"The gliomas are a large group of brain tumors and Glioblastoma Multiforme (GBM) is the most common and lethal primary central nervous system (CNS) tumor in adults. Despite the recent advances in treatment modalities, GBM patients generally respond poorly to all therapeutic approaches and prognosis remain dismal. Standard therapy for GBMs includes resection of the tumor mass, followed by concurrent radiotherapy and chemotherapy, using the alkylating agent temozolomide (TMZ). Nonetheless, GBM patients remain refractory to treatment. Understanding the genetic events that lead to glioma formation and the mechanisms of resistance to therapy will be instrumental for the development of new treatment modalities for gliomas.Maintenance of genomic integrity is essential for embryonic development and adult tissue homeostasis. Defects in the DNA Damage Response (DDR) machinery, a network of protein complexes capable of detecting DNA lesions and signaling to downstream effector pathways (cell cycle checkpoints, DNA repair, apoptosis, etc.), are linked to numerous pathological states including brain cancers. The focus of this proposal is the identification of DDR genes involved in tumor formation and therapy resistance of gliomas. We will also investigate how the tumor microenvironment contributes to resistance to standard treatment modalities. We reason that these studies will help to define new therapeutic targets for treatment of brain tumors."