CDK12 Links Radiation Response to PARPi Sensitivity in Pediatric Glioma
High-grade gliomas (HGGs) are the leading cause of cancer-associated death in children, and new therapies are desperately needed for children with these tumors. The current standard-of-care treatment for HGG is radiation therapy. Radiation controls these tumors for a time, but they inevitably grow back. Understanding how HGG adapts to and recovers from radiation may allow us to interrupt that process, increasing the benefit of radiation and prolonging survival for children undergoing treatment. We have recently described how transcription, or the process by which cells copy from their genetic code, is critical for how HGGs reorganize chromatin to recover from radiation. We have shown that targeting this process by using drugs to inhibit key regulators of transcription called CDKs is an effective therapy in preclinical models of HGG. Our recent data identifies CDK12 activity as essential for HGG cells to survive radiation, and that by blocking this with CDK12 inhibitors, we can significantly improve response to radiation therapy. Doing this also imparts a new susceptibility to drugs targeting PARP, a protein involved in repairing the DNA damage caused by radiation, creating an effective combination strategy for therapy.
The overall goal of this project is to understand how HGG cells adapt their transcriptional machinery as they recover from radiation treatment. By understanding key mechanisms that drive this process, we aim to validate and optimize ways of blocking this response and increasing the therapeutic benefit received from radiation. We know that radiation therapy is effective in HGG, but the ability to change transient responses into durable ones would prove transformative. Our lab employs a range of techniques spanning basic transcription and cancer biology, from cutting-edge sequencing of new RNA to 3D radiation delivery in animal models, that are ideally suited to address this need. CDK12 inhibitors represent a new class of medications with unexplored potential in this disease. Successful completion of our proposal will provide new insights to the biology underlying HGG response to therapy, and it will lay the scientific rationale necessary to bring this promising class of drugs into trials designed to meaningfully benefit children with HGG.