Therapies inhibiting the activity of receptor tyrosine kinases (RTK) in Glioblastoma (GBM) failed in the clinic, in part because the molecular mechanisms that act as roadblocks for RTK-targeted therapies to induce tumor apoptosis and regression remain elusive. To define anti-apoptotic mechanisms limiting the effectiveness of RTK inhibitors (RTK-Is), we conducted transcriptomic profiling of RTK-I resistant glioma cells, and identified RTK-I-driven induction of the sterol regulatory element-binding protein (SREBP)-1- wildtype isocitrate dehydrogenase 1 (wt-IDH1) signaling axis as a critical pro-survival mechanism antagonizing RTK-I treatment. wt-IDH-1 is an SREBP-1-induced enzyme of the tricarboxylic acid cycle (TCA) that catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate and reduction of NADP+ to NADPH. NADPH from this reaction is necessary for the regeneration of reduced glutathione and thioredoxin, and for sustaining fatty acid and cholesterol biosynthesis. Our preliminary studies revealed that RNAi-mediated knockdown of IDH1 sensitized resistant GBM cells toward RTK-Is, and that wt-IDH1 is significantly overexpressed in primary GBM tumors, suggesting that non-mutated IDH1 represents a critical anti-apoptotic oncogene in GBM. Based on these studies and recent reports demonstrating that GBM tumors utilize mitochondrial glucose oxidation via the TCA cycle to support survival and aggressive tumor growth, we will test the hypothesis that elevated wt-IDH1 levels and activity promote growth, and block RTK-I-triggered apoptosis by scavenging reactive oxygen species and increasing lipid metabolism in patient-derived tumor neurospheres (TNS) cultures in vitro (Aim 1) and TNS-derived orthtotopic explant models in vivo (Aim 2). Importantly, we have developed a novel RNAi-based nanotechnological platform, termed spherical nucleic acids (SNAs), i.e., polyvalent gold nanoparticles functionalized with small interfering (si)RNA oligonucleotides. These RNAi-based nanoconjugates potently neutralized gene expression, crossed the blood-brain barrier upon systemic intravenous administration, stably accumulated in and disseminated throughout glioma tissue, and when functionalized with siRNA oligonucleotides targeting critical anti-apoptotic genes, increased survival of glioma-bearing mice in the absence of significant adverse side effects and immunogenicity.
|Effective start/end date||5/1/13 → 4/30/15|
- Alliance for Cancer Gene Therapy (Agmnt Fully-Executed 7/8/13)