Combination therapy for tumors and methods of use

Abstract

Disclosed herein is the treatment of cancer by the combined administration of pnabulin and a PARP inhibitor, such as taprazopalide. Some embodiments disclosed herein relate to compositions comprising plinabulin and a PARP inhibitor, such as taprazopalide. Some embodiments relate to methods of treating cancer by administering plinabulin in combination with one or more PARP inhibitors.

Description

[0001] Cross-reference related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 451517, filed March 10, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to the fields of chemistry and medicine, and more specifically, to combination therapies for the treatment of cancer. Background Technology

[0004] The poly(ADP-ribose) polymerase (PARP) family plays many important roles in cellular processes, including regulating transcription, apoptosis, and DNA damage responses. (Rose et al., Front. Cell Dev. Biol., 8 (2020) (https: / / doi.org / 10.3389 / fcell.2020.564601)). PARP1 possesses poly(ADP-ribose) polymerase activity; when activated by DNA damage, it adds branched PAR chains to promote the recruitment of other repair proteins, thereby driving the repair of single-strand breaks in DNA. PARP inhibitors were among the first approved cancer drugs, specifically targeting DNA damage responses in BRCA1 / 2-mutated breast and ovarian cancers. Several PARP inhibitors are currently approved or undergoing clinical trials for the treatment of ovarian, breast, lung, pancreatic, fallopian tube, primary peritoneal, and prostate cancers.

[0005] Despite the success of PARP inhibitor therapy, treatment resistance is a widespread problem in clinical practice. More than 40% of patients with BRCA1 / 2 deficiency do not respond to PARP inhibitor treatment. (Li et al., Molecular Cancer, 19(107)(2020)(https: / / doi.org / 10.1186 / s12943-020-01227-0). Therefore, there is a need to improve anticancer therapies based on this treatment modality. Summary of the Invention

[0006] Some embodiments described herein include a method of treating cancer, comprising co-administering plinabulin and a PARP inhibitor to a subject in need. In some embodiments, plinabulin is administered intravenously. In some embodiments, the PARP inhibitor is administered orally. In some embodiments, the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, olaparib, rucaparib, veliparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397. In some embodiments, the PARP inhibitor is selected from the group consisting of: tprazole, niraparib, rucaparib, veriparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397. In some embodiments, the PARP inhibitor is tprazole. In some embodiments, the dosage of tprazole is 0.25 mg to 5 mg. In some embodiments, tprazole is administered once daily. In some embodiments, tprazole is administered twice daily. In some embodiments, the dosage of pannabuline is 10 mg / m². 2 Up to 40 mg / m 2 In some embodiments, the dosage of punabulin is 15 mg to 120 mg. In some embodiments, the dosage of punabulin is about 40 mg. In some embodiments, punabulin is administered once a week. In some embodiments, punabulin is administered twice a week. In some embodiments, punabulin is administered once every three weeks.

[0007] Some embodiments described herein include a pharmaceutical composition comprising pravabulin or a pharmaceutically acceptable salt thereof and a PARP inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is selected from the group consisting of tapolaparib, niraparib, olaparib, rucaparib, veriparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397. In some embodiments, the PARP inhibitor is selected from the group consisting of tapolaparib, niraparib, rucaparib, veriparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397. In some embodiments, the PARP inhibitor is tapolaparib.

[0008] Some embodiments described herein include a kit comprising: a first pharmaceutical composition comprising punabulin or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a PARP inhibitor.

[0009] In some embodiments, the first pharmaceutical composition is an intravenous formulation and the second pharmaceutical composition is an oral formulation. Attached Figure Description

[0010] Figure 1 It is a graph showing the average tumor volume after administration of the vector control, tprazole alone, ponabulin alone, and ponabulin and tprazole in the MDA-MB-231 human breast cancer xenograft model.

[0011] Figure 2 This is a bar graph showing the combined tumor wet weight at death after administration of the vector control, tprazole alone, ponabulin alone, and ponabulin and tprazole in the MDA-MB-231 human breast cancer xenograft model.

[0012] Figure 3 The graph shows the survival of animals in the MDA-MB-231 human breast cancer xenograft model after administration of the vector control, tprazole alone, punabulin alone, and punabulin and tprazole in combination.

[0013] Figure 4 It is a graph showing the effect of different treatments on weight changes over time. Detailed Implementation

[0014] This document discloses methods for treating cancer. In some embodiments, the methods include the combined administration of punabulin and a poly(ADP-ribose) polymerase (PARP) inhibitor. Administration of punabulin herein includes administration of a pharmaceutically acceptable salt or solvate (including hydrate) of punabulin. In some embodiments, punabulin is provided in a monohydrate form. Administration of the PARP inhibitor herein includes administration of a pharmaceutically acceptable salt of the PARP inhibitor.

[0015] As used herein, the terms “pharmaceutically acceptable salt” and “its pharmaceutically acceptable salt” are broad terms and should be given the common and customary meaning (and not limited to the particular or customary meaning) to those skilled in the art, and are not limited to salts prepared from pharmaceutically acceptable, non-toxic acids or bases. Suitable pharmaceutically acceptable salts include metal salts such as aluminum, zinc, alkali metal salts such as lithium, sodium, and potassium salts, and alkaline earth metal salts such as calcium and magnesium salts; organic salts such as salts of lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), procaine, and tris; salts of free acids and bases; inorganic salts such as sulfates, hydrochlorides, and hydrobromic acids; and other salts currently widely used in the pharmaceutical industry and listed in sources well known to those skilled in the art, such as the Merck Index. Any suitable component may be chosen to prepare the salt of the therapeutic agent described herein, provided that it is non-toxic and does not significantly interfere with the desired activity.

[0016] As used herein, the terms "co-administered," "in co-administration," or "combined administration" refer to the simultaneous biological effects of two or more agents or therapies on a subject, regardless of the actual timing or manner of administration. In one embodiment, the agents or therapies are administered simultaneously. In one such embodiment, combined administration is achieved by combining the agents in a single dosage form. In another embodiment, the agents or therapies are administered sequentially. In some embodiments, administration may be spaced at intervals, such as 30 minutes, 1 hour, 2 hours, 1 day, 2 days, 3 days, or 1 week. In one embodiment, the agents are administered via the same route, such as orally. In another embodiment, the agents are administered via different routes, such as one orally and the other intravenously.

