Friday, May 23, 2025
5/23/2025
Novel functions of ESRRB in glioblastoma - Glioblastoma (GBM) is the most lethal of all brain malignancies and many patients die within one year of diagnosis. These poor outcomes are driven by GBM's aggressive growth, local invasion, and both de novo and rapid development of radiotherapy and chemotherapy resistance. GBM uses alternative splicing to generate unique mRNAs and proteins that promote its proliferation and invasion. Here, we investigate specific alternative splicing programs and will test if their manipulation has the potential to reveal novel therapeutic strategies to oppose the aggressive biology of this deadly disease. Estrogen-related receptor beta (ESRRB) is an orphan nuclear receptor - it is not bound by estrogen. Upregulated expression and increased ESRRB gene copy number are both associated with longer overall GBM survival. The beta2 isoform of ESRRB is produced by alternative splicing, with current evidence implicating serine/arginine-rich splicing factor 6 (SRSF6) as a key driver of this event. Beta2 activation by the synthetic ESRRB agonist DY131 induces apoptosis in GBM cells. Beta2 localizes to the cytoplasm and interacts with cortactin, an actin binding protein that increases cell motility by controlling actin remodeling and vesicle trafficking. Importantly, the synthetic ESRRB agonist stabilizes beta2/cortactin interaction, leading to loss of GBM cell motility, effects we propose are linked to the antitumor effect of beta2. In this proposal, we hypothesize that the beta2 isoform of ESRRB acts as a potent inhibitor of GBM by interacting with cortactin to inhibit motility/invasion. We further propose that pharmacological upregulation/activation of beta2 may ultimately offer a novel approach to GBM therapy. In Specific Aim 1, we will test if SRSF6 promotes ESRRB splicing to increase beta2 expression levels, and if direct upregulation of beta2 by SRSF6 inhibits GBM motility/invasion. We will complement these focused, mechanistic studies by testing two novel splicing modulatory drugs for their ability to increase beta2 production in GBM. In Specific Aim 2, we will identify how the beta2/cortactin interaction inhibits GBM motility. Specifically, we will test if beta2 suppresses GBM motility by inhibiting cortactin-mediated actin branching and remodeling, and vesicular trafficking in GBM. In parallel, we will perform an unbiased screen to identify other novel cytoplasmic binding partners of beta2, and test their role in suppressing GBM motility. While this grant is focused on foundational mechanistic studies, they will provide powerful preclinical evidence for a future novel therapeutic strategy for GBM. The long-term impact of successfully establishing a new treatment regimen that upregulates and activates beta2 would be a major benefit to the field, in which 1) the current first-line standard of care (surgery, concurrent temozolomide + radiotherapy, adjuvant temozolomide) has remained essentially unchanged for nearly 20 years, and 2) there is no widely accepted second-line standard of care.
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).