Combinations for the treatment of neoplasms using quiescent cell targeting and inhibitors of mitosis

Abstract

The present invention provides compositions and methods for the treatment of neoplasms, in particular, by targeting of quiescent cancer cells with therapeutic agents in combination with other treatments effective against certain neoplastic conditions, in particular, anti-cancer treatment with therapeutic agents that are inhibitors of mitosis (a mitotic inhibitor).

1 . A method for treating a subject having a neoplasm, the method comprising administering to the subject, sequentially or concomitantly,
 (a) a DYRK1 inhibitor which inhibits DYRK1A or DYRK1B kinase activity with an IC 50  of 100 nM or lower in biochemical assays, and reduces the fraction of quiescent cancer cells (in vitro or in vivo) that would otherwise be found in the absence of such inhibitor by at least 10%; and   (b) administering to the subject an inhibitor of mitosis.   
     
     
         2 . The method of  claim 1 , further comprising administering to the subject an effective amount of radiation therapy. 
     
     
         3 . The method of  claim 1 , wherein the neoplasm being treated is either a primary or a metastatic cancer selected from biliary cancer, brain cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, kidney cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, bladder cancer, breast cancer, colorectal cancer, ovarian cancer, and prostate cancer. 
     
     
         4 . The method of  claim 1 , wherein the neoplasm being treated is either a primary or metastatic colon cancer, non-small cell lung cancer, ovarian cancer, prostate cancer, small cell lung cancer, or pancreatic cancer. 
     
     
         5 . The method of  claim 1 , wherein the inhibitor of mitosis is a taxane, a vinca alkaloid, or a PLK1 inhibitor. 
     
     
         6 . The method of  claim 1 , wherein the inhibitor of mitosis is selected from BMS-188796, BMS-188797, cabazitaxel, DEP cabazitaxel, docetaxel, larotaxel (XP9881, RPR109881), paclitaxel, taxoprexin (DHA-paclitaxel), and tesetaxel (DJ-927). 
     
     
         7 . The method of  claim 1 , wherein the inhibitor of mitosis is selected from vinblastine, vincristine, vindesine, vinflunine, and vinorelbine. 
     
     
         8 . The method of  claim 1 , wherein the inhibitor of mitosis is vintafolide. 
     
     
         9 . The method of  claim 1 , wherein the inhibitor of mitosis is selected from a list of BI-2536, GSK461364, GW843682X, HMN-214 and HMN-176, MLN-0905, NMS-P937, rigosertib, Ro3280, SBE 13, and volasertib. 
     
     
         10 . The method of  claim 1 , wherein the DYRK1 inhibitor is selected from I-1, I-2, I-3, I-4, I-5, I-6, and I-7. 
     
     
         11 . A method for treating a subject having a neoplasm, the method comprising administering to the subject, sequentially or concomitantly, a DYRK1 inhibitor and administering to the subject an inhibitor of mitosis, wherein the EC 50  value of the inhibitor of mitosis is at least 20% lower in the combination treatment when compared to the same treatment with the inhibitor of mitosis alone, as determined in cell-based assays. 
     
     
         12 . The method of  claim 11 , wherein the DYRK1 inhibitor has a Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein 
         R 1  is a substituted or unsubstituted C 1-8  alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted benzyl; 
         R 2  is phenyl, optionally substituted with up to four groups independently selected from halo, CN, NO 2 , NHC(O)C 1-4  alkyl, C 1-4  alkyl, OH, OC 1-4  alkyl, wherein two adjacent groups and their intervening carbon atoms may form a 5- to 6-membered ring containing one or more heteroatoms selected from N, O, or S. 
       
     
     
         13 . The method of  claim 11 , further comprising administering to the subject an effective amount of radiation therapy. 
     
     
         14 . The method of  claim 11 , wherein the neoplasm being treated is either a primary or metastatic cancer selected from biliary cancer, brain cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, kidney cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, bladder cancer, breast cancer, colorectal cancer, ovarian cancer, and prostate cancer. 
     