[0017] Punablin

[0018] Punabulin, (3Z,6Z)-3-benzylidene-6-{[5-(2-methyl-2-propyl)-1H-imidazol-4-yl]methylene}-2,5-piperazinedione, is a synthetic analog of the natural compound phenylahistin. Punabulin can be readily prepared according to the methods and procedures detailed in U.S. Patent Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entirety.

[0019] In some implementations, punabrine is used at a concentration of approximately 1-50 mg / m². 2 Administered within a dose range corresponding to body surface area. In some embodiments, punabulin is administered at a dose of about 5 to about 50 mg / m². 2 Administered within a dose range corresponding to body surface area. In some embodiments, punabulin is administered at a dose of approximately 20 to approximately 40 mg / m². 2Administered within a dose range corresponding to body surface area. In some embodiments, punabulin is administered at a dose of approximately 15 to approximately 30 mg / m². 2Dosage range applied to body surface area. In some implementations, Punabulin is used at concentrations of approximately 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 0.5-11, 0.5-12, 0.5-13, 0.5-13.75, 0.5-14, 0.5-15, 0.5-16, 0.5-17, 0.5-18, 0.5-19, 0.5-20, 0.5-22.5, 0.5-25, 0.5-27.5, 0.5-30, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, and 1-13.7. 5, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22.5, 1-25, 1-27.5, 1-30, 1.5-2, 1.5-3, 1.5-4, 1.5-5, 1.5-6, 1.5-7, 1.5-8, 1.5-9, 1.5-10, 1.5-11 1.5-12, 1.5-13, 1.5-13.75, 1.5-14, 1.5-15, 1.5-16, 1.5-17, 1.5-18, 1.5-19, 1.5-20, 1.5-22.5, 1.5-25, 1.5-27.5, 1.5-30, 2.5-2, 2.5-3, 2.5-4 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-11, 2.5-12, 2.5-13, 2.5-13.75, 2.5-14, 2.5-15, 2.5-16, 2.5-17, 2.5-18, 2.5-19, 2.5-20, 2.5-22 0.5, 2.5-25, 2.5-27.5, 2.5-30, 2.5-7.5, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-13.75, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3- 22.5, 3-25, 3-27.5, 3-30, 3.5-6.5, 3.5-13.75, 3.5-15, 2.5-17.5, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-13.75, 4-14, 4-15, 4-16, 4-17 4-18, 4-19, 4-20, 4-22.5, 4-25, 4-27.5, 4-30, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-13.75, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-22.5, 5-25, 5-27.5, 5-30, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-13.75, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-22.5, 6-25, 6-27.5, 6-30, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-13.75, 7-14 7-15, 7-16, 7-17, 7-18, 7-19, 7-20, 7-22.5, 7-25, 7-27.5, 7-30, 7.5-12.5, 7.5-13.5, 7.5-15, 8-9, 8-10, 8-11, 8-12, 8-13, 8-13.75, 8-14, 8-15, 8-16, 8-17, 8-18, 8-19, 8-20, 8-22.5, 8-25 8-27.5, 8-30, 9-10, 9-11, 9-12, 9-13, 9-13.75, 9-14, 9-15, 9-16, 9-17, 9-18, 9-19, 9-20, 9-22.5, 9-25, 9-27.5, 9-30, 10-11, 10-12, 10-13, 10-13.75, 10-14, 10-15, 10-16, 10-17, 10-18, 1 0-19, 10-20, 10-22.5, 10-25, 10-27.5, 10-30, 10-40, 11.5-15.5, 12.5-14.5, 7.5-22.5, 8.5-32.5, 9.5-15.5, 15.5-24.5, 5-35, 17.5-22.5, 22.5-32.5, 25-35, 25.5-24.5, 27.5-32.5, 2-20, t 2.5-22.5, or 9.5-21.5 mg / m². 2 The dosage range is based on body surface area. In some embodiments, Punabulin is administered at doses of approximately 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5. 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 2 6.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / m 2The dosage range is based on body surface area. In some embodiments, pravapol is administered at doses less than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5. 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mg / m² 2 The dosage range is based on body surface area. In some embodiments, punabulin is administered at doses greater than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19. 5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / m² 2 The dosage range is based on body surface area. In some embodiments, punabulin is administered at approximately 10, 13.5, 20, or 30 mg / m². 2 Dosage administered based on body surface area. In some embodiments, punabulin is administered at approximately 20 mg / m². 2 Dosage application based on body surface area.

