Molecular determinants of cellular heterogeneity and therapeutic resistance in GBM.

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Principal Investigator: Hernando Martin Lopez-Bertoni
Organization: HUGO W. MOSER RES INST KENNEDY KRIEGER
Fiscal Year: 2024
Award: $393,854
Funding agency: National Institute of Neurological Disorders and Stroke

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.

Terms: <Advanced Development><Affect><Architecture><Automobile Driving><Brain Neoplasia><Brain Neoplasms><Brain Tumors><Cancer Genes><Cancer-Promoting Gene><Cell Body><Cell model><Cells><Cellular model><Chromatin><Chromium><Cr element><Data><Development><Dimensions><Disease><Disorder><ELF3><ELF3 gene><EPR-1><ERT gene><ERT protein><ESE-1><ESX><Engineering / Architecture><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Esters><Formulation><Gene Delivery><Gene Transcription><Generations><Genetic Transcription><Genomics><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Heterogeneity><Human><Intratumoral heterogeneity><Long-Term Survivors><Maintenance><Messenger RNA><Micro RNA><MicroRNAs><Modern Man><Molecular><Neuroglial Neoplasm><Neuroglial Tumor><Non-Polyadenylated RNA><Nucleosomes><Oncogenes><Oncogenesis><Oncogenic><Operative Procedures><Operative Surgical Procedures><Pathogenesis><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phenotype><Polymers><Population><Position><Positioning Attribute><Progenitor Cells><Progression-Free Survivals><Publishing><RNA><RNA Expression><RNA Gene Products><Radiation><Radio><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Resistance><Resolution><Ribonucleic Acid><Role><Single cell seq><Stem Cell like><Surgical><Surgical Interventions><Surgical Procedure><System><TGF-Beta Type II Receptor><TGFBR2><TGFBR2 gene><Technology><Temodal><Temodar><Testing><Therapeutic><Therapeutic Intervention><Transcription><Transforming Genes><Treatment Efficacy><Xenograft Model><aggressive therapy><aggressive treatment><chemotherapy><design><designing><developmental><driving><epigenetically><glial-derived tumor><glioblastoma multiforme><glioma cell line><global gene expression><global transcription profile><heterogeneity in tumors><improved><in vivo><innovate><innovation><innovative><intervention efficacy><intervention therapy><intra-tumoral heterogeneity><intratumor heterogeneity><longterm survivors><mRNA><methazolastone><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA delivery><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA delivery><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><nano><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm recurrence><neuroglia neoplasm><neuroglia tumor><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next generation><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathway><patient oriented outcomes><polymer><polymeric><pre-clinical><preclinical><prevent><preventing><progenitor-like cell><rational design><resistance to therapy><resistant><resistant to therapy><resolutions><self-renew><self-renewal><single cell genomics><single cell next generation sequencing><single cell sequencing><social role><spongioblastoma multiforme><standard of care><stem cell characteristics><stem cells><stem-like cell><stemness><surgery><targeted agent><temozolomide><therapeutic efficacy><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><therapeutic resistance><therapeutic target><therapy efficacy><therapy resistant><tool><transcriptome><transcriptomics><transforming growth factor-beta type II receptor><transforming growth factor-β type II receptor><treatment resistance><tumor><tumor growth><tumor heterogeneity><tumorigenesis><tumors in the brain><xenograft transplant model><xenotransplant model>