A NOVEL PERSONALIZED STRATEGY TARGETING DNA REPAIR PATHWAY ADDICTIONS IN GLIOBLASTOMA: FROM PATIENT STRATIFICATION TO PRECLINICAL VALIDATION

CLINICAL CHALLENGES IN THE TREATMENT OF GLIOBLASTOMA (GBM): Despite surgery and genotoxic treatment with ionizing radiation and the DNA alkylating agent temozolomide, the median survival of patients with newly diagnosed GBM is only about 15 months. The challenges confronting clinicians and researchers include the inevitable occurrence of therapy resistance driven by DNA repair mechanisms, the limited number of therapeutic options, especially after the first line of therapy has failed, and important inter-tumor heterogeneity hampering patient stratification and personalized therapeutic strategies.
PREVIOUS RESEARCH RESULTS:We recently identified and validated a novel 27 DNA repair and cell-cycle gene signature that results in a novel classification of GBM specimens into two majors groups (G1 and G3) that display an inverse expression profile of the signature, develop discrete cell survival and proliferation programs and are associated with distinct molecular alterations affecting core GBM pathways (Gobin et al (2019). Can Res. 79(6): 1226-1238). Using spheroid GBM cell cultures derived from G1- and G3-representative patients in vitro, we have provided experimental evidence that our signature exposes therapeutic vulnerabilities to specific inhibitors of the DNA damage response (DDR), mitosis disruptors and genotoxic agents, with the prospect of personalized therapeutic strategies.
OBJECTIVES: AN INNOVATIVE STRATEGY TO STRATIFY AND TREAT GBM TUMORS:Here, we plan to validate a novel, personalized therepeutic strategy for the management of GBM, based on patient stratification guided by our signature and specific targeting of DNA repair pathway addictions (Fig. 1). Specific objectives include the implementation of state-of-the art in vitro shRNA screens to identify the DNA repair pathway addictions that define the G1 and G3 groups of tumors identified by our signature, and the validation of such targets in pre-clinical animal models of GBM.
EXPECTED IMPACT: our research results will contribute to precision medicine for glioblastoma and shed new lights on the molecular mechanisms that drive DNA repair pathway addiction in GBM.