EXTH-55. TARGETING RECURRENT IDH MUTANT GLIOMA WITH CDK4/6 INHIBITION

Abstract

Abstract Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressively and lead to untimely death. Recurrent IDH mutant tumors are less responsive to conventional treatments, highlighting the need for improved therapeutic strategies at this stage of the disease. At least 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, which results in aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors, which are approved for use in a variety of other cancer types. We examined the relationship between CDK4/6 inhibitor sensitivity and CDKN2A loss using patient-derived models of IDH mutant glioma with endogenous CDKN2A homozygous deletion as well as with CRIPSR-mediated gene deletion. We observed enhanced cytotoxicity in glioma models with CDKN2A loss in vitro. Studies to examine the efficacy of CDK4/6 inhibitor treatment on slowing tumor growth in patient-derived xenograft models are ongoing. These preclinical results provide foundational data for design of a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.