Abstract 5215: Targeting of HOX-PBX binding in glioblastoma multiforme as a novel therapeutic treatment

Abstract

Abstract The HOX genes encode a family of transcription factors that play an essential role in embryonic patterning. They are also aberrantly expressed in numerous cancers, including glioblastoma (GBM). Three Amino Acid Loop Extension Homeobox (TALE) proteins act as important co-factors for HOX proteins, modulating their binding affinities to genomic targets. TALE proteins include the Pre-B-cell leukemia homeobox (PBX) proteins 1-4, which bind anterior HOX proteins, facilitating their nuclear entry and limiting their degradation. HTL00-1 is a 2nd generation hexapeptide drug that inhibits HOX-PBX dimer formation, and has been shown to induce rapid apoptosis in cancer cells, but not normal cells, through the rapid upregulation of genes including cFos, DUSP1, and EGR1. We have found that both HOX and TALE genes are markedly dysregulated in primary GBM tumors as well as in murine (GL261), adult (LN18, U87-MG, U251-MG) and pediatric (KNS42, SF188) GBM cell lines, all of which are sensitive to HTL-001. These genes were even more highly expressed in experimentally induced GBM cancer stem cells (CSCs) compared with parental lines, with a corresponding increase in sensitivity to HTL-001. We also investigated the in vivo activity of HTL-001 in Black 6 mice carrying GL-261 subcutaneous and orthotropic tumors with twice weekly intraperitoneal delivery. HTL-001 was shown to cross the blood brain barrier using Alexa660 labelled peptide, and significant anti-tumor activity was observed in both subcutaneous and orthotropic models with increased survival (p<0.02 and p<0.0078, respectively). Resected tumors from HTL-001 treated mice showed marked evidence of apoptosis, tumor vasculature disruption and focal necrosis compared to untreated tumors. Taken together, our findings indicate that HOX-PBX inhibition is a potential therapeutic target for adult and pediatric GBM patients. Citation Format: Richard Morgan, Monika Primon, Steven Shnyder, Susan Short, Balveen Kaur, Bangxing Hong, Izhar Bagwan, William Rogers, Hardev S. Pandha. Targeting of HOX-PBX binding in glioblastoma multiforme as a novel therapeutic treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5215.