NT-20 * TARGETING CDK4 AND 6 IN THE CLASSICAL SUBTYPE OF GLIOBLASTOMA

Abstract

BACKGROUND: Glioblastoma is highly refractory to conventional treatment approaches. Since the introduction of concomitant and adjuvant temozolomide and radiotherapy, patients with glioblastoma have shown little improvement in the median survival time of just 15 months. Inhibitors that target the cell cycle of the tumour present an exciting prospect for glioblastoma, in particular the classical subtype. Overexpression of the cyclin dependent kinases (CDK) 4 and 6 as well as the homozygous deletion of CDNK2A are common events in glioblastoma. MATERIALS AND METHODS: We have developed over 15 patient derived xenograft (PDX) models with whole genome sequencing data. We identified the PDX models (n = 4) that were of a "classical" subtype i.e. harbored mutations and amplification of EGFR, homozygous deletion of CDKN2A and wildtype for TP53 and RB1. We also measured the protein expression levels of CDK4/6 to confirm overexpression. We tested a highly specific and potent antiproliferative CDK4/6 inhibitor on this pre-selected panel of patient derived glioblastoma cells. We tested the efficacy of the CDK4/6 inhibitor as a monotherapy and in combination with radiotherapy (RT). Expression of CDK4 and 6 is also regulated by the microRNA (miRNA)-124a. Loss of miR-124a leads to the dysregulation of the CDK proteins and increased cell proliferation. Cells were transfected with miR-124a and then treated with the CDK4/6 inhibitor (+/- RT) to determine if efficacy is increased. RESULTS: We found, as a monotherapy, the CDK4/6 inhibitor to be highly effective in causing cell death on the pre-selected PDX cell lines (IC50: 5-15 µM). Increases in efficacy were observed when we combined the inhibitor with RT and when the cells were transfected with miR-124. In vivo analysis of the drug and in combination with RT and miR-124 are currently underway. CONCLUSION: This study presents a new potential clinical strategy for patients with classical glioblastoma.