Targeting MYC/MYCN-driven Transcriptional Amplification in Pediatric Cancer
The goal of this project is to test a novel strategy for disrupting the effects of MYCN amplification, which is seen in over 50% of high risk neuroblastoma patients. Although the association of MYCN amplification with a poor outcome is well established, attempts to target MYCN have been challenging. Recent studies have shown that tumor cells with abnormal MYC expression (a gene similar to MYCN) are distinguished by massively increased expression of genes (transcription) that are critical for the uncontrolled growth and survival of the tumor. We propose to take advantage of this concept to specifically inhibit such global gene upregulation by targeting CDK7, a kinase that is critical to MYC's role of driving gene expression. We and collaborators have developed a novel covalent CDK7 inhibitor and have shown that this compound selectively kills MYCN amplified neuroblastoma cells at much lower doses than unamplified neuroblastoma cells and normal cells not at all.
In this application, we plan to study the mechanisms by which CDK7 inhibition targets MYCN amplification. Secondly, we will ensure that such a strategy is clinically feasible by testing it in animal models of human neuroblastoma.
Thirdly, we will test inhibitors of other CDKs that are critical to transcription to determine their potential as therapies in MYC/MYCN-driven neuroblastoma and other cancers. Our studies will provide preclinical data to support Phase 1 trials of selective transcriptional CDK inhibitors in children with relapsed neuroblastoma either alone or in combination with currently used cytotoxic agents.