Finding Targeted Therapies for Pediatric Medulloblastoma

Summary

Medulloblastoma, a predominantly pediatric brain tumor, is the most common malignant central nervous system (brain) tumor in children, and high-risk patients continue to have very poor survival. Moreover, the aggressive chemo and radiation therapy exposure they get during cancer treatment has detrimental long-term consequences, including irreversible neurocognitive or endocrine consequences. To drive development of more selective, anti-cancer agents with reduced side effects, we need to determine the molecular drivers of medulloblastoma and design targeted drugs. Unbiased and functional experimentation on human medulloblastoma cells to determine if large druggable gene families regulate cell growth or motility are an essential first step to designing targeted therapy. Ion channels are the third largest family in the human genome, with over 200 gene members, and are also targets of 14% of all FDA approved drugs. The biological role of ion channels in cancer is under-evaluated. Here we propose to do large scale, unbiased screening assays to evaluate if any of the 211 genes in this family that is readily druggable, control medulloblastoma cell growth or migration. We anticipate finding previously unknown ion channel drivers of medulloblastoma cell behavior, and we will conduct follow up studies to determine if existing ion channel-targeted drugs block human medulloblastoma tumor cell survival.

Why is this important?

Our proposed research aims to take an unbiased and functional approach to determine if ion channel genes drive the growth or migration of human medulloblastoma tumor cells. Identifying specific drivers of individual cancer types permits the development  of targeted therapeutic agents that are more selective and therefore have reduced long term adverse side effects. These functional tests may also be further applicable for determining if ion channels are drivers of other cancers with high metastatic potential, including lung cancer, breast cancer and melanoma.

It is estimated that it takes about 12 years and 800 million dollars to bring a novel targeted drug from concept to clinical application. Identifying ion channels as potential cancer cell drivers may permit repurposing existing FDA approved agents, thereby accelerating the time to clinical use and providing a substantial cost savings.