorylated CHK1, phosphorylated CHK2, or any combination thereof.
44. The method of claim 43, wherein the proportion of cancer cells expressing at least one of the one or more markers is increased by at least about 1.25 fold after being contacted with the composition relative to cancer cells not contacted with the composition.
45. The method of claim 43, wherein the proportion of cancer cells expressing at least one of the one or more markers is increased by at least about 1.25 fold after being contacted with the composition and the PARP inhibitor relative to cancer cells contacted with the composition alone or the PARP inhibitor alone.
46. The method of any one of claims 38-45, comprising contacting the cancer cells with the PARP inhibitor, and optionally wherein contacting the cancer cells with the PARP inhibitor occurs in the subject and/or wherein the method further comprises determining the response of the subject to the PARP inhibitor.
47. The method of claim 46, wherein contacting the cancer cells with the PARP
inhibitor is concurrent with the contacting the cancer cells with the composition, or after the contacting the cancer cells with the composition.
48. A kit, comprising onvansertib; and a manual providing instructions for co-administrating onvansertib with a Poly- (ADP-ribose) polymerase (PARP) inhibitor to a subject for treating cancer, wherein the PARP inhibitor is olaparib, niraparib, or AZD53O5, and wherein the cancer is ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, or a combination thereof.
49. The kit of claim 48, wherein the cancer is a homologous recombination (HR)- deficient cancer.
50. The kit of any one of claims 48-49, wherein the cancer is a BRCA1 -homozygous mutant cancer, a BRCA2 -homozygous mutant cancer, a B RCA 1 -heterozygous mutant cancer, a BRCA2 -heterozygous mutant cancer or any combination thereof.
51. The kit of any one of claims 48-50, wherein the cancer is homozygous wild type for BRCAl, BRCA2, or both.
52. The kit of any one of claims 48-51, wherein the instructions comprise instructions for co-administrating onvansertib and the PARP inhibitor simultaneously.
53. The kit of any one of claims 48-51, wherein the instructions comprise instructions for co-administrating onvansertib and the PARP inhibitor sequentially.
54. The kit of any one of claims 48-53, wherein the instructions comprise (1) instructions for administering of onvansertib orally, (2) instructions for administrating the PARP inhibitor orally, or both.
55. The kit of any one of claims 48-54, wherein the instructions comprise instructions the subject has received a prior PARP inhibitor treatment.
56. The kit of any one of claims 48-55, wherein the instructions comprise instructions the subject did not respond to treatment with the PARP inhibitor alone.
57. The kit of any one of claims 48-56, wherein the instructions comprise instructions the subject is known to be resistant to a PARP inhibitor therapy.
58. The kit of any one of claims 48-57, wherein the instructions comprise instructions for administering each of the PARP inhibitor and onvansertib to the subject in a cycle of at least twice or at least five times within a week.
59. The kit of any one of claims 48-58, wherein the instructions comprise instructions for administering the PARP inhibitor, onvansertib, or both in a cycle of at least 7 days; and optionally wherein each cycle of treatment is at least about 21 days, and further optionally each cycle of treatment is from about 21 days to about 28 days.
60. The kit of claim 59, wherein the instructions comprise instructions for administering onvansertib on at least four days, at least 14 days, or at least 21 days in the cycle.
61. The kit of any one of claims 59-60, wherein the instructions comprise instructions for not administering onvansertib on at least one day, at least 7 days, at least 14 days, or at least 21 days in the cycle.
62. The kit of any one of claims 48-61, wherein the instructions comprise instructions for administrating the PARP inhibitor daily.
63. The kit of any one of claims 48-62, wherein the instructions comprise instructions for administrating the PARP inhibitor and onvansertib for at least two cycles.
64. The kit of any one of claims 48-63, wherein the PARP inhibitor is selective and/or specific for PARP1 and/or PARP2 inhibition.
65. The kit of any one of claims 48-64, wherein the instructions comprise instructions for administering onvansertib at 6 mg/m2 - 90 mg/m2.
66. The kit of any one of claims 48-65, wherein the instructions comprise instructions the subject has received at least one prior treatment for the cancer, and optionally wherein the prior treatment does not comprise the use of a PARP inhibitor, onvansertib, or both.
67. The kit of any one of claims 48-66, wherein the instructions comprise instructions the subject was in remission for cancer, and optionally wherein the subject in remission for cancer was in complete remission (CR) or in partial remission (PR).
68. The kit of any one of claims 48-67, further comprising the PARP inhibitor.
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US202263404895P | 2022-09-08 | 2022-09-08 | |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080167345A1 (en) * | 2007-01-10 | 2008-07-10 | Philip Jones | Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors |
US20170100368A1 (en) * | 2014-05-28 | 2017-04-13 | Eisai R&D Management Co., Ltd. | Use of eribulin and poly (adp ribose) polymerase (parp) inhibitors as combination therapy for the treatment of cancer |
-
2023
- 2023-09-07 WO PCT/US2023/073622 patent/WO2024054898A1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080167345A1 (en) * | 2007-01-10 | 2008-07-10 | Philip Jones | Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors |
US20170100368A1 (en) * | 2014-05-28 | 2017-04-13 | Eisai R&D Management Co., Ltd. | Use of eribulin and poly (adp ribose) polymerase (parp) inhibitors as combination therapy for the treatment of cancer |
Non-Patent Citations (2)
Title |
---|
CHIAPPA MICHELA, FEDERICA GUFFANTI; ALESSANDRA DECIO; ALESSANDRO ALIVERTI; FRANCESCA RICCI; EUGENIO SCANZIANI; FEDERICA CAMIN; ILA: "Abstract 3237: Combining PARP inhibition with the polo-like kinase 1 (PLK1) inhibitor onvansertib overcomes PARP inhibitor resistance", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 82, no. 12 Supplement, 15 June 2022 (2022-06-15), US, pages 1 - 4, XP093149521, ISSN: 0008-5472 * |
LI JIE, WANG RUIXIN, KONG YIFAN, BROMAN MEAGHAN M., CARLOCK COLIN, CHEN LONG, LI ZHIGUO, FARAH ELIA, RATLIFF TIMOTHY L., LIU XIAOQ: "Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer", MOLECULAR CANCER THERAPEUTICS, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 16, no. 3, 1 March 2017 (2017-03-01), US , pages 469 - 479, XP093149523, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-16-0361 * |
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