Protein Phosphatase 2A Inhibition and its Interaction with Chemotherapy and Radiotherapy Effects. We studied the inhibitory activity of the protein phosphatase 2A (PP2A) inhibitor LB-100 in the mouse xenograft human GBM animal model. This compound had a mild effect as 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 showed that LB-100-induced inhibition of PP2A overcame daunorubicin cytotoxicity in secondary acute myeloid leukemia cells, suggesting that it could be a useful adjunctive agent with chemotherapy in this and perhaps other tumors. LB-100 also sensitized malignant meningioma cells to the therapeutic effects of radiation. Dr. Zhengping Zhuang (75% effort NOB/NCI and 25% effort SNB/NINDS) collaborated with our lab to develop PP2A inhibitors with greater blood-brain barrier penetration and potential effectiveness against glioblastoma. Immunotherapy of Glioblastoma The Protein Phosphatase 2A (PP2A) inhibitor described above, LB-100, was found to enhance the anti-tumor effects of an immune checkpoint inhibitor in an animal model of glioblastoma. This combination of a PP2A inhibitor and LB100 may be translated to human clinical trials by our collaborators in the Neuro Oncology Branch, NCI. Dr. Nduom in the Surgical Neurology Branch (SNB) examined the immune effect of tumor luciferase transgene expression in the GL261 murine glioma model. He found that cells expressing the transgene had a proinflammatory phenotype compared to non-transfected tumor cells. A manuscript was submitted reporting their findings. Dr. Nduom continued his research into the expression of FAPa in human glioblastoma and its immunosuppressive effects in glioblastoma. An abstract describing his research will be presentation at the Congress of Neurological Surgeons meeting in October 2018 with the title, FAP alpha-CXCL12-CXCR4 pathway in glioblastoma: an under-appreciated therapeutic target? This year Dr. Nduom finished the last stages of the approval process of his 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 granted by the Food and Drug Administration and the protocol was approved 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 enrolling patient in late 2018. Dr. Nduom is an expert in microdialysis, serving as the neurosurgeon consultant and Associate Investigator on the recently published Neuro-Oncology Branch (NOB), NCI, trial that used microdialysis to evaluate if regadenoson could open the blood-brain barrier and increase levels of a chemotherapeutic agent in and around the tumor in patients with glioblastoma.
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