Abstract 2699: Targeting GSK-3: a novel approach to enhance glioblastoma chemosensitivity

Glioblastoma (GBM) is, in essence, an incurable cancer, with most patients surviving 12-15 months following initial diagnosis. Previously published studies identified Glycogen Synthase Kinase-3 (GSK-3) as a new therapeutic target in GBM. Because GSK-3beta is a positive regulator of NF-kappaB-mediated survival and chemoresistance in cancer cells, we hypothesize that the inhibition of GSK-3 may overcome NF-kappaB-mediated chemoresistance to conventional drugs in human GBM. Using IVIS imaging of live mice, we found that: 1) NF-kappaB is constitutively active in orthotopic GBM patient-derived xenograft (PDX) tumors expressing an NF-kappa luciferase reporter; and 2) a single intravenous injection of our novel GSK-3 inhibitor 9-ING-41 (25 mg/kg) significantly reduced NF-kappaB transcriptional activity in orthotopic GBM PDX. Using 3 different orthotopic GBM PDX- tumor models, enabled for bioluminescence imaging through luciferase modification, we evaluated antitumor effects of 9-ING-41, alone as well as in combination with irinotecan, CCNU and temozolomide. Our in vivo results revealed that treatment with a combination of 9-ING-41 and irinotecan delays GBM PDX tumor growth, relative to either agent as a monotherapy, and, even more promising, 9-ING-41+CCNU leads to a complete tumor regression. Histological evaluation of mouse brain confirmed the absence of cancer cells and a formation of cyst at the location of intracranial tumor in mice treated with 9-ING-41+CCNU. Our results provide a rationale to advance 9-ING-41 for clinical evaluation in treating GBM, especially when combined with CCNU cytotoxic therapy. Citation Format: Andrey Ugolkov, Oleksii Dubrovskyi, Irina Gaisina, Alex Yemelyanov, Gennadiy Bondarenko, Charles James, James Chandler, Thomas O'Halloran, Alan Kozikowski, Jeffry Raizer, Andrew Mazar. Targeting GSK-3: a novel approach to enhance glioblastoma chemosensitivity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2699. doi:10.1158/1538-7445.AM2015-2699