     
         15 . The method of  claim 11 , wherein the neoplasm being treated is either a primary or metastatic colon cancer, non-small cell lung cancer, ovarian cancer, prostate cancer, small cell lung cancer, or pancreatic cancer. 
     
     
         16 . The method of  claim 11 , wherein the inhibitor of mitosis is a taxane, a vinca alkaloid, or a PLK1 inhibitor. 
     
     
         17 . The method of  claim 11 , wherein the inhibitor of mitosis is selected from BMS-188796, BMS-188797, cabazitaxel, DEP cabazitaxel, docetaxel, larotaxel (XRP9881, RPR109881), paclitaxel, taxoprexin (DHA-paclitaxel), and tesetaxel (DJ-927). 
     
     
         18 . The method of  claim 11 , wherein the inhibitor of mitosis is selected from a list of vinblastine, vincristine, vindesine, vinflunine, and vinorelbine. 
     
     
         19 . The method of  claim 11 , wherein the inhibitor of mitosis is vintafolide. 
     
     
         20 . The method of  claim 11 , wherein the inhibitor of mitosis is selected from BI-2536, GSK461364, GW843682X, HMN-214 and HMN-176, MLN-0905, NMS-P937, rigosertib, Ro3280, SBE 13, and volasertib. 
     
     
         21 . The method of  claim 11 , wherein the DYRK1 inhibitor is selected from I-1, I-2, I-3, I-4, I-5, I-6, and I-7. 
     
     
         22 . A method for treating a subject having a neoplasm, the method comprising administering to the subject, sequentially or concomitantly, a DYRK1 inhibitor and administering to the subject an inhibitor of mitosis, wherein the combination treatment increases fraction of apoptotic cells in a treated population as compared to either agent alone by at least by 2-fold, as determined by fraction of sub-G 0  cells by a FACS assay. 
     
     
         23 . The method of  claim 22 , wherein the DYRK1 inhibitor has a Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein, 
         R1 is a substituted or unsubstituted C1-8 alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted benzyl; 
         R2 is phenyl, optionally substituted with up to four groups independently selected from halo, CN, NO2, NHC(O)C1-4 alkyl, C1-4 alkyl, OH, OC1-4 alkyl, wherein two adjacent groups and their intervening carbon atoms may form a 5- to 6-membered ring containing one or more heteroatoms selected from N, O, or S. 
       
     
     
         24 . The method of  claim 22 , further comprising administering to the subject an effective amount of radiation therapy. 
     
     
         25 . The method of  claim 22 , wherein the neoplasm being treated is a either a primary or metastatic cancer selected from biliary cancer, brain cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, kidney cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, bladder cancer, breast cancer, colorectal cancer, lung cancer, ovarian cancer, and prostate cancer. 
     
     
         26 . The method of  claim 22 , wherein the neoplasm being treated is either a primary or metastatic colon cancer, non-small cell lung cancer, ovarian cancer, prostate cancer, small cell lung cancer, pancreatic cancer. 
     
     
         27 . The method of  claim 22 , wherein the inhibitor of mitosis is a taxane, a vinca alkaloid, or a PLK1 inhibitor. 
     
     
         28 . The method of  claim 22 , wherein the inhibitor of mitosis is selected from BMS-188796, BMS-188797, cabazitaxel, DEP cabazitaxel, docetaxel, larotaxel (XRP9881, RPR109881), paclitaxel, taxoprexin (DHA-paclitaxel), and tesetaxel (DJ-927). 
     
     
         29 . The method of  claim 22 , wherein the inhibitor of mitosis is selected from a list of vinblastine, vincristine, vindesine, vinflunine, and vinorelbine. 
     
     
         30 . The method of  claim 22 , wherein the inhibitor of mitosis is vintafolide. 
     
     
         31 . The method of  claim 22 , wherein the inhibitor of mitosis is selected from BI-2536, GSK461364, GW843682X, HMN-214 and HMN-176, MLN-0905, NMS-P937, rigosertib, Ro3280, SBE 13, and volasertib. 
     
     
         32 . The method of  claim 22 , wherein the DYRK1 inhibitor is selected from I-1, I-2, I-3, I-4, I-5, I-6, and I-7.