ATPS-68COMBINATION OF TOPOISOMERASE II POISON BERUBICIN WITH STAT3 INHIBITOR WP1066BLOCKS POTENTLY TUMOR GROWTH IN GMB MODELS

Abstract

BACKGROUND: Berubicin (WP744) is a DNA binding agent and potent topoisomerase II poison designed and synthesized in our laboratory. Preclinical studies demonstrated that WP744 is a potent anticancer agent with nanomolar potency in glioma cells. WP744 was shown to effectively cross blood-brain barrier (BBB) and displayed antitumor activity in orthotopic glioma models. WP744 gained IND approval and subsequent Phase I clinical trials shows clinical benefits (including complete response) in selected brain tumor patients. Signal Transducer and Activator of Transcription 3 (STAT3) is an oncogenic transcription factor that is activated in numerous tumors including GBM. WP1066, an analog of caffeic acid benzyl ester (CABE, a component of propolis), is a potent inhibitor of activated STAT3 (STAT3-Y705) designed in our laboratory. WP1066 is currently undergoing preclinical development and has demonstrated anticancer activity in multiple cancer models including GBM. WP1066 similarly to WP744 is able to cross BBB. The goal of this study is to assess therapeutic effects of WP744 in combination with WP1066 in the in vitro and in vivo GBM models. RESULTS: WP744 and WP1066 were tested in a panel of GBM cell lines including GSC cell lines. Both, WP744 and WP1066, effectively induce apoptosis and inhibit cells growth at low nanomolar and micromolar concentrations, respectively. Dosing schedule for a combination in vivo therapy was tested in CD-1 mice. The proof-of-principle efficacy study was performed in subcutaneous U87 GBM tumor model and demonstrated superior tumor growth inhibition in a group receiving combination of WP1066 and WP744. CONCLUSION: Proposed novel therapeutic strategy involving two compounds (WP744 and WP1066) with significant CNS uptake that are mechanistically complementary is highly promising and our results warrant further evaluation in different brain tumor models. Consistent activity of WP744 combination with WP1066 in a broader range of tumors would open possibility for its future clinical evaluation.