Small-molecule screening for novel pediatric glioma radiosensitizers.

Primary brain tumors are one of the most common solid neoplasms in children, and they are a leading cause of cancer-related mortality. In particular, pediatric high grade gliomas are clinically devastating tumors, with associated 5-year survival rates of less than 20%. The current treatment for these cancers begins with surgical removal of the tumor, followed by radiation therapy (RT) and chemotherapy. RT consists of ionizing radiation (IR), which kills residual tumor cells by inducing DNA breaks in the genomes of these cells. Unfortunately, the majority of tumors re-appear at the same location soon after treatment, suggesting that they are highly resistant to damage induced by both radiation therapy and chemotherapy. Several molecular pathways are responsible for the repair of DNA breaks in response to IR, and they are a critical determinant of tumor cell survival after radiation therapy. Therapies which impair the ability of brain tumor cells to properly repair DNA damage after ionizing radiation are thus likely to enhance the response to radiation therapy. The applicant recently has created a novel system to identify modulators of DNA repair in cancer cells. In this application, we propose to apply this system in a small molecule screen for DNA repair inhibitors in pediatric glioma cells. Experiments then will be performed to determine whether they specifically enhance tumor cell kill when combined with IR in a mouse model in vivo. Such drugs, referred to as 'radiosensitizers', have the potential to significantly improve the survival of children diagnosed with pediatric high grade gliomas.