[0020] In some embodiments, the dose of pravastatin is about 5 mg to 100 mg, or about 10 mg to 80 mg. In some embodiments, the dose of pravastatin is about 15 mg to 100 mg, or about 20 mg to 80 mg. In some embodiments, the dose of pravastatin is about 15 mg to 60 mg. In some embodiments, the dose of pravastatin is about 0.5 mg to 3 mg, 0.5 mg to 2 mg, 0.75 mg to 2 mg, 1 mg to 10 mg, 1.5 mg to 10 mg, 2 mg to 10 mg, 3 mg to 10 mg, 4 mg to 10 mg, 1 mg to 8 mg, 1.5 mg to 8 mg, 2 mg to 8 mg, 3 mg to 8 mg, 4 mg to 8 mg, 1 mg to 6 mg, 1.5 mg to 6 mg, 2 mg to 6 mg, 3 mg to 6 mg, or about 4 mg to 6 mg. In some embodiments, the dosage of punabulin is about 2 mg-6 mg or 2 mg-4.5 mg. In some embodiments, the dosage of punabulin is about 5 mg-7.5 mg, 5 mg-9 mg, 5 mg-10 mg, 5 mg-12 mg, 5 mg-14 mg, 5 mg-15 mg, 5 mg-16 mg, 5 mg-18 mg, 5 mg-20 mg, 5 mg-22 mg, 5 mg-24 mg, 5 mg-26 mg, 5 mg-28 mg, 5 mg-30 mg, 5 mg-32 mg, 5 mg-34 mg, or 5 mg. -36mg, 5mg-38mg, 5mg-40mg, 5mg-42mg, 5mg-44mg, 5mg-46mg, 5mg-48mg, 5mg-50mg, 5mg-52mg, 5mg-5 4mg, 5mg-56mg, 5mg-58mg, 5mg-60mg, 7mg-7.7mg, 7mg-9mg, 7mg-10mg, 7mg-12mg, 7mg-14mg, 7mg-15mg , 7mg-16mg, 7mg-18mg, 7mg-20mg, 7mg-22mg, 7mg-24mg, 7mg-26mg, 7mg-28mg, 7mg-30mg, 7mg-32mg, 7 mg-34mg, 7mg-36mg, 7mg-38mg, 7mg-40mg, 7mg-42mg, 7mg-44mg, 7mg-46mg, 7mg-48mg, 7mg-50mg, 7mg- 52mg, 7mg-54mg, 7mg-56mg, 7mg-58mg, 7mg-60mg, 9mg-10mg, 9mg-12mg, 9mg-14mg, 9mg-15mg, 9mg-16 mg, 9mg-18mg, 9mg-20mg, 9mg-22mg, 9mg-24mg, 9mg-26mg, 9mg-28mg, 9mg-30mg, 9mg-32mg, 9mg-34mg,9mg-36mg、9mg-38mg、9mg-40mg、9mg-42mg、9mg-44mg、9mg-46mg、9mg-48mg、9mg-50mg、9mg-52mg、9mg-54mg、9mg-56mg、9mg-58mg、9mg-60mg、10mg-12mg、10mg-14mg、10mg-15mg、10mg-16mg、10mg-18mg、10mg-20mg、10mg-22mg、10mg-24mg、10mg-26mg、10mg-28mg、10mg-30mg、10mg-32mg、10mg-34mg、10mg-36mg、10mg-38mg、10mg-40mg、10mg-42mg、10mg-44mg、10mg-46mg、10mg-48mg、10mg-50mg、10mg-52mg、10mg-54mg、10mg-56mg、10mg-58mg、10mg-60mg、12mg-14mg、12mg-15mg、12mg-16mg、12mg-18mg、12mg-20mg、12mg-22mg、12mg-24mg、12mg-26mg、12mg-28mg、12mg-30mg、12mg-32mg、12mg-34mg、12mg-36mg、12mg-38mg、12mg-40mg、12mg-42mg、12mg-44mg、12mg-46mg、12mg-48mg、12mg-50mg、12mg-52mg、12mg-54mg、12mg-56mg、12mg-58mg、12mg-60mg、15mg-16mg、15mg-18mg、15mg-20mg、15mg-22mg、15mg-24mg、15mg-26mg、15mg-28mg、15mg-30mg、15mg-32mg、15mg-34mg、15mg-36mg、15mg-38mg、15mg-40mg、15mg-42mg、15mg-44mg、15mg-46mg、15mg-48mg、15mg-50mg、15mg-52mg、15mg-54mg、15mg-56mg、15mg-58mg、15mg-60mg、15mg-120mg、17mg-18mg、17mg-20mg、17mg-22mg、17mg-24mg、17mg-26mg、17mg-28mg、17mg-30mg、17mg-32mg、17mg-34mg、17mg-36mg、17mg-38mg、17mg-40mg、17mg-42mg、17mg-44mg、17mg-46mg、17mg-48mg、17mg-50mg、17mg-52mg、17mg-54mg、17mg-56mg、17mg-58mg、17mg-60mg、20mg-22mg、20mg-24mg、20mg-26mg、20mg-28mg、20mg-30mg、20mg-32mg、20mg-34mg、20mg-36mg、20mg-38mg、20mg-40mg、20mg-42mg、20mg-44mg、20mg-46mg、20mg-48mg、20mg-50mg、20mg-52mg、20mg-54mg、20mg-56mg、20mg-58mg、20mg-60mg、22mg-24mg、22mg-26mg、22mg-28mg、22mg-30mg、22mg-32mg、22mg-34mg、22mg-36mg、22mg-38mg、22mg-40mg、22mg-42mg、22mg-44mg、22mg-46mg、22mg-48mg、22mg-50mg、22mg-52mg、22mg-54mg、22mg-56mg、22mg-58mg、22mg-60mg、25mg-26mg、25mg-28mg、25mg-30mg、25mg-32mg、25mg-34mg、25mg-36mg、25mg-38mg、25mg-40mg、25mg-42mg、25mg-44mg、25mg-46mg、25mg-48mg、25mg-50mg、25mg-52mg、25mg-54mg、25mg-56mg、25mg-58mg、25mg-60mg、27mg-28mg、27mg-30mg、27mg-32mg、27mg-34mg、27mg-36mg、27mg-38mg、27mg-40mg、27mg-42mg、27mg-44mg、27mg-46mg、27mg-48mg、27mg-50mg、27mg-52mg、27mg-54mg、27mg-56mg、27mg-58mg、27mg-60mg、30mg-32mg、30mg-34mg、30mg-36mg、30mg-38mg、30mg-40mg、30mg-42mg、30mg-44mg、30mg-46mg、30mg-48mg、30mg-50mg、30mg-52mg、30mg-54mg、30mg-56mg、30mg-58mg、30mg-60mg、33mg-34mg、33mg-36mg、33mg-38mg, 33mg-40mg, 33mg-42mg, 33mg-44mg, 33mg-46mg, 33mg-48mg, 33mg-50mg, 33mg-52mg, 33mg-54mg, 33mg-56mg, 33mg-58mg, 33mg-60mg, 36mg-38mg, 36mg-40mg, 36mg-42mg, 36mg-44mg, 36mg-46mg, 36mg-48mg, 36mg-50mg, 36mg-52mg, 36mg-54mg, 36mg-56mg, 36mg-58mg, 36mg-60mg, 40mg-42mg, 40mg-44mg, 40mg-46mg, 40mg-48mg, 40mg-50mg, 40mg-52mg, 40mg-54mg, 40mg-56mg, 40mg-58mg, 40mg-60mg, 43mg-46mg, 43mg-48mg, 43mg-50mg, 43mg-52mg, 43mg-54mg, 43mg-56mg, 43mg-58mg, 42mg-60mg, 45mg-48mg, 45mg-50mg, 45mg-52mg, 45mg-54mg, 45mg-56mg, 45mg-58mg, 45mg-60mg, 48mg-50mg, 48mg-52mg, 48mg-54mg, 48mg-56mg, 48mg-58mg, 48mg-60mg, 50mg-52mg, 50mg-54mg, 50mg-56mg, 50mg-58mg, 50mg-60mg, 52mg-54mg, 52mg-56mg, 52mg-58mg, or 52mg-60mg. In some embodiments, the dose of punabulin is greater than about 0.5mg, 1mg, 1.5mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, about 10mg, about 12.5mg, about 13.5mg, about 15mg, about 17.5mg, about 20mg, about 22.5mg, about 25mg, about 27mg, about 30mg, or about 40mg. In some embodiments, the dose of punabulin is less than about 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, or about 50 mg.

