The Role of Oncometabolites in Glioma Development. Our laboratory collaborated with researchers in Dalian and Harbin, China in examining hypotaurine levels in gliomas of various grades. Hypotaurine levels strongly correlated with glioma grade. The mechanism by which hypotaurine increases malignancy was examined by in vitro studies that showed that hypotaurine competively inhibits prolyl hydroxylase and activates hypoxia signaling, which in turn enhances glioma cell proliferation and invasion. This work suggests that the hypotaurine metabolic pathway could be a new target for glioblastoma therapy. Protein Phosphatase 2A Inhibition and its Interaction with Chemotherapy and Radiotherapy Effects. We studied the inhibitory activity of protein phosphatase 2A (PP2A) inhibitors, LB-100, and LB-102, in the mouse xenograft human GBM animal model. These compounds had a mild effect as single agents in slowing GBM growth in animals. However, their 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 in glioblastoma patients. We showed that LB-100-induced inhibition of PP2A overcame cisplatin cytotoxicity in medulloblastoma cells, suggesting that it could be a useful adjunctive agent in glial tumors other than glioblastoma. Our lab is developing other PP2A inhibitors with greater blood-brain barrier penetration and potential effectiveness against glioblastoma. This research is being conducted in collaboration with the Neuro-Oncology Branch, NCI, under the supervision of Dr. Zhengping Zhuang, who is an NCI Principal Investigator with a 25% appointment in NINDS. Biology of Central Nervous System (CNS) Tumors To see if the effects of pediatric gliomas were different than the effects of adult gliomas on the blood-brain barrier, our laboratory examined the effects of pediatric gliomas, including pilocytic astrocytoma, medulloblastoma, and low-grade diffuse astrocytoma on the blood-brain barrier. We found that blood-brain barrier (BBB) breakdown in pediatric tumors resulted from disruption of the normal relationship between endothelial cells and astrocytic foot processes of the BBB, like what occurs in adult gliomas. Immunotherapy of Glioblastoma This year Dr. Nduom of SNB developed a pilot clinical trial to use cerebral microdialysis for immune monitoring of recurrent glioblastoma patients undergoing immune checkpoint inhibition. This study passed NINDS internal scientific review and received drug-only sponsorship from Bristol-Myers Squibb. An Investigational New Drug Application was sent to the Food and Drug Administration and the protocol is now awaiting approval by the Central Nervous System (CNS) Institutional Review Board (IRB). Proteomic testing for this trial will be provided through a collaborative agreement with the multi-institute Center for Human Immunology. This clinical trial is projected to start in late 2017. Dr. Nduom is an expert in microdialysis, serving as the neurosurgeon consultant and Associate Investigator on a Neuro-Oncology Branch (NOB), NCI, trial that uses microdialysis to evaluate if regadenoson can open the blood-brain barrier and increase levels of a chemotherapeutic agent in and around the tumor in patients with glioblastoma. Dr. Nduom is examining the expression of FAPa in human glioblastoma and its immunosuppressive effects in glioblastoma. He is also testing combinations of immune therapeutics in murine models of glioma in his quest to develop improved immunotherapy for glioblastoma. This year he was a co-author of a study showing that nanoparticles could deliver immune modulatory agents to tumor tissue in an animal model of intracerebral glioma. Our laboratory collaborated with researchers in Shanghai, China, on the effect of B7-H4 activation on glioma prognosis. B7-H4 is a member of the B7 family that transmits negative signals to T cells to effectively inhibit their activation, proliferation and clonal expansion. Suppressing the effects of B7-H4 prolonged survival of human glioma xenografts in mice. This study showed that B7-H4 activation on macrophages/microglia in the microenvironment of gliomas was an important immunosuppressive event blocking effective T-cell immune responses to the tumor.
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