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. Drs. Zhuang and Gilbert, in the Neurooncology Branch, NCI, are exploring the role of LB100 as a chemosensitizer or radiosensitizer in GBM therapeutics. 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 (1). Our earlier 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 that reviewed the medical and scientific literature about the potential impact of PP2A inhibition on brain tumor therapeutics (1). 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 Neuro-Oncology Advances (1). Dr. Banasavadi also collaborated on another project testing the impact of NOTCH blockade on virus-induced immunotherapy in GBM (2). He was also part of the research team that deciphered the dual and opposing roles of PKR, wherein PKR activates antivirus innate immunity and induces TGF- signaling to inhibit antitumor adaptive immune responses (3). He also helped identify HMGB1-RAGE signaling as a promising target to improve the efficacy of oHSV therapy (4). Dr. Banasavadi participated in the biomaterial research that efficiently synthesized and characterized fluorescent nanoformulations that serve as a platform technology for delivering multiple therapeutic agents to compartmentalized tissue such as the Intervertebral disc (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). Study of an Etiologic Role of Human Endogenous Retroviruses in Glioma Pathogenesis We continued our research to evaluate the role of endogenous retroviruses in glioma pathogenesis. This research depended heavily on collaborations with the laboratories of Dr. Ashish Shah, Assistant Professor of Neurosurgery at the University of Miami School of Medicine, Dr. Avindra Nath in the Section of Infections of the Nervous System (SINS) in NINDS, and Dr. Zhengping Zhuang in NOB/NCI. With the University of Miami and NINDS investigators, Dr. Shah was the first author of an article on a GBM pharmacogenomic therapeutic strategy (7). Dr. Mendez Valdez at the University of Miami published an article with NIH and University of Miami investigators reporting a retrospective clinical study of the survival and quality of life of patients with HIV and GBM (8). In collaboration with Dr. Avindra Nath in NINDS, Dr. Shah showed that differential expression of the endogenous retroviral element HERV-K(HML-6) is associated with shortened survival of glioblastoma patients (9). Sarah Rivas in the Surgical Neurology Branch and Dr. Shah reviewed the scientific literature on the role of human endogenous retroviruses in cancer stemness (10). Dr. Shah and collaborators later published an experimental article showing that human endogenous retrovirus K contributes to a stem cell niche in glioblastoma (11). Immunotherapy of Glioblastoma The Protein Phosphatase 2A (PP2A) inhibitor described above, LB100, enhanced 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 is being translated to a human clinical trial 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. 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, 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. This year, several basic, translational, and clinical research publications and review articles about topics in neuro-oncology, vasculogenesis, and immunology resulted from these collaborative efforts (12-20).