CHE YUXUAN (US)
LI YIJING (US)
LIU YANG (US)
YAO YIXIN (US)
LIAO SUE JIN A/K/A SUE JIN YI (US)
WO2010075074A1 | 2010-07-01 | |||
WO2018017410A1 | 2018-01-25 | |||
WO2018063873A1 | 2018-04-05 |
CH3279951A |
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CLAIMS 1. A method of treating mantle cell lymphoma in a patient in need thereof, said method comprising administering to said patient an effective amount of abemaciclib or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a PI3K and/or a mTOR inhibitor or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein the PI3K and/or mTOR inhibitor is a dual PI3K/mTOR inhibitor. 3. The method of claim 1, wherein the PI3K and/or mTOR inhibitor is a pan PI3K inhibitor. 4. The method of claim 1, wherein the PI3K and/or mTOR inhibitor is selected from: Copanlisib; Samotolisib; BGT-226; DS-7423; PF-04691502; PKI-179; Omipalisib; Panulisib; SB2343/VS-5584; Dactolisib; Paxalisib Apitolisib ; Bimiralisib (PQR309); Voxtalisib; SF-1126; Gedatolisib; XH00230381967, SN20229799306; Pictilisib; Sonolisib; TG100–115; CH5132799; Pilaralisib; ZSTK474; Buparlisib; Fimepinostat; Rigosertib; AZD8835; WX-037; AZD8186; KA2237; Acalisib; Zandelisib; AMG 319; GSK2636771; Parsaclisib; Serabelisib; Umbralisib; Tenalisib; Taselisib; Alpelisib; Duvelisib; and idelalisib; sirolimus, nab-rapamycin, temsirolimus, everolimus, ridaforolimus; OSI-027; vistusertib; sapanisertib (MLN0128/INK128/TAK-228); Torkinib; ML-223; and AZD8055; and prodrugs, metabolites, and derivatives thereof, and pharmaceutically acceptable salts thereof. 5. The method of claim 1, wherein the PI3K and/or mTOR inhibitor is copanlisib or a pharmaceutically acceptable salt thereof. 6. The method of claim 1, wherein the mantle cell lymphoma has acquired resistance to one or more BCL-2 inhibitors. 7. The method of claim 1, wherein the mantle cell lymphoma has acquired resistance to venetoclax. 8. The method of claim 1, wherein the mantle cell lymphoma has acquired resistance to ibrutinib. 9. The method of claim 1, wherein the mantle cell lymphoma is selected from, or characterised as one of, nodal mantle cell lymphoma; and leukaemic non-nodal mantle cell lymphoma. 10. The method of claim 1, wherein the mantle cell lymphoma is selected from, or characterised as, refractory and/or relapsed mantle cell lymphoma. 11. The method of claim 1, wherein said mantle cell lymphoma is associated with one or more mutations in: ATM; TP53; CCND1; KMT2D; CDK2NA; BIRC3; CDKN2B; KHSC1; SMARCA4; SDHD; UBR5; NOTCH1; CARD11; SAMHD1; BCL10; MEF2B; IRS2; FGF19; FGF4; FGF3; FAT1; ROBO1; DIS3; CRLF2; CDKN2C; ARID2; ARID1A; ARID1B; NOTCH2; BCOR; TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3. 12. The method of claim 1, wherein said mantle cell lymphoma is associated with cyclin D1 overexpression; t(11;14) and/or t(11;14)(q13;q32) translocation; Ki67 overexpression; lactate dehydrogenase overexpression; and/or beta-2 microglobulin overexpression. 13. The method of claim 1, wherein said mantle cell lymphoma is retinoblastoma protein (Rb) proficient. 14. The method of claim 1, wherein said method comprises further administering to the patient an effective amount of a BTK inhibitor. 15. The method of claim 1, wherein said method comprises further administering to the patient an effective amount of one or more additional agents selected from fulvestrant or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; AR inhibitors; immune-checkpoint inhibitors such as PD-L1 or PD-1 inhibitors; CDK4/6 inhibitors; AKT inhibitors; cyclinE/CDK2 inhibitors; autophagy inhibitors; anti-EGFR inhibitors; and PARP inhibitors. 16. A combination of abemaciclib or a pharmaceutically acceptable salt thereof and a PI3K and/or mTOR inhibitor or a pharmaceutically acceptable salt thereof, for use in treating mantle cell lymphoma in a patient in need thereof. 17. Abemaciclib or a pharmaceutically acceptable salt thereof for use in treating mantle cell lymphoma in a patient in need thereof, wherein said use comprises administering to said patient said abemaciclib or pharmaceutically acceptable salt thereof in combination with a PI3K and/or mTOR inhibitor or a pharmaceutically acceptable salt thereof. 18. A PI3K and/or mTOR inhibitor or a pharmaceutically acceptable salt thereof for use in treating mantle cell lymphoma in a patient in need thereof, wherein said use comprises administering to said patient said PI3K and/or mTOR inhibitor or pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof. 19. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 18, wherein said use comprises the simultaneous, separate or sequential administration of said abemaciclib or pharmaceutically acceptable salt thereof and said PI3K and/or mTOR inhibitor or pharmaceutically acceptable salt thereof to said patient. 20. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 19, wherein the PI3K and/or mTOR inhibitor is a dual PI3K/mTOR inhibitor. 21. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 20, wherein the PI3K and/or mTOR inhibitor is a pan PI3K inhibitor. 22. