EXTH-63. PRECLINICAL EFFICACY OF A CDK INHIBITOR (TG02) IN GLIOBLASTOMA

Abstract

Radiation is the most effective treatment for glioblastoma (GBM), however tumor recurrence develops in all patients. Novel treatment strategies targeting multiple pathways in combination with radiation are needed. TG02 is an orally-bioavailable multi-kinase inhibitor of CDK5 and CDK9 targeting MYC and the Bcl-2 family survival protein, Mcl-1, both commonly overexpressed in GBM. MYC and Mcl-1 overexpression leads to increased proliferation and is associated with treatment resistance. We examined the preclinical efficacy of TG02 both as monotherapy and in combination with radiation in a panel of 10 GBM patient derived cell lines (PDCLs). TG02 treated PDCLs were subjected to luminescent ATP assays and cell viability was determined relative to DMSO control. TG02 was found to decrease cell viability in all PDCLs tested, with IC50 values ranging from 25nM to 3μM. PDCLs highly expressing Mcl-1 or MYC showed increased sensitivity to treatment with TG02. Furthermore, PDCLs treated with TG02 followed by a range of doses of ionizing radiation showed that TG02 synergizes with radiation in some but not all PDCLs, but TG02 was effective in radiation resistant lines suggesting possible hypothetical synergy in a theoretic mixed clonal population. These results provide evidence for the efficacy of TG02 against GBM patient derived cell lines and supports the development of TG02 in combination with radiation for clinical testing in glioblastoma.