There is presently no cure for high grade gliomas which are associated with a bleak prognosis and a poor quality of life. GBM patients typically undergo surgical resection followed by radiation therapy (RT) combined with the alkylating agent temozolomide (TMZ). However, virtually all GBM patients either fail to respond to this treatment, or ultimately develop resistance, underlining the urgency for effective adjuvant therapies. Both RT and TMZ can target tumor cells by causing lethal DNA double-strand breaks, which could be recognized and repaired by the intrinsic DNA damage response (DDR) thus protecting against DNA damage-induced cell death. Further, GBMs are enriched in a subset population of glioma cancer stem cells (GSCs), characterized by an upregulated DDR which contributes to their superior therapeutic resistance. Targeting DNA repair can increase/restore sensitivity of brain tumors to TMZ and RT, thus increasing therapeutic efficacy and minimizing tumor recurrence. We have designed a rapid, versatile and highly sensitive reporter that can detect and quantify minute amounts of DNA double-strand break repairs such as homology-directed repair as well as non-homologous end joining without disrupting cells. Here we propose to use this reporter in order to identify modulators of DNA damage repair in GSCs.
In Aim 1 (R61 phase), we will develop and optimize a high-throughput screening assay to monitor DDR in GSCs.
In Aim 2 (R33 phase), we will use this assay to screen for compounds which inhibit DNA damage repair. Upon completion of this project, this screen should identify novel compounds which effectively sensitize GSCs to chemoradiotherapy and increase the efficacy of genotoxic therapeutics.
Glioblastoma is an aggressive and incurable type of brain tumors enriched in a subset population of glioma stem cells (GSCs) that are resistant to radiation and chemotherapy, and responsible for tumor recurrence. We describe a screening platform which we will use to identify small molecules that inhibit DNA damage repair in GSCs, thus sensitizing them to conventional genotoxic therapy. Our proposed study is poised to identify adjuvant therapeutic strategies for brain tumors.