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 21, wherein the PI3K and/or mTOR inhibitor is selected from: Copanlisib; Samotolisib; BGT-226; DS-7423; PF- 04691502; PKI-179; Omipalisib; Panulisib; SB2343/VS-5584; Dactolisib; Paxalisib Apitolisib ; Bimiralisib (PQR309); Voxtalisib; SF-1126; Gedatolisib; XH00230381967, SN20229799306; Pictilisib; Sonolisib; TG100–115; CH5132799; Pilaralisib; ZSTK474; Buparlisib; Fimepinostat; Rigosertib; AZD8835; WX-037; AZD8186; KA2237; Acalisib; Zandelisib; AMG 319; GSK2636771; Parsaclisib; Serabelisib; Umbralisib; Tenalisib; Taselisib; Alpelisib; Duvelisib; and idelalisib; sirolimus, nab-rapamycin, temsirolimus, everolimus, ridaforolimus; OSI-027; vistusertib; sapanisertib (MLN0128/INK128/TAK-228); Torkinib; ML-223; and AZD8055; and prodrugs, metabolites, and derivatives thereof, and pharmaceutically acceptable salts thereof. 23. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 22, wherein the PI3K and/or mTOR inhibitor is copanlisib or a pharmaceutically acceptable salt thereof. 24. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 23, wherein the mantle cell lymphoma has acquired resistance to one or more BCL-2 inhibitors. 25. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 24, wherein the mantle cell lymphoma has acquired resistance to venetoclax. 26. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 25, wherein the mantle cell lymphoma has acquired resistance to ibrutinib. 27. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 26, wherein the mantle cell lymphoma is selected from, or characterised as one of, nodal mantle cell lymphoma; and leukaemic non-nodal mantle cell lymphoma. 28. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 27, wherein the mantle cell lymphoma is selected from, or characterised as, refractory and/or relapsed mantle cell lymphoma. 29. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 28, wherein said mantle cell lymphoma is associated with one or more mutations in: ATM; TP53; CCND1; KMT2D; CDK2NA; BIRC3; CDKN2B; KHSC1; SMARCA4; SDHD; UBR5; NOTCH1; CARD11; SAMHD1; BCL10; MEF2B; IRS2; FGF19; FGF4; FGF3; FAT1; ROBO1; DIS3; CRLF2; CDKN2C; ARID2; ARID1A; ARID1B; NOTCH2; BCOR; TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3. 30. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 29, wherein said mantle cell lymphoma is associated with cyclin D1 overexpression; t(11;14) and/or t(11;14)(q13;q32) translocation; Ki67 overexpression; lactate dehydrogenase overexpression; and/or beta-2 microglobulin overexpression. 31. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 30, wherein said mantle cell lymphoma is retinoblastoma protein (Rb) proficient. 32. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 31, wherein said use comprises further administering to the patient an effective amount of a BTK inhibitor. 33. A combination for use, abemaciclib for use, or a PI3K and/or mTOR inhibitor for use according to any one of claims 16 to 32, wherein said use comprises further administering to the patient an effective amount of one or more additional agents selected from fulvestrant or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; AR inhibitors; immune-checkpoint inhibitors such as PD-L1 or PD-1 inhibitors; CDK4/6 inhibitors; AKT inhibitors; cyclinE/CDK2 inhibitors; autophagy inhibitors; anti-EGFR inhibitors; and PARP inhibitors. 34. Use of a combination of abemaciclib or a pharmaceutically acceptable salt thereof and a PI3K and/or mTOR inhibitor or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating mantle cell lymphoma in a patient in need thereof. 35. Use of abemaciclib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating mantle cell lymphoma in a patient in need thereof by administering to said patient said abemaciclib or pharmaceutically acceptable salt thereof in combination with a PI3K and/or mTOR inhibitor or a pharmaceutically acceptable salt thereof. 36. Use of a PI3K and/or mTOR inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating mantle cell lymphoma in a patient in need thereof by administering to said patient said PI3K and/or mTOR inhibitor or pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof. 37. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor as defined in any one of claims 34 to 36, wherein: - said PI3K and/or mTOR inhibitor is as defined in any one of claims 20 to 23; - said medicament is for treating mantle cell lymphoma as defined in any one of claims 24 to 31; and/or - said treatment is as defined in any one of claims 19 or 32 to 33. |
Alpelisib (BYL719), (2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan- 2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarbox amide, is a potent and selective PI3K inhibitor with nanomolar IC50 against PI3Kα/β/γ/δ. Alpelisib is of structure Duvelisib (IPI-145), 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6- ylamino)ethyl]isoquinolin-1-one, is a potent and selective PI3K inhibitor with nanomolar IC50 against PI3Kδ. Duvelisib is of structure Idelalisib (CAL-101), 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6- ylamino)propyl]quinazolin-4-one, is a potent and selective PI3K inhibitor with nanomolar IC50 against PI3Kδ. Idelalisib is of structure Other PI3K inhibitors include WX-037 and KA2237. mTOR inhibitors include the following compounds: Sirolimus, rapamycin, (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S ,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3- methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,2 9,35-hexamethyl- 11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26 ,28-tetraene-2,3,10,14,20- pentone, is a potent and selective mTOR inhibitor with nanomolar IC50. Nab-rapamycin, is nanoparticle albumin-bound rapamycin. Temsirolimus, [(1R,2R,4S)-4-[(2R)-2- [(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R) -1,18-dihydroxy- 19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pe ntaoxo-11,36-dioxa-4- azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12 -yl]propyl]-2- methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate, is a potent inhibitor of mTOR with micromolar IC50. Everolimus, (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R )-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)- 3- methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,2 9,35-hexamethyl- 11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26 ,28-tetraene-2,3,10,14,20- pentone, is a Rapamycin derivative and a potent, selective and orally active mTOR1 inhibitor. Ridaforolimus, (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,3 5R)-12-[(2R)-1-[(1S,3R,4R)-4-dimethylphosphoryloxy-3-methoxy cyclohexyl]propan- 2-yl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexam ethyl-11,36-dioxa-4- azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2 ,3,10,14,20-pentone , is a Rapamycin derivative and a potent, selective and orally active mTOR1 inhibitor. OSI-027, 4-[4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[5,1-f][1,2,4]t riazin- 7-yl]cyclohexane-1-carboxylic acid, is a potent and selective mTOR inhibitor with nanomolar IC50. OSI-027 is of structure
Vistusertib (AZD2014), 3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3- d]pyrimidin-7-yl]-N-methylbenzamide, is a potent and selective mTOR inhibitor with nanomolar IC50. Sapanisertib (MLN0128/INK128/TAK-228), 5-(4-amino-1-propan-2- ylpyrazolo[3,4-d]pyrimidin-3-yl)-1,3-benzoxazol-2-amine, is a potent and selective mTOR inhibitor with nanomolar IC50. Sapanisertib is of structure Torkinib (PP242), 2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H- indol-5-ol, is a potent and selective mTOR inhibitor with nanomolar IC50. AZD8055, [5-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimid in-7- yl]-2-methoxyphenyl]methanol, is a potent and selective mTOR inhibitor with nanomolar IC50. AZD8055 is of structure Other mTOR inhibitors include ML-223. Dual PI3K and mTOR inhibitors include the following compounds: Samotolisib (LY3023414), 8-[5-(2-hydroxypropan-2-yl)pyridin-3-yl]-1-[(2S)-2- methoxypropyl]-3-methylimidazo[4,5-c]quinolin-2-one, potently and selectively inhibits class I PI3K isoforms, DNA-PK and mTORC1/2 with IC50s of 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM and 165 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, DNA-PK and mTOR, respectively. Samotolisib potently inhibits mTORC1/2 at low nanomolar concentrations. BGT-226, 8-(6-methoxypyridin-3-yl)-3-methyl-1-[4-piperazin-1-yl-3- (trifluoromethyl)phenyl]imidazo[4,5-c]quinolin-2-one, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR. BGT-226 is of structure PF-04691502, 2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6- methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7-one, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR. PF- 04691502 is of structure PKI-179, 1-[4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-y l)-1,3,5- triazin-2-yl]phenyl]-3-pyridin-4-ylurea, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR. PKI-179 is of structure
Omipalisib (GSK2126458/GSK458), 2,4-difluoro-N-[2-methoxy-5-(4-pyridazin- 4-ylquinolin-6-yl)pyridin-3-yl]benzenesulfonamide, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR. Panulisib (P7170), [8-[6-amino-5-(trifluoromethyl)pyridin-3-yl]-1-[6-(2- cyanopropan-2-yl)pyridin-3-yl]-3-methylimidazo[4,5-c]quinoli n-2-ylidene]cyanamide, is a potent PI3K and mTOR dual inhibitor. SB2343/VS-5584, 5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6- yl)pyrimidin-2-amine, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR. SB2343 is of structure Dactolisib (BEZ235), 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3- ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR. Paxalisib (GDC-0084), 5-(6,6-dimethyl-4-morpholin-4-yl-8,9- dihydropurino[8,9-c][1,4]oxazin-2-yl)pyrimidin-2-amine, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR. Apitolisib (GDC-0980), (2S)-1-[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4- morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1 -yl]-2-hydroxypropan-1- one, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR. Bimiralisib (PQR309), 5-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)-4- (trifluoromethyl)pyridin-2-amine, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR Voxtalisib (SAR245409/XL765), 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7-one, is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/β/γ/δ and mTOR. SF-1126, (2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneam ino)-2- [[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4- yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propa noyl]amino]-3- hydroxypropanoate, is a potent PI3K and mTOR dual inhibitor. SF-1126 is of structure Gedatolisib (PF-05212384/PKI-587), 1-[4-[4-(dimethylamino)piperidine-1- carbonyl]phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- yl)phenyl], is a potent PI3K and mTOR dual inhibitor with nanomolar IC50s against PI3Kα/γ and mTOR. Other dual PI3K and mTOR inhibitors include DS-7423, XH00230381967, and SN20229799306. In preferred embodiments of the invention, the PI3K and/or mTOR inhibitor is copanlisib or a pharmaceutically acceptable salt thereof. Subject In some embodiments, the patient is a human subject. In some embodiments the patient is a human female subject. In some embodiments the patient is a human male subject. In some embodiments the patient is aged from about 18 to about 80 years, such as from about 20 to about 75, e.g. from about 25 to about 60 such as from about 30 to about 50 years. Often the patient is less than 60 years of age, such as less than 55 years, e.g. less than 50 years, such as less than 45 years, e.g. less than 40 years of age. Mantle cell lymphoma may be characterised according to the Mantle Cell International Prognostic Index (MIPI). Patients may be assigned in accordance with the following table ECOG PS, Eastern Cooperative Oncology Group Performance Status; LDH (ULN), lactate dehydrogenase (upper limit of the normal range); WBC, white blood cell (leukocyte) count. Total point score: 0–3, low; 4–5, intermediate and 6–11, high risk. In some embodiments, the subject may have stage 1 mantle cell lymphoma. Stage 1 mantle cell lymphoma is typically associated with detected lymphoma at one lymph node region or a single organ. In some embodiments, the subject may have stage 2 mantle cell lymphoma. Stage 2 mantle cell lymphoma is typically associated with detected lymphoma at two or more lymph node regions on the same side of the diaphragm. In some embodiments, the subject may have stage 3 mantle cell lymphoma. Stage 3 mantle cell lymphoma is typically associated with detected lymphoma at two or more lymph node regions above and below the diaphragm. In some embodiments, the subject may have stage 4 mantle cell lymphoma. Stage 4 mantle cell lymphoma is typically associated with widespread disease in lymph nodes and/or other parts of the body. The stage of the mantle cell lymphoma can be readily assessed by the skilled person In some embodiments the patient may have cancer metastatic to one or more sites selected from lung/pleura, liver, bone, breast/chest wall, soft tissue, distant lymph nodes, regional lymph nodes, central nervous system/brain, bone marrow, bloodstream, and bowel. In some embodiments the patient has one or more mutations associated with mantle cell lymphoma. In some embodiments the patient has one or more mutations in one or more of ATM; TP53; CCND1; KMT2D; CDK2NA; BIRC3; CDKN2B; KHSC1; SMARCA4; SDHD; UBR5; NOTCH1; CARD11; SAMHD1; BCL10; MEF2B; IRS2; FGF19; FGF4; FGF3; FAT1; ROBO1; DIS3; CRLF2; CDKN2C; ARID2; ARID1A; ARID1B; NOTCH2; and BCOR. The patient may have one or more mutations in one or more of TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3. In some embodiments the patient has one or more mutations in one or more of ATM, TP53, CCND1, KMT2D, and CDKN2A. In some embodiments the patient has one or more mutations in ATM. In some embodiments the patient has one or more mutations in TP53. In some embodiments the patient has one or more mutations in CCND1. In some embodiments the patient has one or more mutations in KMT2D. In some embodiments the patient has one or more mutations in CDKN2A. Mutations in such genes can be detected using techniques available to those skilled in the art, for example by DNA sequencing of a biological sample from the patient, e.g. a blood sample, with optional PCR to amplify the DNA encoding the gene to be assessed. In some embodiments, the patient has mantle cell lymphoma which is resistant to treatment to treatment with a BCL-2 inhibitor such as venetoclax or navitoclax. The patient may have mantle cell lymphoma which has acquired resistance to the BCL-2 inhibitor. Resistance to BCL-2 inhibitors can be determined by failed therapeutic treatment of the mantle cell lymphoma with the BCL-2 inhibitor (e.g. by administering the inhibitor to the patient and the mantle cell lymphoma progressing during or after such treatment), or by determining the mantle cell lymphoma as being associated with a genetic profile known to be resistant to BCL-2 inhibitors. Those skilled in the art will appreciate that treatment of a mantle cell lymphoma which has acquired resistance to an inhibitor such as a BCL-2 inhibitor is a different challenge to treatment of a mantle cell lymphoma which has innate or primary resistance to said inhibitor. Treatment of mantle cell lymphoma which has acquired resistance to an inhibitor is provided by the therapies provided herein. For example, in some embodiments the patient has mantle cell lymphoma which is resistant to treatment with venetoclax. The patient may have mantle cell lymphoma which has acquired resistance to venetoclax. Resistance to venetoclax can be determined by failed therapeutic treatment of the mantle cell lymphoma with venetoclax (e.g. by administering venetoclax to the patient and the mantle cell lymphoma progressing during or after such treatment), or by determining the mantle cell lymphoma as being associated with a genetic profile known to be resistant to venetoclax. For example, mutations associated with venetoclax resistance may include one or more mutations in one or more of TRAF2, TRAF3, MAP3K14, CARD11, MYD88, CCND1, BKT, and PCLG2. In some embodiments