RCMI Pilot Project- Christopher Bolden

Project title: : Modulation of SorLA in the Glioblastoma Tumor Microenvironment

PI: Christopher Bolden

Email: cbolden6@xula.edu

Project Summary/Abstract :

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, with a median survival of 12–15 months despite current therapeutic strategies. GBM progression is driven by a highly infiltrative phenotype, resistance to chemotherapy, and protection by the blood-brain barrier (BBB), creating a critical need for novel therapeutic approaches. Recent evidence implicates SorLA (SORL1), a multifunctional intracellular trafficking receptor, as a regulator of signaling pathways critical to tumor proliferation, invasion, and therapy resistance. SorLA influences growth factor signaling (e.g., EGFR, PDGFR), extracellular matrix remodeling, and endosomal trafficking, all processes that underpin GBM’s resistance and invasiveness. However, the contribution of astrocytic SorLA signaling within the tumor microenvironment (TME) and its potential as a therapeutic target remain unexplored. This proposal leverages an innovative 3-D perfused BBB model to investigate SorLA mediated mechanisms in GBM.

Our central hypothesis is that SorLA signaling in astrocytes promotes GBM progression and that its inhibition can disrupt tumor supportive pathways and restore treatment responsiveness. Aim 1 will determine the role of SorLA in tumor-reactive astrocytes using CRISPR/Cas9-mediated deletion of SorLA and single-nucleus RNA sequencing to identify downstream transcriptional programs influencing GBM proliferation and angiogenesis. Aim 2 will evaluate pharmacological targeting of SorLA with the selective antagonist AF38469, alone and in combination with anti–PD-1 immunotherapy, assessing effects on GBM invasion, BBB integrity, and microenvironmental signaling using the 3-D BBB platform. The proposed research will elucidate the mechanistic role of SorLA in GBM-associated astrocytes and establish its viability as a therapeutic target. These studies could lay the groundwork for innovative combination strategies integrating SorLA inhibition with immunotherapy, offering transformative potential for improving GBM patient outcomes.