Combinations for the treatment of neoplasms using quiescent cell targeting with egfr inhibitors

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 EGFR inhibitor agents.

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) an EGFR TKI.   
     
     
         2 . The method of  claim 1 , wherein the neoplasm being treated is 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, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, bladder cancer, breast cancer, colorectal cancer, small cell lung cancer, ovarian cancer, and prostate cancer. 
     
     
         3 . The method of  claim 1 , wherein the neoplasm being treated is either a primary or metastatic non-small cell lung cancer. 
     
     
         4 . The method of  claim 1 , wherein the neoplasm being treated is either a primary or metastatic pancreatic cancer. 
     
     
         5 . The method of  claim 1 , wherein the EGFR TKI is a reversible inhibitor, selected from a list of brigatinib, CUDC-101, erlotinib, gefitinib, icotinib, lapatinib, sapitinib, tesevatinib, Tyrphostin AG 1478, vandetanib, and varlitinib. 
     
     
         6 . The method of  claim 1 , wherein the EGFR TKI is EGFR TKI is selected from AZD3759 and MTKi-327 (JNJ-26483327). 
     
     
         7 . The method of  claim 1 , wherein the EGFR TKI is an irreversible inhibitor, selected from a list of afatinib, canertinib, CL-387785 (EKI-785), CNX-2006, dacomitinib, naquotinib (ASP8273), neratinib, olmutinib (HM61713), osimertinib, PD168393, pelitinib, poziotinib, TAK285, rociletinib, and WZ4002. 
     
     
         8 . The method of  claim 1 , wherein the EGFR TKI is selected from a list of allitinib (ALS-1306; AST-1306), AV-412 (MP-412), nazartinib (EGF816), and pyrotinib. 
     
     
         9 . 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. 
     
     
         10 . 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 EGFR TKI, wherein the EC 50  value of the EGFR TKI is at least 20% lower in the combination treatment when compared to the same treatment with the EGFR TKI alone, as determined in cell-based assays. 
     
     
         11 . The method of  claim 10 , 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. 
       
     
     
         12 . The method of  claim 10 , further comprising administering to the subject an effective amount of radiation therapy. 
     
     
         13 . The method of  claim 10 , wherein the neoplasm being treated is 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, small cell lung cancer, lymphoma, ovarian 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. 
     
     
         14 . The method of  claim 10 , wherein the neoplasm being treated is either a primary or metastatic non-small cell lung cancer. 
     
     
         15 . The method of  claim 10 , wherein the neoplasm being treated is either a primary or metastatic pancreatic cancer. 
     
     
         16 . The method of  claim 10 , wherein the EGFR TKI is a selected from brigatinib, CUDC-101, erlotinib, gefitinib, icotinib, lapatinib, sapitinib, tesevatinib, Tyrphostin AG 1478, vandetanib, and varlitinib. 
     
     
         17 . The method of  claim 10 , wherein the EGFR TKI is EGFR TKI is selected from AZD3759 and MTKi-327 (JNJ-26483327). 
     
     
         18 . The method of  claim 10  wherein the EGFR TKI is selected from afatinib, canertinib, CL-387785 (EKI-785), CNX-2006, dacomitinib, naquotinib (ASP8273), neratinib, olmutinib (HM61713), osimertinib, PD168393, pelitinib, poziotinib, TAK285, rociletinib, and WZ4002. 
     
     
         19 . The method of  claim 10 , wherein the EGFR TKI is selected from allitinib (ALS-1306; AST-1306), AV-412 (MP-412), nazartinib (EGF816), and pyrotinib. 
     
     
         20 . The method of  claim 10 , wherein the DYRK1 inhibitor is selected from I-1, I-2, I-3, I-4, I-5, I-6, and I-7. 
     
     
         21 . 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 EGFR TKI, 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. 
     
     
         22 . The method of  claim 21 , 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. 
       
     
     
         23 . The method of  claim 21 , further comprising administering to the subject an effective amount of radiation therapy. 
     
     
         24 . The method of  claim 21 , 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, small cell lung cancer, lymphoma, ovarian 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. 
     
     
         25 . The method of  claim 21 , wherein the neoplasm being treated is either a primary or metastatic non-small cell lung cancer. 
     
     
         26 . The method of  claim 21 , wherein the neoplasm being treated is either a primary or metastatic pancreatic cancer. 
     
     
         27 . The method of  claim 21 , wherein the EGFR TKI is selected from a list of brigatinib, CUDC-101, erlotinib, gefitinib, icotinib, lapatinib, sapitinib, tesevatinib, Tyrphostin AG 1478, vandetanib, and varlitinib. 
     
     
         28 . The method of  claim 21 , wherein the EGFR TKI is selected from AZD3759 and MTKi-327 (JNJ-26483327). 
     
     
         29 . The method of  claim 21 , wherein the EGFR TKI is selected from a list of afatinib, canertinib, CL-387785 (EKI-785), CNX-2006, dacomitinib, naquotinib (ASP8273), neratinib, olmutinib (HM61713), osimertinib, PD168393, pelitinib, poziotinib, TAK285, rociletinib, and WZ4002. 
     
     
         30 . The method of  claim 21 , wherein the EGFR TKI is selected from allitinib (ALS-1306; AST-1306), AV-412 (MP-412), nazartinib (EGF816), and pyrotinib. 
     
     
         31 . The method of  claim 21 , wherein the DYRK1 inhibitor is selected from I-1, I-2, I-3, I-4, I-5, I-6, and I-7. 
     
     
         32 . 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) an EGFR TKI, the treatment with which of a cell population (in vitro or in vivo) increases the fraction of quiescent cells (cells in G 0  phase of the cell cycle) by at least 20% relative to the untreated population of same cells, as determined by a FACS assay.   
     
     
         33 . The method of  claim 32 , 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. 
       
     
     
         34 . The method of  claim 32 , further comprising administering to the subject an effective amount of radiation therapy. 
     
     
         35 . The method of  claim 32 , wherein the neoplasm being treated is 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, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, bladder cancer, breast cancer, colorectal cancer, small cell lung cancer, ovarian cancer, and prostate cancer. 
     
     
         36 . The method of  claim 32 , wherein the neoplasm being treated is either a primary or metastatic non-small cell lung cancer. 
     
     
         37 . The method of  claim 32 , wherein the neoplasm being treated is either a primary or metastatic pancreatic cancer. 
     
     
         38 . The method of  claim 32 , wherein the EGFR TKI is selected from brigatinib, CUDC-101, erlotinib, gefitinib, icotinib, lapatinib, sapitinib, tesevatinib, Tyrphostin AG 1478, vandetanib, and varlitinib. 
     
     
         39 . The method of  claim 32 , wherein the EGFR TKI selected from AZD3759 and is MTKi-327 (JNJ-26483327). 
     
     
         40 . The method of  claim 32 , wherein the EGFR TKI is selected from afatinib, canertinib, CL-387785 (EKI-785), CNX-2006, dacomitinib, naquotinib (ASP8273), neratinib, olmutinib (HM61713), osimertinib, PD168393, pelitinib, poziotinib, TAK285, rociletinib, and WZ4002. 
     
     
         41 . The method of  claim 32 , wherein the EGFR TKI is selected from allitinib (ALS-1306; AST-1306), AV-412 (MP-412), nazartinib (EGF816), and pyrotinib. 
     
     
         42 . The method of  claim 32 , wherein the DYRK1 inhibitor is selected from I-1, I-2, I-3, I-4, I-5, I-6, and I-7.