the patient has mantle cell lymphoma which is resistant to treatment to ibrutinib. The patient may have mantle cell lymphoma which has acquired resistance to ibrutinib. Resistance to ibrutinib can be determined by failed therapeutic treatment of the mantle cell lymphoma with ibrutinib (e.g. by administering ibrutinib to the patient and the mantle cell lymphoma progressing during or after such treatment), or by determining the mantle cell lymphoma as being associated with a genetic profile known to be resistant to ibrutinib. For example, mutations associated with ibrutinib resistance may include one or more mutations in one or more of SMARCA4, BCL2, TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM. In some embodiments the patient has mantle cell lymphoma which is characterised by or associated with one or more of cyclin D1 overexpression; t(11;14) and/or t(11;14)(q13;q32) translocation; Ki67 overexpression; lactate dehydrogenase overexpression; and beta-2 microglobulin overexpression. In some embodiments the patient has mantle cell lymphoma which is characterised by or associated with cyclin D1 overexpression. The patient may have mantle cell lymphoma which is characterised by or associated with cyclin D1, D2 and/or D3 overexpression. Cyclin overexpression can be easily determined by those skilled in the art. In some embodiments the patient has mantle cell lymphoma which is characterised by or associated with t(11;14) translocation. In some embodiments the patient has mantle cell lymphoma which is characterised by or associated with t(11;14)(q13;q32) translocation. In t(11;14), the result is juxtaposition of the immunoglobulin heavy-chain (IgH) locus and the cyclin D1 gene (CCND1, PRAD1, BCL1). Without being bound by theory, it is believed that this translocation drives the overexpression of cyclin D1 by juxtaposition of a transcriptional enhancer from the IgH locus (14q32) next to the CCND1 gene (11q13). Cyclin D1 is a nuclear protein that promotes entry of cell from G 1 -phase to S-phase in the cell cycle. Detection of such translocation is routine for those skilled in the art. For example, the t(11;14) translocation may be detected using cytogenetics, Southern blot, polymerase chain reaction (PCR) analysis, or interphase fluorescence in situ hybridization. In some embodiments, the patient has mantle cell lymphoma which is characterised by or associated with overexpression of Ki67; lactate dehydrogenase; and/or beta-2 microglobulin. In some embodiments the patient has mantle cell lymphoma which is characterised by or associated with Ki67 overexpression. In some embodiments the patient has mantle cell lymphoma which is characterised by or associated with lactate dehydrogenase overexpression. In some embodiments the patient has mantle cell lymphoma which is characterised by or associated with beta-2 microglobulin overexpression. Determination of such overexpression is routine for those skilled in the art. In some embodiments, the patient has refractory and/or relapsed mantle cell lymphoma. As used herein, the term “refractory” relates to mantle cell lymphoma which does not respond to treatment or wherein said response is short term. The term “relapsed” refers to mantle cell lymphoma that reappears or grows again after a period of remission. In some embodiments, the patient has mantle cell lymphoma which is selected from, or characterised as one of, nodal mantle cell lymphoma; and leukaemic non-nodal mantle cell lymphoma. Nodal mantle cell lymphoma affects lymph nodes but often spreads to other parts of the body, such as the bone marrow, bloodstream, bowel and liver. In some embodiments the nodal mantle cell lymphoma is selected from or characterised by one or more of blastoid mantle cell lymphoma and pleomorphic mantle cell lymphoma. Retinoblastoma (Rb) is a protein which exerts a tumour suppression function. Deregulation of Rb has been associated with various cancer types. Lymphoma cells may be Rb proficient (also referred to as Rb positive, Rb+) or Rb deficient (also referred to as Rb negative, Rb-). Rb status has been shown to be independent of susceptibility to many chemotherapeutic agents such as cisplatin (CDDP), 5- fluorouracil, idarubicin, epirubicin, PRIMA-1met, fludarabine and PD-0332991. In some embodiments provided herein, the patient has Rb-negative mantle cell lymphoma. Thus, in some embodiments the patient has mantle cell lymphoma which is Rb deficient. In some embodiments provided herein, the patient has Rb-positive mantle cell lymphoma. Thus, in some embodiments the patient has mantle cell lymphoma which is Rb proficient. The therapies provided herein are useful in treating both Rb-positive and Rb- negative mantle cell lymphoma.. However, without being bound by theory in any way, it is believed that the therapies provided herein may be particularly beneficial in treating mantle cell lymphoma which is Rb-proficient. Further without being bound by theory, it is considered that in Rb-proficient mantle cell lymphoma, mTOR (mechanistic target of rapamycin) deregulation may promote cellular growth and proliferation. mTOR is believed to form two structurally and functionally distinct complexes, mTORC1 and mTORC2. It is believed that phosphorylated Rb may interact with the mTORC2 complex to suppress AKT activation, such that inhibition