Exploring New Strategies to Overcome Resistance in Glioblastoma Multiforme: A Dissertation

摘要: Glioblastoma multiforme (GBM) tumors are highly malignant in nature and despite an aggressive therapy regimen, long–term survival for glioma patients is uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. This creates need investigate new therapies enhancing GBM outside of standard care, which includes Temozolomide (TMZ). Our lab focused on two novel strategies overcome GBMs. In our first approach, cellular responses cell lines TMZ analogues, DP68 DP86, reported. The efficacy these compounds was independent DNA repair mediated by Methyl Guanine Transferase (MGMT) mismatch (MMR) pathway. DP86 treated do not give rise secondary spheres, demonstrating that they no longer capable self-renewal. DP68-induced damage interstrand crosslinks exhibits a distinct S-phase accumulation before G2/M arrest; profile observed TMZ-treated cells. induces strong response suppression FANCD2 expression ATR expression/kinase activity enhanced antiGBM effects DP68. Collectively, data demonstrate DP68, lesser extent potent anti-GBM circumvent inhibit recovery cultures. second approach stems from previous discovery demonstrated combination Notch inhibition, using gamma secretase inhibitor (GSI), enhances therapy. Efficacy + GSI partially due shifting into permanent senescent state. We sought identify miR signature mimics alternative