Abstract 5102: TRXE-009-1 has pan-acting anticancer activity and potently inhibits colony formation of prostate cancer epithelial cell explants
Authors: Ager Eleanor I. , Butler Dominika , Stevenson Alex , Eiffe Eiffe , Heaton Andrew , Gabrielli Brian , Maitland Norman J. , Brown David 
Published: July 2017

Abstract
Background: TRXE-009-1 is a novel small molecule from the super benzopyran (SBP) drug family under development as an intravenous cytotoxic agent. Cantrixil (TRXE-002-1), our lead SBP candidate targeting ovarian cancer, recently achieved Investigational New Drug (IND) status and is undergoing safety assessment in a multi-center Phase I clinical trial. Our aim was to investigate pathways associated with response to TRXE-009-1 and identify cancer types for clinical translation.
Methods: Eurofins Oncopanel240 with multiplex analysis and bioinformatic assessment was used to identify cytotoxic and pathway response across a panel of cancer types. Western blot and live cell imaging were used to investigate protein levels and cell cycle progression.
Results: TRXE-009-1 demonstrated broad cytotoxic activity across a large panel of cell lines and was particularly active against kidney (RCC), liver (HCC), head and neck cancer, lung cancer, sarcoma, prostate cancer, osteosarcoma, and neuroblastoma. Further, TRXE-009-1 combined synergistically with two targeted agents used extensively in the clinical treatment of RCC patients. Cleaved caspase 3/7 and G2/M arrest were strongly associated with TRXE-009-1 activity. Live imaging confirmed G2/M arrest and implicated cytoskeleton disruption in TRXE-009-1 induced cell death. When compared to 43 reference oncology compounds, TRXE-009-1 clustered with a known epigenetic modifier. Additional analysis indicated that, compared to the least sensitive lines, the most sensitive cancer cell lines were more likely to be positive for LIN28B, a stemness marker associated with aggressive cancers. This is in line with historical studies suggesting that SBPs may preferentially target cancer-stem like cells. Using a panel of prostate cancer epithelial explants in a colony forming assay, we confirmed strong activity against colony-initiating cells. Studies are current to confirm protein changes associated with SBP activity and to further investigate the impact of TRXE-009-1 on the cytoskeleton. In vivo studies previously established activity of TRXE-009-1 against melanoma, prostate, and brain cancer and additional studies are current to optimize the delivery formulation to be used in preclinical safety studies prior to clinical progression.
Conclusion: Given that cancer stem-like cells are typically more chemoresistant and are thought to support tumor recurrence, the activity of TRXE-009-1 against this subpopulation of cancer cells makes it a particularly promising candidate for further development.
Citation Format: Eleanor I. Ager, Dominika Butler, Alex Stevenson, Eiffe Eiffe, Andrew Heaton, Brian Gabrielli, Norman J. Maitland, David Brown. TRXE-009-1 has pan-acting anticancer activity and potently inhibits colony formation of prostate cancer epithelial cell explants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5102. doi:10.1158/1538-7445.AM2017-5102