of CDK4/6 by abemaciclib may reduce Rb phosphorylation and thus attenuate Rb suppression on mTORC2 activation, resulting in elevated AKT phosphorylation and activation and providing a biological rationale for treating Rb+ mantle cell lymphoma with a combination of abemaciclib and a PI3K and/or mTOR inhibitor. As noted herein, mantle cell lymphoma may be characterised in some embodiments by expression of androgen receptor (AR) (e.g. in LAR mantle cell lymphoma.). Androgen receptor (AR) is a steroid hormonal receptor that links a transcription factor that controls specific genes involved in different, sometimes opposite, cellular processes: it can stimulate or suppress both cell proliferation and apoptosis, depending on the concurrent signaling pathways activated. AR is expressed in some, but not all, mantle cell lymphoma. Accordingly, in some embodiments the subject has mantle cell lymphoma which is AR positive (AR proficient). However, in other embodiments the subject has mantle cell lymphoma which is AR negative (AR deficient). In some embodiments, e.g. in embodiments wherein the subject has mantle cell lymphoma which is AR positive, the subject may be administered an anti-AR therapy. In embodiments wherein an anti-AR therapy is administered to the subject, any suitable anti-AR therapy may be used. The preferred anti-AR therapy may be determined according to various parameters, especially according to the severity and histology of the mantle cell lymphoma, age, weight and condition of the subject to be treated; the route of administration; and the required regimen. A physician will be able to determine the preferred anti-AR therapy to use and the required route of administration and dosage for any particular subject. Preferably, an anti-AR therapy may be selected from AR inhibitors such as bicalutamide (Casodex), enzalutamide (Xtandi), and abiraterone acetate (Zytiga). For example, bicalutamide may be administered at a dose of about 50 mg per day. Enzalutamide may be administered at a dose of about 160 mg per day. Abiraterone acetate may be administered at a dose of about 1000 mg once daily. Mantle cell lymphoma may be characterised in some embodiments by expression of PD-L1. PD-L1 (Programmed Cell Death Ligand 1) is a ligand of PD-1 (Programmed Cell Death Protein 1) which is an immune checkpoint receptor that limits T cell effector function within tissues. PD-L1 expression may be promoted by loss of PTEN expression or function e.g. via mutation. Accordingly, in some embodiments the subject has mantle cell lymphoma which express PD-L1 (PD-L1 positive). However, in other embodiments the subject has mantle cell lymphoma which does not express PD-L1 (PD-L1 negative). In some embodiments, e.g. in embodiments wherein the subject has mantle cell lymphoma which is PD-L1 positive, the subject may be administered an inhibitor of PD-1 or PD-L1. In embodiments wherein an inhibitor of PD-1 or PD-L1 is administered to the subject, any suitable inhibitor of PD-1 or PD-L1 may be used. The preferred inhibitor of PD-1 or PD-L1 may be determined according to various parameters, especially according to the severity and histology of the mantle cell lymphoma, age, weight and condition of the subject to be treated; the route of administration; and the required regimen. A physician will be able to determine the preferred inhibitor of PD-1 or PD-L1 to use and the required route of administration and dosage for any particular subject. Preferably, an inhibitor of PD-1 or PD-L1 may be selected from Pembrolizumab (Keytruda), Nivolumab (Opdivo), Cemiplimab (Libtayo), Atezolizumab (Tecentriq), Avelumab (Bavencio) and Durvalumab (Imfinzi). For example, Pembrolizumab may be administered at a dose of about 200 mg every 3 weeks. Nivolumab may be administered at a dose of about 240 mg every 2 weeks or 480 mg every 4 weeks. Cemiplimab may be administered at a dose of about 350 mg once every 3 weeks. Atezolizumab may be administered at a dose of about 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks. Avelumab may be administered at a dose of about 800 mg every 2 weeks. Durvalumab may be administered at a dose of about 10 mg/kg every 2 weeks or 1500 mg every 3 or 4 weeks. Further embodiments Also provided herein is a product which is a combination of abemaciclib, or a pharmaceutically acceptable salt thereof, and a PI3K and/or mTOR inhibitor as described here. The product may comprise one or more pharmaceutically acceptable components such as any one of the excipients, diluents or adjuvants described herein. The product may comprise one or more additional active agents as described herein. The product may be formulated as a dosage form, e.g. as an oral dosage form or as dosage form for injection or infusion as described herein. The product may be provided as a kit as described herein. Further aspects The following are further numbered aspects of the invention: 1. Use of a combination of abemaciclib or a pharmaceutically acceptable salt thereof and a PI3K and/or mTOR inhibitor or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating mantle cell lymphoma in a patient in need thereof. 2. Use of abemaciclib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating mantle cell lymphoma in a patient in need thereof by administering to said patient said abemaciclib or pharmaceutically acceptable salt thereof in combination with a PI3K and/or mTOR inhibitor or a pharmaceutically acceptable salt thereof. 