[0021] In some implementations, the dose of punabrine is 40 mg.

[0022] In various embodiments, pranabuline is administered once, twice, or three times during a PARP inhibitor treatment cycle. In other embodiments, pranabuline is administered once daily, twice daily, three times daily, four times daily, every other day, once weekly, twice weekly, three times weekly, every other week, once every two weeks, and once every three weeks.

[0023] PARP inhibitors

[0024] The PARP inhibitors used herein may include any agent that inhibits the activity of poly(ADP-ribose) polymerase, including small molecules or biologics. Specific PARP inhibitors that may be used as described herein include tapolaparib (e.g., TALZENNA), niraparib (e.g., ZEJULA), olaparib (e.g., LYNPARZA), rucaparib (e.g., RUBRACA), veriparib (ABT-888), pamiparib (e.g., PARTRUVIX), NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397. Therefore, some embodiments include the combined administration of pravastatin and tapolaparib. In some embodiments, the PARP inhibitor is not olaparib.

[0025] In some embodiments, the dose of the PARP inhibitor used is the dose at which the PARP inhibitor is effective as a single agent. In other embodiments, the dose of the PARP inhibitor used in combination therapy is lower than the effective dose as a single agent.

[0026] In various embodiments, the dosage of the PARP inhibitor is 0.1 mg to 4000 mg, 0.25 mg to 3500 mg, 0.25 mg to 3000 mg, 0.25 mg to 2500 mg, 0.25 mg to 2000 mg, 0.25 mg to 1500 mg, 0.25 mg to 1000 mg, 0.25 mg to 600 mg, 0.5 mg to 600 mg, 0.75 mg to 600 mg, 1 mg to 600 mg, 150 mg to 600 mg, 200 mg to 600 mg, 300 mg to 600 mg, 0. 5mg-500mg, 0.5mg-200mg, 0.75mg-200mg, 1.0mg-100mg, 1.5mg-100mg, 2.0mg-100mg, 3.0mg-100mg, 4.0mg-100mg, 1.0mg-80mg, 1.5mg-80mg, 2.0mg-80mg, 3.0mg-80mg, 4.0mg-80mg, 1.0mg-60mg, 1.5mg-60mg, 2.0mg-60mg, 3.0mg-60mg, or approximately 4.0mg-60mg.

[0027] In various implementations, the PARP inhibitor is administered once daily, twice daily, three times daily, four times daily, every other day, once weekly, once every two weeks, and once every three weeks.

[0028] In various embodiments, the dosage of tapolaparib is 0.1 mg to 5 mg, 0.25 mg to 5 mg, 0.2 mg to 4 mg, 0.25 mg to 3 mg, 0.5 mg to 2 mg, 0.75 mg to 1.5 mg, or about 1 mg. In some embodiments, the dosage of tapolaparib is 0.25 mg. In some embodiments, the dosage of tapolaparib is 0.5 mg. In some embodiments, the dosage of tapolaparib is 0.75 mg. In some embodiments, the dosage of tapolaparib is 1 mg. In some embodiments, tapolaparib is administered once daily. In some embodiments, tapolaparib is administered twice daily.

[0029] In various embodiments, the dosage of niraparib is 50 mg to 500 mg, 100 mg to 400 mg, 150 mg to 350 mg, or 200 mg to 300 mg. In some embodiments, the dosage of niraparib is 200 mg. In some embodiments, the dosage of niraparib is 300 mg. In some embodiments, niraparib is administered once daily. In some embodiments, the dosage of niraparib is 300 mg. In some embodiments, niraparib is administered twice daily.

[0030] In various embodiments, the dosage of olaparib is 50 mg to 500 mg, 75 mg to 400 mg, 100 mg to 350 mg, or 100 mg to 300 mg. In some embodiments, the dosage of olaparib is 100 mg. In some embodiments, the dosage of olaparib is 150 mg. In some embodiments, the dosage of olaparib is 300 mg. In some embodiments, olaparib is administered once daily. In some embodiments, olaparib is administered twice daily.

[0031] In various embodiments, the dosage of rucaparib is 50 mg to 500 mg, 100 mg to 1000 mg, 200 mg to 800 mg, or 300 mg to 600 mg. In some embodiments, the dosage of rucaparib is 300 mg. In some embodiments, the dosage of rucaparib is 400 mg. In some embodiments, the dosage of rucaparib is 500 mg. In some embodiments, the dosage of rucaparib is 600 mg. In some embodiments, rucaparib is administered once daily. In some embodiments, rucaparib is administered twice daily.

[0032] In various embodiments, the dosage of pamiparib is 10 mg to 100 mg, 30 mg to 80 mg, 50 mg to 70 mg, or about 60 mg. In some embodiments, the dosage of pamiparib is 60 mg. In some embodiments, pamiparib is administered once daily. In some embodiments, pamiparib is administered twice daily.

[0033] Pharmaceutical Composition

[0034] In some embodiments, punabulin and the PARP inhibitor are administered in the same pharmaceutical composition. In other embodiments, punabulin and the PARP inhibitor are administered in separate pharmaceutical compositions.

[0035] The pharmaceutical compositions described herein can be administered via any recognized mode of administration, including but not limited to oral, sublingual, buccal, subcutaneous, intravenous, intranasal, topical, transdermal, intradermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the pharmaceutical compositions are administered orally and / or parenterally. In some embodiments, pufabulin is administered intravenously, and the PARP inhibitor is administered orally.

