Development of the first topo II inhibitor for brain tumors

DESCRIPTION (provided by applicant): We proposed to bring the first orally active topoisomerase II inhibitor to the clinic for the treatment of brain tumors. Specifically, in the course of this award we propose to synthesize 5 g of RTA 769, develop and validate bioanalytical methods, develop GMP procedures for the synthesis of RTA 769, preparing drug with a purity suitable for preclinical GLP evaluation and human clinical studies, use an in vivo murine model to asses the pharmacokinetics/metabolism of RTA 769, and evaluate the efficacy of RTA 769 administered orally in an orthotopic mouse model of malignant glioblastoma. We propose to complete this research using an existing relationship between Reata and UTMDACC, which has already been successful in the commercial development of 3 other UTMDACC compounds over a similar 18-24 month timeframe. Our technological innovation will be in the development a novel anticancer agent, capable of cross the blood brain barrier following oral administration. We intend, upon completion of an SBIR Phase II award, to file an IND and begin Phase I clinical trials. It is our intent to commercialize RTA 769 for the treatment of GBM, though the use of this drug would ultimately include other cancers. RTA 769 was invented using an innovative modular approach; libraries of high-affinity and sequence-selective DNA-binding agents were created. Promising agents were synthesized and screened to identify those compounds, which could circumvent the limitations of currently available topo II inhibitors. From this process RTA 769 was selected and hypothesized to 1) be orally bioavailable, 2) cross the blood-brain barrier (BBB), 3) penetrate tumor tissue, 4) induce more double-strand DNA damage, 5) be less cardiotoxic and 6) be more apoptotic. Invention of these novel compounds is important given the difficulty in treating a life threatening disease like glioblastoma multiforme (GBM). GBM is a common and deadly brain tumor; untreated the median survival time is 3 months following diagnosis. Despite the development multimodality therapeutic strategies over the past 3 decades, the overall survival time is still < 1 year. Due to the invasiveness of these tumors and their association with critical brain structures complete surgical ablation of these tumors is impossible: radiation and chemotherapy is required. Development of new agents like RTA 769 is of paramount importance so that we can change the natural history of this lethal disease. Glioblastoma multiforme (GBM) is a common and deadly brain tumor that despite the development new therapeutic strategies over the past 30 years has a survival of less than 1 year. Most anticancer drug cannot cross into the brain due to a "blood-brain" barrier. Here we propose to develop WP769, the first "blood-brain" barrier penetrating anticancer drug targeting a key protein in brain tumors, that can be taken orally and should improve the over all survival of this disease.