3. Use of a PI3K and/or mTOR inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating mantle cell lymphoma in a patient in need thereof by administering to said patient said PI3K and/or mTOR inhibitor or pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof. 4. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor as defined in any one of aspects 1 to 3, wherein said medicament is for treating mantle cell lymphoma in said patient by simultaneously, separately or sequentially administering said abemaciclib or pharmaceutically acceptable salt thereof and said PI3K and/or mTOR inhibitor or pharmaceutically acceptable salt thereof to said patient. 5. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 4, wherein the PI3K and/or mTOR inhibitor is a dual PI3K/mTOR inhibitor. 6. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 5, wherein the PI3K and/or mTOR inhibitor is a pan- PI3K inhibitor. 7. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 6, wherein the PI3K and/or mTOR inhibitor is selected from: Copanlisib (BAY80–6946); Samotolisib (LY3023414); BGT-226; DS- 7423; PF-04691502; PKI-179; Omipalisib (GSK2126458/GSK458); Panulisib (P7170); SB2343/VS-5584; Dactolisib (BEZ235); Paxalisib (GDC-0084); Apitolisib (GDC-0980); Bimiralisib (PQR309); Voxtalisib (SAR245409/XL765); SF-1126; Gedatolisib (PF-05212384/PKI-587); XH00230381967, SN20229799306; Pictilisib (GDC-0941); Sonolisib (PX-866); TG100–115; CH5132799; Pilaralisib (XL147); ZSTK474; Buparlisib (BKM- 120); Fimepinostat (CUDC-907); Rigosertib (ON-01910); AZD8835; WX-037; AZD8186; KA2237; Acalisib (GS-9820/CAL-120); Zandelisib (ME401/PWT- 143); AMG 319; GSK2636771; Parsaclisib (INCB050465); Serabelisib (INK- 1117); Umbralisib (TGR-1202); Tenalisib (RP6530); Taselisib (GDC-0032); Alpelisib (BYL719); Duvelisib (IPI-145); and idelalisib (CAL-101); sirolimus, nab-rapamycin, temsirolimus, everolimus, ridaforolimus; OSI-027; vistusertib (AZD2014); sapanisertib (MLN0128/INK128/TAK-228); Torkinib (PP242); ML-223; and AZD8055; and prodrugs, metabolites, and derivatives thereof, and pharmaceutically acceptable salts thereof. 8. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 7, wherein the PI3K and/or mTOR inhibitor is copanlisib (BAY80–6946) or a pharmaceutically acceptable salt thereof. 9. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 8, wherein the mantle cell lymphoma has acquired resistance to one or more BCL-2 inhibitors. 10. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 9, wherein the mantle cell lymphoma has acquired resistance to venetoclax. 11. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 10, wherein the mantle cell lymphoma has acquired resistance to ibrutinib. 12. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 11, wherein the mantle cell lymphoma is selected from, or characterised as one of, nodal mantle cell lymphoma; and leukaemic non-nodal mantle cell lymphoma. 13. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 12, wherein the mantle cell lymphoma is selected from, or characterised as, refractory and/or relapsed mantle cell lymphoma. 14. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 13, wherein said mantle cell lymphoma is associated with one or more mutations in: ATM; TP53; CCND1; KMT2D; CDK2NA; BIRC3; CDKN2B; KHSC1; SMARCA4; SDHD; UBR5; NOTCH1; CARD11; SAMHD1; BCL10; MEF2B; IRS2; FGF19; FGF4; FGF3; FAT1; ROBO1; DIS3; CRLF2; CDKN2C; ARID2; ARID1A; ARID1B; NOTCH2; BCOR; TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3. 15. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 14, wherein said mantle cell lymphoma is associated with cyclin D1 overexpression; t(11;14) and/or t(11;14)(q13;q32) translocation; Ki67 overexpression; lactate dehydrogenase overexpression; and/or beta-2 microglobulin overexpression. 16. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 15, wherein said mantle cell lymphoma is retinoblastoma protein (Rb) proficient. 17. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 16, wherein said medicament is for treating mantle cell lymphoma by further administering to the patient an effective amount of a BTK inhibitor. 18. Use of a combination, abemaciclib, or a PI3K and/or mTOR inhibitor according to any one of aspects 1 to 17, wherein said medicament is for treating mantle cell lymphoma by further administering to the patient an effective amount of one or more additional agents selected from fulvestrant or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; AR inhibitors; immune-checkpoint inhibitors such as PD-L1 or PD- 1 inhibitors; CDK4/6 inhibitors; AKT inhibitors; cyclinE/CDK2 inhibitors; autophagy inhibitors; anti-EGFR inhibitors; and PARP inhibitors. The following examples are provided to solely illustrate the invention and are non-limiting. In particular, there are many assays available to demonstrate anti-cancer efficacy of combinations of pharmaceutically acceptable drugs and potential synergy, and so a negative result in any one assay is not determinative. EXAMPLES These examples illustrate the utility of the claimed therapy in treating mantle cell lymphoma. Summary Although novel therapeutic strategies including BTK and Bcl-2 inhibitors have dramatically improved the prognosis of MCL patients, resistance to these treatments is inevitable. The tumor suppressor gene CDKN2A was commonly deleted in ibrutinib- resistant tumors, leading to upregulation of CDK4/6 signaling. Among the other hallmarks are the mTOR/PI3K, Myc and OXPHOS pathways. Therefore, we attempt to exploit combinatory targeting of CDK4/6 and PI3K pathways to overcome therapy resistance using in vitro and PDX models. Methods Ibrutinib or venetoclax sensitive and resistant MCL cell lines were used in this preclinical study. 