[0036] In various embodiments, the pharmaceutical composition comprises an active agent (e.g., punabulin and / or a PARP inhibitor) and one or more pharmaceutically acceptable carriers or excipients. The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, etc. Such media and reagents are well known in the art for use with pharmaceutically active substances. Unless any conventional media or reagent is incompatible with the active ingredient, its use in therapeutic compositions is considered. Furthermore, various adjuvants commonly used in the art may be included. Considerations for including various components in a pharmaceutical composition are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman, *Pharmacological Basis of Therapeutics*, 8th ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0037] Some examples of substances that can serve as pharmaceutically acceptable carriers or components of other substances are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; tragacanth gum; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols, such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as TWEENS; wetting agents, such as sodium lauryl sulfate; colorants; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0038] The compositions described herein are preferably provided in unit dosage forms. As used herein, "unit dosage form" means a composition comprising a compound or composition suitable for a single dose to an animal (preferably a mammalian subject) according to good medical practice. However, the preparation of a single dose or unit dosage form does not imply that the dosage form is administered once daily or once per course of treatment. Such dosage forms are contemplated for administration once, twice, three or more times daily, and may be administered as an infusion over a period of time (e.g., about 30 minutes to about 2-6 hours), or as a continuous infusion, and may be administered multiple times during a course of treatment, although single administration is not specifically excluded. Those skilled in the art will recognize that this formulation does not specifically consider the entire course of treatment, and such decisions are left to those skilled in the art of treatment rather than those skilled in the art of formulation.

[0039] Depending on the specific route of administration required, a variety of pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotalcites, surfactants, and encapsulating substances. Optional pharmaceutically active materials may be included that do not substantially interfere with the inhibitory activity of the compound or composition. The amount of carrier used in conjunction with the compound or composition is sufficient to provide the actual amount of material per unit dose of the compound administered. Techniques and compositions for preparing dosage forms that can be used in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmacy, 4th Edition, Chapters 9 and 10 (Banker & Rhodes, eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004).

[0040] Various oral dosage forms can be used, including solid forms such as tablets, capsules (e.g., solid gelatin capsules and liquid gelatin capsules), granules, and bulk powders. In some embodiments, the PARP inhibitor is provided in such oral dosage forms. Tablets can be compressed, tablet-formulated, enteric-coated, sugar-coated, film-coated, or multi-compressed, containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, and meltsinks. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent particles, and effervescent formulations reconstituted from effervescent particles, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, meltsinks, colorants, and flavorings.

[0041] Tablets typically contain pharmaceutically compatible adjuvants such as inert diluents like calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders like starch, gelatin, and sucrose; disintegrants like starch, alginate, and croscarmellose sodium; and lubricants like magnesium stearate, stearic acid, and talc. Flow aids such as silica can be used to improve the flow properties of powder mixtures. Colorants, such as FD&C dyes, can be added to improve appearance. Sweeteners and flavorings, such as aspartame, saccharin, menthol, peppermint, and fruit flavorings, are effective adjuvants for chewable tablets. Capsules typically contain one or more of the aforementioned solid diluents. The choice of carrier components depends on secondary considerations such as taste, cost, and storage stability, which are not critical and can be readily determined by those skilled in the art.

[0042] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers used in syrups, elixirs, emulsions, and suspensions include ethanol, glycerin, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth gum, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as the sweeteners, flavoring agents, and coloring agents described above.

[0043] Such compositions can also be coated using conventional methods, typically pH- or time-dependent coatings, to release the subject composition in the gastrointestinal tract near the desired application, or at various times to prolong the desired action. Such dosage forms typically include, but are not limited to, one or more of the following: cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coating, waxes, and shellac.

[0044] Other useful compositions for achieving systemic delivery of the subject compound include sublingual, buccal, and nasal dosage forms. Such compositions typically contain one or more soluble fillers, such as sucrose, sorbitol, and mannitol; and binders, such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. They may also include the aforementioned flow aids, lubricants, sweeteners, colorants, antioxidants, and flavoring agents.

[0045] Liquid compositions formulated for topical ophthalmic use are formulated for topical application to the eye. Comfort should be maximized as much as possible, although sometimes formulation considerations (such as drug stability) may necessitate a lower level of comfort than optimal. Where maximizing comfort cannot be achieved, the liquid may be formulated to be tolerable for topical ophthalmic use. Additionally, ophthalmologically acceptable liquids may be packaged for single use or contain preservatives to prevent contamination during repeated use.

[0046] For ophthalmic applications, physiological saline solutions are typically used as the primary carrier for preparing solutions or medications. Ophthalmic solutions are preferably maintained at a comfortable pH using a suitable buffering system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0047] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, polyhexylguanidine (PHMB), chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Useful surfactants are, for example, Tween 80. Similarly, various useful carriers may be used in the ophthalmic preparations disclosed herein. These carriers include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water.

[0048] Tension modulators may be added as needed or as convenient. These include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerol, or any other suitable ophthalmologically acceptable tension modulator.

[0049] Various buffers and pH adjustment methods can be used, provided the resulting formulation is ophthalmologically acceptable. For many compositions, the pH will be between 4 and 9. Therefore, buffers include acetate buffer, citrate buffer, phosphate buffer, and borate buffer. The pH of these formulations can be adjusted using acids or bases as needed.

[0050] Ophthalmologically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0051] Other excipient components that can be included in ophthalmic preparations are chelating agents. A useful chelating agent is disodium edetate, but other chelating agents can be used instead or in combination with it.

[0052] For topical application, creams, ointments, gels, solutions, or suspensions containing the compositions disclosed herein are used. Topical formulations typically consist of a drug carrier, a cosolvent, an emulsifier, a penetration enhancer, a preservative system, and an emollient.

[0053] For intravenous administration, the compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or glucose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the final composition has a pH range of 2 to 8, or preferably 4 to 7. Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfite, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as glucose, mannitol, and dextran. Other acceptable excipients are described in Powell et al., Overview of Excipients in Parenteral Preparations, PDA J Pharm Sci and Tech 1998, 52238-311, and Nema et al., Excipients in Approved Injectable Products and Their Roles: Current Use and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve bacteriostatic or antifungal solutions, including but not limited to phenylmercuric nitrate, thimerosal, benzyl chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0054] Intravenous compositions may be provided to caregivers in one or more solid forms, which are reconstituted with a suitable diluent (such as sterile water, saline, or glucose solution) shortly before administration. In other embodiments, the composition is provided as a ready-to-use solution for parenteral administration. In still other embodiments, the composition is provided as a solution that is further diluted before administration.

