Molecular Pathogenesis of Neoplasia

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

Protein Phosphatase 2A Inhibition and its Interaction with Chemotherapy and Radiotherapy Effects: We previously studied the inhibitory activity of LB100, 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 animal GBM growth. 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 in clinical trials of glioblastoma patients. We continue to study PP2A. We are exploring PP2A inhibition as a chemosensitizer or radiosensitizer in GBM therapeutics (1,2). Protein Arginine Methyltransferase 5 Inhibition in Models of Glioblastoma Under Dr. Banasavadi, the Molecular and Therapeutics Unit of SNB studies 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 (3). Our previous research showed that inhibition of PRMT5 causes senescence in stem-like GBM tumor cells. We also showed that combined inhibition of PRMT5 and PP2A had a more significant anti-GBM effect than either agent alone. We published a manuscript this year that reviewed the medical and scientific literature regarding the potential impact of PP2A inhibition on brain tumor therapeutics. Trametinib is a dual-kinase inhibitor used for the treatment of advanced malignant melanoma. Adaptive treatment resistance to trametinib precluded its clinical translation in GBM. We tested whether inhibition of PRMT5 can enhance the efficacy of trametinib against GBM. PRMT5 depletion enhanced trametinib-induced cytotoxicity in GBMNS. PRMT5 knockdown significantly decreased trametinib-induced AKT and ERBB3 escape pathways. However, ERBB3 inhibition alone failed to block trametinib-induced AKT activity, suggesting that the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib-treated GBMNS resulted from AKT inhibition and not ERBB3 inhibition. In orthotopic murine xenograft models, PRMT5-depletion extended the survival of tumor-bearing mice, and combination with trametinib further increased survival. This study was published in the journal Neuro-Oncology Advances (4). Dr. Banasavadi also collaborated on another project testing the impact of NOTCH blockade on virus-induced immunotherapy in GBM (5). Further, he contributed to a project exploring the ability of insulin-functionalized electrospun nanofiber matrices with or without mesenchymal stem cells to enhance tendon repair in a rat Achilles injury model (6,7). Study of an Etiologic Role of Human Endogenous Retroviruses in Glioma Pathogenesis Dr. Ashish Shah in SNB collaborated with the laboratories of Dr. Avindra Nath in the Section of Infections of the Nervous System (SINS)in NINDS and Dr.Zhengping Zhuang in NOB/NCI to evaluate the role of endogenous retroviruses in glioma pathogenesis. Dr. Shah reviewed the scientific literature regarding the role of human endogenous retroviruses in glioma etiology and its potential therapeutic implications (8). This review suggested that HERVs can serve a dichotomous role as an oncogenic driver or a stimulator of the antiviral immune response. Dr. Shah then completed laboratory studies characterizing HERV expression in several glioma cell lines using a custom ensemble workflow developed through the NINDS Bioinformatics core (9). He found that regional methylation is involved in regulating the expression of endogenous retroviruses in glioma cell lines, as previously shown in other cancers. In collaboration with Dr. Avindra Nath in NINDS, Dr. Shah demonstrated that differential expression of the endogenous retroviral element HERV-K is associated with shortened survival of glioblastoma patients. With the University of Miami and NINDS investigators, Dr. Shah published an article on GBM in patients with HIV and another on a GBM pharmacogenomic therapeutic strategy (10,11). 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. 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 (12). The NOB/NCI group plans to test this vaccine in animal models of glioblastoma. Collaborative Efforts to Improve the Treatment of Brain and Spinal Neoplasms The Surgical Neurology Branch works with investigators in other NINDS branches, other NCI branches, including the Neuro-Oncology, Laboratory of Pathology, and Clinical Genetics Branches of NCI, and other sites outside the NIH to find better ways to evaluate and treat brain and spinal malignancies. Several basic, translational, and clinical research publications and review articles this year resulted from these collaborative efforts (13-19).