Platelet-derived growth factor receptor mutations and compositions and methods relating thereto

Abstract

In certain embodiments the present invention involves methods of killing tumor cells that comprise an oncogenic PDGFR mutation, and methods of treating subjects having tumors that comprise such tumor cells. In some embodiments such methods involve using PI3K inhibitors, or a combination of a PI3K inhibitor and an mTOR inhibitor, or a dual PI3K/mTOR inhibitor. The present invention also provides methods for determining whether a subject is a candidate for treatment, methods for evaluating the efficacy of treatment, and other methods, compositions, model systems, and assays.

1 - 54 . (canceled) 
     
     
         55 . A method of inducing apoptotic cell death in PDGFRA-mutant glioma cells, the method comprising: (a) determining if glioma cells comprise an oncogenic PDGFRA mutation, and (b) subsequently contacting glioma cells having an oncogenic PDGFRA mutation with an effective amount of a PDGFR/PI3K/mTOR pathway inhibitor, thereby killing the PDGFRA-mutant glioma cells. 
     
     
         56 . The method of  claim 55 , comprising contacting the glioma cells with an effective amount of a PDGFR inhibitor, a PI3K inhibitor or an Akt inhibitor. 
     
     
         57 . The method of  claim 56 , further comprising contacting the glioma cells with an effective amount of an mTOR inhibitor. 
     
     
         58 . The method of  claim 55 , comprising contacting the glioma cells with an effective amount of: (a) a PI3K inhibitor, (b) both a PI3K inhibitor and a mTOR inhibitor, (c) a dual PI3K/mTOR inhibitor, and (c) an Akt inhibitor, (d) both an Akt inhibitor and an mTOR inhibitor, (e) a PDGFR inhibitor, or (f) both a PDGFR inhibitor and an mTOR inhibitor. 
     
     
         59 . The method of  claim 55 , wherein the oncogenic PDGFRA mutation is selected from the group consisting of a PDGFRA mutation that results in a deletion of a portion of the PDGFRA extracellular domain, a PDGFRA mutation that results in constitutive activation of a PDGRFA receptor molecule, a PDGFRA mutation that results in constitutive PDGRFA phosphorylation and AKT activation, a PDGFRA mutation that results in overexpression of a PDGRFA receptor molecule, a PDGFRA mutation that results in increased activity of a PDGRFA receptor molecule, a PDGFRA gene amplification and a focal amplification of the human PDGFRA locus on human chromosome 4q12. 
     
     
         60 . The method of  claim 55 , wherein the oncogenic PDGFRA mutation comprises a mutation in the third IG-like domain of the extracellular domain of PDGRFA located in the region spanning amino acids 202-306 of human PDGRFA. 
     
     
         61 . The method of  claim 55 , wherein the oncogenic PDGFRA mutation comprises one or more of a G228V mutation, a P250S mutation, or a D842V mutation. 
     
     
         62 . The method of  claim 55 , wherein the glioma cells are human glioma cells. 
     
     
         63 . The method of  claim 55 , wherein the glioma cells are human glioblastoma cells. 
     
     
         64 . The method of  claim 56 , wherein the PI3K inhibitor is selected from the group consisting of SAR245409, SAR245408, BYL-719, GDC-0980, GDC-0941, wortmannin, Ly294002, demethoxyviridin, perifosine, delalisib, idelaisib, PX-866, IPI-145, BAY 80-6946, BEZ235, RP6530, TGR 1202, RP5264, SF1126, INK1117, BKM120, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, RP6503, PI-103, GNE-477, CUDC-907 and AEZS-136. 
     
     
         65 . The method of  claim 58 , wherein the PI3K inhibitor is selected from the group consisting of SAR245409, SAR245408, BYL-719, GDC-0980, GDC-0941, wortmannin, Ly294002, demethoxyviridin, perifosine, delalisib, idelaisib, PX-866, IPI-145, BAY 80-6946, BEZ235, RP6530, TGR 1202, RP5264, SF1126, INK1117, BKM120, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, RP6503, PI-103, GNE-477, CUDC-907 and AEZS-136. 
     
     
         66 . The method of  claim 57 , wherein the mTOR inhibitor is selected from the group consisting of SAR245409, GDC-0980, CCI-779, KU-0063794, rapamycin, epigallocatechin gallate (EGCG), caffeine, curcumin, resveratrol, sirolimus, temsirolimus, everolimus, and ridaforolimus. 
     
     
         67 . The method of  claim 58 , wherein the mTOR inhibitor is selected from the group consisting of SAR245409, GDC-0980, CCI-779, KU-0063794, rapamycin, epigallocatechin gallate (EGCG), caffeine, curcumin, resveratrol, sirolimus, temsirolimus, everolimus, and ridaforolimus. 
     
     
         68 . The method of  claim 58 , wherein the dual PI3-kinase/mTOR inhibitor selected from the group consisting of SAR245409, PWT33597, PI-103, GNE-477, NVP-BEZ235, BGT226, SF1126, PKI-587, XL765, PF-04691502, PF-05212384, and LY3023414. 
     
     
         69 . The method of  claim 56 , wherein the Akt inhibitor is selected from the group consisting of MK-2206, perifosine,GSK690693, ipatasertib (GDC-0068), AZD5365, afuresertib (GSK2110183), At13148, PF-04691502, AT7867, triciribine, CCT128930, A-674563, PHT0427, miltefosine, honokiol, and TIC10. 
     
     
         70 . The method of  claim 58 , wherein the Akt inhibitor is selected from the group consisting of of MK-2206, perifosine,GSK690693, ipatasertib (GDC-0068), AZD5365, afuresertib (GSK2110183), At13148, PF-04691502, AT7867, triciribine, CCT128930, A-674563, PHT0427, miltefosine, honokiol, and TIC10. 
     
     
         71 . The method of  claim 56 , wherein the PDGFR inhibitor is imatinib. 
     
     
         72 . The method of  claim 58 , wherein the PDGFR inhibitor is imatinib.