Understanding Mechanisms of Alkylation Chemoresistance in Pediatric Glioblastoma
Nima Mosammaparast, M.D., Ph.D.
Pathology and Immunology
- McDonnell Pediatric Cancer Center
Interdisciplinary Research Initiative
7/1/2015 - 6/30/2017
Pediatric glioblastoma multiforme (GBM) is an aggressive brain tumor associated with a very poor prognosis. Commonly used chemotherapeutic drugs for adult GBM are typically not effective in the pediatric population. We recently discovered a new protein complex that regulates the molecular pathways critical for GBM chemotherapy. This complex consists of OTUD4 and USP7/9X enzymes, which enhance DNA repair through a process called deubiquitination. We propose to inhibit the OTUD4-USP7/9X enzyme complex to improve the response of pediatric GBM to specific chemotherapeutic agents that function by damaging DNA. This proposal will expand on promising preliminary data on the OTUD4 pathway into preclinical testing of pediatric GBM using available inhibitors that target this complex. The specific aims are to test whether:
• The OTUD4-USP7/9X complex is overexpressed in GBM cells and promotes resistance to a chemotherapy agent called temozolomide (TMZ).
• USP7/USP9X small molecule inhibitors can promote TMZ chemosensitization in an established mouse model of pediatric GBM.
Understanding how tumor cells regulate the proteins responsible for repairing damage induced by chemotherapy will have broad implications not only for pediatric GBM, but also for numerous other tumors that are treated with these drugs.
Translational Impact: This work supports pre-clinical studies on pediatric GBM in a mouse xenograft model to test efficacy of a new therapeutic strategy (mid T1).