Ependymomas are rare central nervous system tumors, occurring predominantly in children. Tumor size can make gross total resection exceptionally difficult, and post-operative radiation may be of benefit but CNS toxicity prevents its wide application in patients <2yrs. Development of new therapies for this tumor is limited by the absence of optimal in vivo and in vitro model systems. Drug therapy options are limited because few compounds can cross the blood-brain barrier, and almost all tumors of this type display significant resistance to chemotherapeutic agents.
Using an antracycline scaffold and our own modular approach to designing DNA-binding agents, we have synthesized a chemical library of novel DNA binders. In screening this library against a panel of multidrug-resistant cell lines, we discovered novel structures, one of which was termed WP744 (AKA RTA 744 and Berubicin). Recent Phase 1 clinical studies in patients with glioblastoma demonstrated that Berubicin is active and crosses the blood-brain barrier to reach therapeutic concentrations in the CNS. Clinical studies showed that the dose-limiting toxicity was myelosuppression, with an MTD of 7.5 mg/m²/day given three consecutive days every 21 days. Pharmacokinetic studies showed dose-independent clearance, with a mean half-life of 36-hours and large colume of distribution.
Read the entire poster: Berubicin: A Novel Topoisomerase II Inhibitor with Activity in Ependymoma