[0055] In some embodiments, purnabulin for intravenous administration is provided as a pharmaceutical composition comprising one or more pharmaceutically acceptable diluents. In some embodiments, the pharmaceutically acceptable diluent may include... (Polyethylene glycol (15)-hydroxystearate). In some embodiments, the pharmaceutically acceptable diluent may include propylene glycol. In some embodiments, the pharmaceutically acceptable diluent may include Kolliphor (Kolliphor HS15) and propylene glycol. In some embodiments, the pharmaceutically acceptable diluent may include Kolliphor and propylene glycol, wherein the content of Kolliphor is about 40% by weight and the content of propylene glycol is about 60% by weight based on the total weight of the diluent. In some embodiments, the composition may also contain one or more other pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition may be diluted prior to administration, for example, with water, saline, or D5W (5% glucose solution).

[0056] Treatment

[0057] In some embodiments, pravabulin and a PARP inhibitor are co-administered to treat cancer. In various embodiments, the cancer comprises a homologous recombination repair-deficient tumor. In some embodiments, the cancer comprises a mutation in a homologous recombination repair gene. In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation. In various embodiments, the cancer is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, and prostate cancer.

[0058] In some embodiments, pranabulin is administered after the administration of the PARP inhibitor. In other embodiments, pranabulin is administered before or simultaneously with the administration of the PARP inhibitor. In some embodiments, pranabulin is administered 1 minute to 5 hours, 5 minutes to 4 hours, 10 minutes to 3.5 hours, 30 minutes to 3 hours, 30 minutes to 2 hours, 30 minutes to 1.5 hours, 1 hour to 2.5 hours, about 1 hour, or about 2 hours after the administration of the PARP inhibitor. In some embodiments, pranabulin is administered 1 minute to 5 hours, 5 minutes to 4 hours, 10 minutes to 3.5 hours, 30 minutes to 3 hours, 30 minutes to 2 hours, 30 minutes to 1.5 hours, 1 hour to 2.5 hours, about 1 hour, or about 2 hours before the administration of the PARP inhibitor.

[0059] In some embodiments, pranabulin is administered on the day PARP inhibitor treatment begins. In other embodiments, pranabulin is administered on the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and / or tenth days after the start of PARP inhibitor treatment.

[0060] In some embodiments of the treatment, farnesyl pyrophosphate synthase (FPPS) inhibitors are not administered co-administered with punabulin and PARP inhibitors. In some embodiments of the treatment, immune checkpoint inhibitors (e.g., pembrolizumab) are not administered co-administered with punabulin and PARP inhibitors. In some embodiments, subjects receiving co-administration of punabulin and PARP inhibitors have not previously received immune checkpoint inhibitor treatment. In some embodiments of the treatment, compounds having the structure of formula (I) are not administered co-administered with punabulin and PARP inhibitors:

[0061]

[0062] in:

[0063] R 1It is -COOH, -COOR 1a -COO(CH2) m C(O)NR 1a R 2a -CONHR 1b -COR 4 or -CONH(CH2) m COOR 2b ;

[0064] R 2 Is it -CH(O) or -CH(=NOR) 1a );

[0065] R 3 It is H, -C(O)R 1a Optional substitution of -C 1-10 Alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl group, optionally substituted C 3-7 Cycloalkyl, optionally substituted 3-8 membered heterocyclic groups, optionally substituted 5-6 membered monosaccharide rings, optionally substituted C 6-10 Aryl, or optionally substituted 5-10 heteroaryl;

[0066] R 4 These are amino acid residues linked by an N-terminal amine;

[0067] Each R 1a R 2a R 1b and R 2b Independently selected from -H, halogen -OH, -COOH, -COO(C 1-4 Alkyl), optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl group, optionally substituted C 3-7 Cycloalkyl, optionally substituted 3-8 membered heterocyclic groups, optionally substituted 5-6 membered monosaccharide rings, optionally substituted C 6-10 aryl, or optionally substituted 5-10 heteroaryl; and

[0068] m is an integer between 0 and 3.

[0069] In some embodiments of the treatment, compounds having the structure of formula (II) are not administered in combination with punabulin and PARP inhibitors:

[0070]

[0071] in:

[0072] Y1 Selected from hydroxyl, C 1-4 Alkylamino and having C 1-4 Acylamino groups of alkyl moieties;

[0073] Y 2 Y 3 and Y 4 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkyl, trifluoromethyl, hydroxy, and benzyloxy; and

[0074] Q 1 yes Among them, Q 2 and Q 3 Independently selected from hydrogen and C 1-4 alkyl;

[0075] X is selected from cyano, carboxyl or their derivatives, 5-tetrazole, and those having their C group. 1-6 The alkyl moiety is alkylsulfonyl carbamoyl; and

[0076] n is 0 or an integer selected from 1, 2, 3, 4, 5, and 6.

[0077] To further illustrate the present invention, the following embodiments are included. Of course, these embodiments should not be construed as specifically limiting the invention. Variations of these embodiments within the scope of the claims of the invention are within the capabilities of those skilled in the art and are considered to fall within the scope of the invention described and claimed herein. The reader will recognize that those skilled in the art, with knowledge of this disclosure, can prepare and use the invention without exhaustive examples.

[0078] Example

[0079] The antitumor activity of punabulin as a single agent compared with tprazole in the MDA-MB-231 human breast cancer xenograft model in Athymic nude mice was evaluated.

[0080] Punabulin is provided as a 4 mg / mL solution in a solvent of 40% Solutol and 60% propylene glycol. Before use, dilute the solution with D5W and mix gently to obtain a clear solution with a concentration of 0.75 mg / mL. A dose of 7.5 mg / kg is delivered at a dosing volume of 10 mL / kg.

[0081] Taprazoparib is provided in crystalline solid form. Prior to administration, weigh an appropriate amount of taprazoparib solid and dissolve it in DMA, then add Kolliphor (Solutol) HS15 and PBS sequentially to a final concentration of 0.0165 mg / mL. The final ratio is 10% DMA, 5% Kolliphor (Solutol) HS, and 85% PBS. Taprazoparib is administered as a clear solution at a concentration of 0.0165 mg / mL, delivering a dose of 0.165 mg / kg at a dosage volume of 10 mL / kg.

[0082] The carrier control consisted of 8% Kolliphor (Solutol) HS15, 12% propylene glycol, and 80% D5W, freshly prepared before each administration. The carrier control was administered intraperitoneally at a dose volume of 10 mL / kg.

