Exploiting Epigenetic Reprogramming of NGFR/NTRK Signaling in CARM1-Deficient Glioblastoma

About This Grant

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Despite aggressive therapy, survival remains poor because GBM is sustained by glioma stem-like cells (GSCs) that are highly plastic, therapy-resistant, and able to rewire signaling pathways. Epigenetic regulators are key drivers of this plasticity, but the specific molecular events that connect epigenetic changes to druggable signaling pathways are still not well understood. Our preliminary data identify the arginine methyltransferase CARM1 as a critical regulator of GSC biology. CARM1 methylates the transcription factor NFIA, which represses NGFR expression and downstream NTRK signaling. When CARM1 is lost, NGFR levels increase, GSCs shift toward a radial glial-like lineage state, and cells become more sensitive to the brain-penetrant NTRK inhibitor Entrectinib. These findings suggest a direct mechanistic link, CARM1¨NFIA(R389)¨NGFR, that connects an epigenetic modification to lineage programming and therapeutic vulnerability. First, we will test how CARM1-dependent methylation of NFIA controls NGFR/NTRK signaling and pathway responsiveness. We will use CRISPR editing, NFIA point mutants, proteomics, and chromatin assays to define the molecular mechanism. Second, we will evaluate the impact of CARM1 loss on tumor growth and drug sensitivity in vivo using orthotopic xenografts in immunodeficient mice treated with Entrectinib. Animal studies are necessary because cell culture systems cannot reproduce the intracranial microenvironment, blood.brain barrier.dependent drug exposure, tumor progression, and survival outcomes required to evaluate this therapeutic strategy. Immunodeficient mice are required to permit reliable engraftment of human patient-derived GSCs and to determine whether the molecular and pharmacologic effects observed in vitro translate to tumors growing within the brain. Together, these aims will dissect both the molecular mechanism and therapeutic implications of CARM1 loss in glioblastoma. The innovation of this proposal focuses on post-translational modification of a transcription factor as a switch that controls a clinically relevant signaling pathway. We will determine how CARM1 regulates GSC lineage states and creates a new vulnerability that can be targeted with an FDA-approved drug. Overall, this project will provide mechanistic insight into how epigenetic enzymes reprogram glioblastoma and establish a framework for exploiting these changes therapeutically. If successful, the study will open a new avenue for treating glioblastoma by linking epigenetic regulation to targeted therapy