Molecular Pathogenesis of Neoplasia

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Protein Phosphatase 2A Inhibition and its Interaction with Chemotherapy and Radiotherapy Effects: We previously studied the inhibitory activity LB-100,a first-in-class small molecular inhibitor of Protein Phosphatase 2A (PP2A), in the mouse xenograft human GBM animal model. This compound had a mild effect as a single agent in slowing GBM growth in animals. However, its effects against GBM increased when combined with radiation or chemotherapy. LB-100 was well-tolerated against solid tumors in a Phase 1 clinical trial conducted outside the NIH, suggesting that LB-100 would also be well-tolerated if used as a chemosensitizer or radiosensitizer in clinical trials of glioblastoma patients. We continue to study the effects of PP2A and the role of PP2A inhibition in GBM therapeutics. Protein Arginine Methyltransferase 5 Inhibition in Models of Glioblastoma: Under the supervision of Dr. Banasavadi, the Molecular and Therapeutics unit of SNB is interested in studying the role of Protein Arginine Methyltransferase 5 (PRMT5) in brain tumors. PRMT5 catalyzes the symmetric di-methylation of arginine residues and is overexpressed in GBM. Our previous findings show that inhibition of PRMT5 causes senescence in stem-like GBM tumor cells. We conducted an extensive literature review compiling the significance of arginine methylation in brain tumors that was published as a review manuscript. We also tested the anti-GBM effect of concurrent PRMT5 and PP2A inhibitionWe found that PRMT5-depletion increased PP2A activity in GBM neurospheres (GMBNS). LB-100 treatment significantly reduced the viability of PRMT5-depleted GBMNS compared to PRMT5 intact GBMNS. LB100 enhanced G1 cell cycle arrest induced by PRMT5-depletion. Combination therapy also increased the expression of phospho-MLKL. Necrostatin-1 rescued PRMT5-depleted cells from the cytotoxic effects of LB100, indicating that necroptosis caused the enhanced cytotoxicity of combination therapy. In the in vivo mouse tumor xenograft model, LB100 treatment combined with transient depletion of PRMT5 significantly decreased tumor size and prolonged survival, while LB100 treatment alone had no survival benefit. Overall, combined PRMT5 and PP2A inhibition had significantly greater antitumor effects than PRMT5 inhibition alone. This study was published in the journal, Neuro-Oncology. Further, we published a review article that details the significance of PP2A in nervous tumors and the effectiveness of PP2A inhibitor, LB100, in treating nervous system tumors. As a part of collaborative projects, Dr. Banasavadi contributed to testing the effect of the RAMBO virus on vascularized tumors. Further, he was involved in a project exploring the glucagon-like peptide 1 receptor agonist Extendin-4's role in inducing tenogenesis in human mesenchymal stem cells. Study of an Etiologic Role of Human Endogenous Retroviruses in Glioma Pathogenesis: Dr. Ashish Shah in SNB is collaborating with Dr. Avindra Nath's lab (Section of Infections of the Nervous System, SINS) in NINDS and Dr. Zhengping Zhuang's laboratory in NOB/NCI to evaluate the role, if any, of endogenous retroviruses in glioma pathogenesis. Dr. Shah wrote a review of the scientific literature regarding the role of human endogenous retroviruses in glioma etiology and potential therapeutic implications in preparing for his laboratory studies. The review suggested that HERVs can serve a dichotomous role as either an oncogenic driver or a stimulator of the antiviral immune response. Dr. Shah has characterized HERV expression in several glioma cell lines using a custom ensemble workflow developed through the NINDS Bioinformatics core. As demonstrated in other cancers, regional methylation may also regulate the expression of these endogenous retroviruses in glioma cell lines. Immunotherapy of Glioblastoma The Protein Phosphatase 2A (PP2A) inhibitor described above, LB-100, was found to enhance the antitumor effects of an immune checkpoint inhibitor in an animal model of glioblastoma. We published a report with Dr. Zhuang and other Neuro-Oncology Branch, NCI (NOB/NCI) colleagues showing that pharmacologic inhibition of protein phosphatase-2A achieved durable immune-mediated antitumor activity when combined with PD-1 blockade (7). This combination of a PP2A inhibitor and PD-1 blockade may be translated to human clinical trials by our collaborators in NOB/NCI. The SNB laboratory also collaborated with NOB/NCI to study the immune effects of vaccination with Mannan-BAN (Biocompatible Anchor for Cell Membrane), toll-like receptor (TLR) ligands, and Anti-CD40 antibody (MBTA) against primary and metastatic tumors of the CT26 murine colon carcinoma cell line. MBTA triggered a potent antitumor immune response, including against intracranial metastatic tumors (8). The NOB/NCI group is planning on testing this vaccine in animal models of glioblastoma. Collaborative Efforts to Improve the Treatment of Brain and Spinal Neoplasms The Surgical Neurology Branch joined forces with investigators in the Neuro-Oncology, Laboratory of Pathology, and Clinical Genetics Branches of NCI, and outside the NIH to find better ways to evaluate and treat brain and spinal malignancies. This year, several basic, translational, and clinical research publications resulted from these collaborative efforts.