Advisory Committee Chair
Advisory Committee Members
Christopher Ryan Miller
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) School of Medicine
Treatment options for the universally lethal brain tumor, glioblastoma (GBM), are severely limited and often unsuccessful in fully eradicating the disease. Extremely aggressive in nature, GBM cells often implore suppressive mechanisms to evade therapeutic detection which aids in the dismal 15-month median survival rate. Facilitating disease severity and more importantly, disease recurrence, are the immunosuppressive and chemoresistant phenotypes of GBM cells. Specifically, the DNA alkylating agent, temozolomide (TMZ) possesses lymphodepleting properties shunting robust immune cell infiltration into an immunologically cold tumor microenvironment. Additionally, through inherent or acquired mechanisms, GBM tumors commonly become resistant to the DNA damaging effects of TMZ diminishing therapeutic potential. Our body of work utilizes both gamma-delta T cell mediated immunotherapy and tumor treating fields (TTFields) to overcome these respective hurdles. From our findings, we provide support that using DNA damage driven stress ligand induction via combined PARP inhibition with niraparib and DNA alkylation with TMZ aids in the gamma delta T cell mediated killing of GBM iv cells. Additionally, we demonstrate that TTFields can disrupt the growth of TMZ sensitive and resistant cells. Furthermore, we showed that combinatorial treatment of TTFields with the platelet derived growth factor receptor (PDGFR) inhibitor, crenolanib, further attenuated cell growth supporting our kinomic analysis predicting PDGFR as being increased potentially serving a compensatory survival mechanism. Interestingly in both of our investigation, there were varied levels of sensitivity to the respective treatments imploring further investigation to identify specific regulators. Collectively, we provide molecular basis for combinatorial strategies that can be further explored for therapeutic implementation in GBM.
Jones, Amber B., "Understanding Molecular Mechanisms of Glioblastoama Resistance to Design Novel Combinatorial Therapies" (2023). All ETDs from UAB. 419.