Saturday, November 23, 2024
11/23/2024
SUMMARY: OVERALL The overarching goal of this Brain Cancer SPORE renewal application is to reverse the notoriously poor outcome of patients with glioblastoma (GBM) and medulloblastoma (MB), the most common primary tumors in adults and children, respectively. This goal is achieved through a focused pursuit of our central hypothesis that an organized, multidisciplinary, integrated, flexible, and highly translational (“bench-to-bedside-and-back”) research program will lead to advances in the treatment of brain cancers. We seek to discover mechanistically diverse therapeutic strategies (including bio-therapies, targeted therapies, cellular therapies and immunotherapies) that attack intrinsic vulnerabilities of brain cancers, develop these strategies through rigorous preclinical testing, and deploy them in novel window-of-opportunity clinical trials. By pursuing this hypothesis over the past three funding cycles, we have successfully transitioned multiple agents from the bench to bedside by successfully undertaking a remarkable twelve clinical trials, including trials of Delta-24-RGD, an oncolytic virus , which we tested alone or in combination with the checkpoint inhibitor (ICI) pembrolizumab; Delta-24-RGDOX, an immune activating oncolytic viruses; bone marrow mesenchymal stem cells loaded with Delta-24; targeted therapies including BKM120, a PI3Kinase inhibitor; WP1066, a pSTAT3 inhibitor; IACS-010759, an OxPhos inhibitor; and engineered cord blood-derived Natural Killer (NK) cells. Also, in our current funding cycle we deciphered the genomic landscape of gliomas in underrepresented minority Black and Hispanic populations. Building on this exceptional track record, in this renewal we propose three fully translational projects that are specifically focused on overcoming the notoriously immunosuppressive tumor microenvironment (TME) of GBMs and MBs, and which are supported by four mission-critical Cores (Administrative, Pathology/Biorepository, Biostatistics/ Bioinformatics, Animal). Our Developmental Research and Career Enhancement Programs continue as incubators of new projects and portals for new investigators, with two of our proposed projects coming directly from these programs. The aims of our projects are: Combine Delta-24-RGD with genetically engineered NK cells, testing the hypothesis that oncolytic viruses and NK cells can shape the GBM immune TME to synergistic therapeutic effect (Aim 1): Restore phagocytosis in GBM-associated myeloid (GAMs) cells by targeting the QKI/PPARβ/RXRα (QPR) complex, testing the hypothesize that QPR agonists (bexarotene/ KD3010) can drive GAMs from an immunosuppressive to an anti-glioma state through QPR’s role in phagocytosis and antigen presentation (Aim 2); And exploit the immune consequences of U1 mutations in Sonic Hedgehog (Shh) MB, testing the hypothesis that the post transcriptional hyper-mutated state caused by a point mutation (r.3A>G) in the non-coding small nuclear RNA U1 of Shh MBs will exquisitely sensitize Shh MBs to ICIs and will provide novel antigens for the development of CAR T-cell strategies (Aim 3). Through these projects we will reverse the poor outcomes of GBM and MB and give new hope to patients with these devastating cancers.
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).
