DDIS-17. POLYNITROXYL ALBUMIN INHIBITS BRAIN TUMORIGENIC CASCADE THROUGH A REACTIVE OXYGEN SPECIES MECHANISM ACROSS THE BLOOD BRAIN BARRIER

Abstract

This study seeks to develop a safe therapy with potential for a broad spectrum of brain tumors. For this pilot study, we have selected medulloblastoma (MB), the most common malignant pediatric brain cancer that arises from the cerebellum. MB can disseminate through the cerebrospinal fluid to the leptomeninges covering the brain and spinal cord. Leptomeningeal metastasis, a frequent finding at diagnosis and recurrence, is a serious complication for which innovative therapies are urgently needed to improve patient survival while reducing treatment-related toxicity. Polynitroxyl albumin (PNA) has been tested at Sanford Research and shown to reduce intracellular levels of reactive oxygen species (ROS) and inhibition of the tumorigenic cascade: proliferation, progression, and metastasis. This ROS inhibition appears to be responsive in multiple cancers, including triple negative breast cancer and two chemoradiation-resistant head & neck squamous cell carcinoma cell lines. Because intracellular ROS are readily membrane permeable, we have tested efficacy of PNA across the blood brain barrier (BBB) in treating MB. For this we used a metastatic mouse model of the Sonic Hedgehog (SHH) subgroup. PNA was administered i.p. on a thrice weekly schedule; an albumin-only control group was also treated. Survival analysis was obtained, along with histopathology of both brain and spinal cord; primary tumor, leptomeningeal dissemination, and secondary tumor growth were examined. In our preclinical model, a significant decrease in disseminated MB within the brain was detected (P < 0.05), along with secondary tumor growth along the spinal cord (P < 0.05), compared to the control group. Our results compliment PNA studies in other cancer models; PNA works across the BBB to decrease proliferation of tumor cells and inhibit metastatic growth. Follow up studies are warranted to compare the therapeutic index of intra- vs extra-cerebral PNA delivery to generate preclinical efficacy data in support of conjunctive MB clinical therapy.