[0083] The MDA-MB-231 human breast tumor cell line was maintained in RPMI-1640 containing 5% FBS and 1% penicillin / streptomycin. Cells were cultured in a 5% CO2 atmosphere. The culture was expanded in tissue culture flasks at a split ratio of 1:5 until a sufficient number of cells were harvested. Cells were harvested using a 0.25% trypsin / EDTA mixture.

[0084] Female Athymic nude mice (Crl:NU(NCr)-Foxn1) nu Mice were received at 5 weeks of age. All mice were acclimatized for at least 5–7 days before the start of the study. Mice were housed in microisolated enclosures and maintained under specific pathogen-free conditions. Mice were fed TekladGlobal Diet 2920x irradiated laboratory animal diet and had free access to autoclaved water. DietGel76A was provided as a supplemental nutrient as needed.

[0085] Female mice were anesthetized with isoflurane and inoculated with 0.1 mL of a solution containing 1×10⁻⁶ mg / L of urea solution into the fat pad of the mammary gland in the right inguinal region. 7 A 50% RPMI-1640 / 50% Matrigel mixture of live MDA-MB-231 tumor cell suspension per mouse. Mice were 6 weeks old at the time of inoculation.

[0086] Monitor the tumor-bearing animals and measure the tumors regularly until they reach the designated initial size. 28 days post-inoculation, tumors in 40 animals were measured to be 76-128 mm in size. 3 Mice were randomly divided into four groups of 10 each, with an average tumor volume of 96 mm. 3Tumor volume and body weight were recorded upon randomization and subsequently twice weekly. Clinical observation was performed daily. As shown in Table 1, the carrier control group and the punabulin group were administered via intraperitoneal injection, while the tirazopal group was administered via oral gavage. Tirazopal was administered twice daily (BID) at eight-hour intervals. On days of combined administration, punabulin was administered one hour after the morning administration of tirazopal.

[0087] Table 1 Study Groups

[0088]

[0089] *On the day of combined administration, punabrine is administered 1 hour after taprazole is administered in the morning (AM).

[0090] The interval between BID administrations is 8 hours.

[0091] When the mouse reached the individual tumor volume endpoint (greater than or equal to 1,500 mm), 3 Euthanasia was performed at day 60. At the end of the study, all remaining mice that had not reached the tumor volume endpoint were euthanized as long-term survivors.

[0092] At the individual mouse endpoint or the end of the study (day 60), the mice were euthanized and the tumors were removed. The wet weight of the tumors was recorded, and the tissues were then discarded.

[0093] The mean tumor growth inhibition rate (TGI) on day 33 (the last day of the study for all mice) was calculated using the following formula. All mice were included in the TGI calculation.

[0094]

[0095] All statistical analyses in the xenotransplantation study were performed using GraphPad Prism software. p ≤ 0.05 was considered statistically significant.

[0096] One-way ANOVA, unpaired, parametric tests, and Tukey's multiple comparison test were used to confirm differences in tumor volume and percentage changes in body weight at days 33, 43, and 51. A two-tailed Student's test with Welch correction was also used to verify any differences between each group and the vector control group, as well as between the single drug and its respective combination groups.

[0097] Increased survival scores were confirmed using a log-rank test, and each treatment group was compared to the vector control group. All animals that reached the individual tumor volume endpoint or were sacrificed as long-term survivors (LTS) were included in the statistical analysis. These data were used to calculate the mean and median survival for each group and to perform log-rank comparisons. For statistical analysis purposes, any mouse sacrificed as an LTS was designated as day 60.

[0098] The vector control group [Group 1] produced 1004.7 mm on day 33. 3 The mean tumor volume was [data missing]. The median survival in this group was 42 days (minimum: 33, maximum: 60). Nine out of ten mice were euthanized when their individual tumor volume reached the endpoint. The remaining mouse was euthanized on day 60 and recorded as a long-term survivor. At necropsy, the mean wet tumor weight in this group was 1,136.5 mg (n=10), with the smallest individual tumor weight being 652 mg and the largest being 1,838 mg.

[0099] Treatment with taporabárib 0.165 mg / kg [Group 2] resulted in a tumor size of 405.7 mm on day 33. 3 The mean tumor volume was [not specified]. Compared with the vector control group at day 33, this group produced 65.9% (n=10) of the TGI. Statistically significant reductions in mean tumor volume were observed at days 33 and 43 compared with the vector control group (ANOVA and Student's t-test; p<0.05). The median survival in this group was 60 days (min: 51, maximum: 60). Statistically significant increases in survival were observed compared with the vector control group. Four out of ten mice were sacrificed upon reaching the individual tumor volume endpoint. The remaining six mice were euthanized on day 60 and recorded as long-term survivors. At necropsy, the mean tumor wet weight in this group was 1,040.4 mg (n=10), with a minimum individual tumor weight of 591 mg and a maximum of 1,703 mg.

[0100] Treatment with pannabulin 7.5 mg / kg [Group 3] resulted in a tumor size of 385.2 mm on day 33. 3The mean tumor volume was [not specified]. Compared with the vector control group on day 33, this group produced 68.2% (n=10) of the TGI. Statistically significant reductions in mean tumor volume were observed on days 33 and 43 compared with the vector control group (ANOVA and Student's t-test; p<0.05). No significant differences in mean tumor volume were observed on days 33, 43, and 51 compared with tprazole monotherapy (Group 2). The median survival in this group was 60 days (min: 51, maximum: 60). Two out of ten mice were euthanized upon reaching the individual tumor volume endpoint. Mice 3 were euthanized on day 46 due to severe abdominal distension. The remaining seven mice were euthanized on day 60 and recorded as long-term survivors. At necropsy, the mean tumor wet weight in this group was 721.9 mg (n=10), with a minimum individual tumor weight of 371 mg and a maximum of 1,250 mg.

[0101] Treatment with taporabárib 0.165 mg / kg + ponabulin 7.5 mg / kg [Group 4] resulted in a tumor size of 363.5 mm on day 33. 3 The mean tumor volume was [data missing]. Compared with the vector control group on day 33, this group produced 70.6% (n=10) of the TGI. Statistically significant reductions in mean tumor volume were observed on days 33, 43, 51, and 60 compared with the vector control group (ANOVA and Student's t-test; p<0.05). Furthermore, statistically significant reductions in mean tumor volume were observed on days 43 and 60 compared with tprazole monotherapy (Group 2) (Student's t-test; p<0.05); however, no significant difference in mean tumor volume was observed on days 33 and 51 compared with tprazole monotherapy (Group 2). Additionally, no significant difference in mean tumor volume was observed on days 33, 43, 51, and 60 compared with punabulin monotherapy (Group 3). The median survival in this group was 60 days (min: 60, maximum: 60).