1x10 4 cells per well were seeded in 96-well plates and treated with abemaciclib monotherapy or in combination with copanlisib (PI3K inhibitor) in triplicate for 72h and then mixed with CellTiter-Glo Luminescent Cell viability Assay Reagent. For cell cycle assay, cells were seeded in 6 well plates and treated with vehicle or abemaciclib for 24h. Cells were fixed in 70% pre-cold ethanol and stained with propidium iodide. The cell cycle stages were quantified through the Novocyte Flow Cytometer. The molecular events at the protein level after treatment were determined by immunoblotting. For in vivo experiment, the combination of abemaciclib (25mg/kg, oral, daily) and copanlisib (5mg/kg, IP, three times a week) was assessed in Mino-venetoclax- resistant xenograft model. IC50 values were calculated using GraphPad Prism 8 for each cell line. Student’s t-test was performed to compare the difference between vehicle and treated groups. Two-way analysis of variance (ANOVA) was conducted to analyze the tumor growth in vivo experiments. P values less than 0.05 were considered statistically significant. Results Our previous studies identified a subset of MCL cells that were resistant to venetoclax (JeKo-1) or ibrutinib treatment (Maver-1 and Z-138). To overcome the resistance, we first treated MCL cell lines with abemaciclib and the result showed that abemaciclib as a single agent showed potent anti-MCL activity in a subset of MCL cell lines (IC50 = 70-952 nM) including venetoclax sensitive- (Mino, Rec-1, Maver-1, and Z138) and primary resistant- MCL cells (JeKo- 1). (Figure 1) However, the cell lines Mino-ven-R and Rec-ven-R with acquired venetoclax resistance are highly resistant to abemaciclib treatment (IC50 = 6.0 and 4.4 µM). PI3K/ATK pathway has been reported to be highly upregulated in Mino-ven-R and Rec-ven-R cells compared to their parental cells. To further increase the efficacy of the targeted therapy, we treated the resistant MCL cells with a combination of abemaciclib and copanlisib and the result showed synergistically enhanced cytotoxicity in ibrutinib or venetoclax-resistant MCL cell lines. Consistent with the role of CDK4/6 in cell cycle progression, inhibition of CDK4/6 with abemaciclib resulted in the cell cycle arrest at G1 phase in MCL cell lines. (Figure 2) To validate whether abemaciclib in combination with copanlisib can overcome venetoclax resistance in vivo, we assessed the antitumor effect of abemaciclib in combination with copanlisib using a venetoclax-resistant xenograft models derived from Mino-ven-R cell line in immunodeficient NSG mice (Figure 3). As a result, abemaciclib (25 mg/kg, oral, daily), but not venetoclax (5 mg/kg, oral, daily) or copanlisib (5 mg/kg, IP, three times a week), significantly reduced tumor volume compared to the vehicle control (n = 5, p < 0.0001). Remarkably, the combination of abemaciclib and copanlisib also exhibited significantly in vivo synergistic efficacy compared with single-agent treatment (p<0.0001). Of note, the combination did not cause major decreases in body weight. Taken together, these results suggest that the combinatory therapy is effective in overcoming venetoclax resistance in MCL. Conclusions Clinically, synergistic drug combinations would allow administration of lower doses of each drug to achieve an equivalent therapeutic effect. Reduced administrated dose of drug may mitigate dose-limiting toxicities, a major factor responsible for ceasing treatment in patients. The results presented here indicate the value of combinations of abemaciclib and a PI3K and/or mTOR inhibitor such as copanlisib in treating MCL. In particular, the data presented here confirm that combinatory treatment with abemaciclib and PI3K and/or mTOR inhibitors such as copanlisib exerts robust anti-lymphoma effects both in vitro and in vivo models. Such data indicates that such combinations may achieve clinical actionable efficacy through overcoming the venetoclax-resistance in MCL that may become an effective treatment regimen for refractory/relapsed MCL patients in the future. References Wang, M.L., et al., Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med, 2013.369(6): p.507-16 Tam, C.S., et al., Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N Engl J Med, 2018.378(13): p.1211-1223 Morschhauser, F., et al., Clinical activity of abemaciclib in patients with relapsed or refractory mantle cell lymphoma - a phase II study. Haematologica, 2021.106(3): p. 859-862. Beà, S. and E. Campo, Secondary genomic alterations in non-Hodgkin's lymphomas: tumor-specific profiles with impact on clinical behavior. Haematologica, 2008.93(5): p. 641-5. Jares, P., D. Colomer, and E. Campo, Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer, 2007. 7(10): p.750-62.
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