Friday, November 22, 2024
11/22/2024
Despite aggressive therapy consisting of surgery followed by radio/chemotherapy GBM recurs in almost all patients with a progression-free survival of only 10 weeks. Currently there are no proven therapies to treat recurrent GBM largely due to our inadequate molecular understanding of the disease. Glioma stem-cells (GSCs) are critical determinants of intra-tumor heterogeneity, tumor propagation, therapeutic resistance, and recurrence following treatment. This project entitled Molecular determinants of cellular heterogeneity and therapeutic resistance in GBM brings together a cross-disciplinary team of experts using state-of-the art GBM cell models, single-cell genomics, and innovative gene-delivery technology to understand how GSC-driving mechanisms contribute to the generation of tumor-propagating and therapy resistant cells in GBM with the goal of defining novel therapeutic targets. Aim 1 of this proposal will seek to determine how stem-cell driving mechanisms induce therapy resistant GSCs. Mechanistically, we will test the hypothesis that Oct4 and Sox2 drive/maintain a therapy-resistant phenotype in GSCs by activating TGFBR2 expression and function via an Oct4/Sox2:ELF3:TGFBR2 axis. As a mid-term strategy to dissect the molecular mechanism driving therapy- resistance in GBM we will combine our validated cell systems and the state-of-the-art 10x Genomics Chromium pipeline to interrogate the transcriptome and chromatin state of patient-derived glioma cell lines their therapy- resistant counterparts at the single cell level. Aim 2 of this proposal will focus on developing novel molecular agents that target therapy-resistant GBM cell populations. We will build on the positive momentum of our recent novel developments in miRNA-based therapeutics to design molecular approaches to better inhibit tumor growth, prevent emergence of therapy-resistant cell subpopulations, and sensitize therapy-resistant cells to chemo/radiation in human xenograft models of GBM. Our preliminary data shows that miR-149-3p can inhibit 8 putative oncogenes simultaneously whose coordinate action drive tumor maintenance and therapeutic resistance. Aim 2.1 of this proposal will explore the mechanistic contribution of miR-149-3p to the therapy- resistant phenotype of GSCs. Aim 2.2 will investigate the pre-clinical translatability of our new-found concepts by testing novel combinations of miRNAs to more effectively normalize oncogenic networks dysregulated by stem-cell driving mechanisms in GBM. Completion of this study will: (i) Define the cell sub-populations capable of tumor propagation; (ii) define cell populations capable of transitioning to a therapy-resistant state; (iii) determine transcriptomic and chromatin changes associated with these cell populations that are amenable to therapeutic targeting; (iv) provide novel rational pre-clinical therapeutics to potentially treat recurrent GBM. Completion of this project will provide a roadmap to both understanding and more effectively treating resistant GBM, hence improving patient outcomes and saving lives.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