[0102] The effect of different treatments on mean tumor volume (using the last observed value carried forward) is as follows: Figure 1 As shown. The average wet weight of the tumor obtained at the end of the procedure is as follows. Figure 2 As shown. Notably, the combination therapy (Group 4) produced the greatest efficacy, with a TGI of 71% on day 33. TGIs of tprazole monotherapy (Group 2) and punabulin monotherapy (Group 3) were 66% and 68%, respectively, on day 33.

[0103] Efficacy was also assessed by tumor growth delay (survival) compared to the vector control group. The effect of treatment on survival (including tumor-related deaths only) was as follows: Figure 3As shown. Tprazole treatment (Group 2), punabulin treatment (Group 3), and tprazole + punabulin treatment (Group 4) all achieved a median survival of 60 days; compared with the vector control group, the median survival increased by 18 days. Tprazole + punabulin (Group 4) clearly prevented all mice from reaching the tumor volume endpoint (≥1,500 mm) on day 60. 3 ).

[0104] These results demonstrate the improved efficacy of the combination of tapolaparib and punabulin. Without being limited to the single-mechanism theory, combinations of these types of drugs allow for complementary mechanisms of action, thus inhibiting tumor growth more effectively than either drug alone. In some embodiments, combinations according to this disclosure can utilize the unique mechanisms of the disclosed drugs to achieve synergistic anticancer effects. For example, punabulin's interference with microtubule dynamics may enhance the accumulation of DNA damage by simultaneously disrupting cell division, while PARP inhibitors may exacerbate deficiencies in the cell's ability to repair such damage. In some embodiments, this combination can lead to increased DNA damage, thereby enhancing apoptosis (programmed cell death) in cancer cells. Furthermore, combinations of punabulin, PARP inhibitors, and optionally one or more anticancer compounds may help overcome resistance to monotherapy or dual therapy. Combinations of these therapies can also extend the therapeutic potency of one or more compounds of this disclosure to a wider range of cancers.

[0105] Figure 4 This study demonstrates the effects of different treatments on weight changes over time and can be used as a surrogate indicator for assessing drug toxicity in animal studies. Group 1, the carrier control group, showed healthy weight gain, indicating no drug-induced toxicity. Groups 2 and 3, treated with tapolaparib and punabulin respectively, also showed weight gain relative to Group 1. Group 4, receiving a combination of tapolaparib and punabulin, also showed weight gain. Despite the administration of two drugs, which could potentially produce an additive toxicity effect leading to greater weight changes, the curves for this group remained similar to those for the control group, indicating that the combination did not exacerbate the toxicity of either drug alone. This result may be counterintuitive, as combining two drugs might be expected to increase overall toxicity.

[0106] Therefore, in some embodiments, the combination of tprazole and punabulin can reduce the side effects typically associated with PARP inhibitors such as tprazole. Furthermore, in some embodiments, the combination of tprazole and punabulin can reduce neutropenia, a common side effect of decreased white blood cell counts in PARP inhibitor cancer treatment.

[0107] Figure 4It was also shown that higher total doses of the drug could be administered without increasing side effects, as the combination therapy group maintained a similar weight to the control group. Therefore, in some embodiments, this disclosure provides more flexible dosing regimens that achieve therapeutic effects without the increased toxicity typically associated with higher total drug doses.

Claims

1. A method for treating cancer, comprising co-administering punabrine and a PARP inhibitor to a subject in need.

2. The method as described in claim 1, characterized in that, Punabrine is administered intravenously.

3. The method as described in claim 1 or 2, characterized in that, The PARP inhibitor is administered orally.

4. The method according to any one of claims 1-3, characterized in that, The PARP inhibitors are selected from the following group: tapolaparib, niraparib, olaparib, rucaparib, veriparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297 and RBN-2397.

5. The method according to any one of claims 1-3, characterized in that, The PARP inhibitors are selected from the following group: tapolaparib, niraparib, rucaparib, veriparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297 and RBN-2397.

6. The method according to any one of claims 1-3, characterized in that, The PARP inhibitor is taprazole.

7. The method as described in claim 6, characterized in that, The dosage of tapolaparib is 0.25 mg to 5 mg.

8. The method as described in claim 6 or 7, characterized in that, Tapazoli is administered once daily.

9. The method as described in claim 6 or 7, characterized in that, Taprazopride is administered twice daily.

10. The method according to any one of claims 1-9, characterized in that, The dosage of purnabulin is 10 mg / m². 2 Up to 40 mg / m 2 .

11. The method according to any one of claims 1-9, characterized in that, The dosage of purnabulin is 15 mg to 120 mg.

12. The method as described in claim 11, characterized in that, The dosage of purnabulin is approximately 40 mg.

13. The method according to any one of claims 1-12, characterized in that, Punabrine is applied once a week.

14. The method according to any one of claims 1-12, characterized in that, Punabrine is applied twice a week.

15. The method according to any one of claims 1-12, characterized in that, Punabrine is applied once every three weeks.

16. A pharmaceutical composition comprising punabrine or a pharmaceutically acceptable salt thereof and a PARP inhibitor or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of claim 16, characterized in that, The PARP inhibitors are selected from the following group: tapolaparib, niraparib, olaparib, rucaparib, veriparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297 and RBN-2397.

18. The pharmaceutical composition of claim 16, characterized in that, The PARP inhibitors are selected from the following group: tapolaparib, niraparib, rucaparib, veriparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297 and RBN-2397.

19. The pharmaceutical composition of claim 16, characterized in that, The PARP inhibitor is taprazole.

20. A reagent kit comprising: A first pharmaceutical composition comprising punabulin or a pharmaceutically acceptable salt thereof; and A second pharmaceutical composition containing a PARP inhibitor.

21. The kit according to claim 20, characterized in that, The first pharmaceutical composition is an intravenous preparation, and the second pharmaceutical composition is an oral preparation.

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