Abstract 2648: A dual functional agent inhibits the angiogenesis and DNA synthesis resulting in the growth suppression of consensus molecular subtypes 1 and 4 in colorectal cancer xenografts
Authors: Vaikar Navakanth Rao, Ramajayam Kuppuswamy, Kuo Chu Lai, Tsann-Long Su, Te-Chang Lee
Journal: Cancer Research (2021)

Abstract Purpose: We have synthesized a series of bifunctional molecules, which are able to induce DNA interstrand crosslinks and inhibit angiogenesis as potent anticancer agents [1] and leads to develop new hybrids molecules. To analyze one of the novel bifunctional agent BO-2762 activity in consensus molecular subtype (CMS) classified as colorectal cancer (CRC) which are classified into four subtypes [ CMS1, MSI-immune; CMS2, epithelial and canonical; CMS3, epithelial and metabolic; and CMS4, mesenchymal] in in vitro and in vivo models. Experimental Design: We analyzed the anticancer effect of BO-2762 in CMS primary colorectal cancer cells which are reported in previous studies [2] and their respective xenografts (CMS-1: LoVo; CMS-2: LS1034; CMS-3: HT-29 and CMS-4: SW620). CMS provided a new platform to analyze BO-2762 functionalized subtype-specific sensitivity in CRC. Results: BO-2762 has a distinct bifunctional activity by DNA crosslinking in CRC cells and inhibiting angiogenesis in endothelial cells at IC50 of nanomolar to micromolar ranges. Angiogenesis inhibition was likely due to the suppression of VEGFR-2 phosphorylation in EA.hy 926 cells. Additionally, BO-2762 could inhibit cell migration, invasion, and induce apoptotic cell death in CRC. In our observation, no subtype-sensitivity has observed in in vitro conditions as reported in previous studies [3]. Using xenograft models, 20 mg/kg BO-2762 suppressed remarkably LoVo (CMS-1), and SW620 (CMS-4) subtypes, moderately in LS1034 (CMS-2) which was administrated via i.v. injection. However, HT29 cells classified as metabolic dysregulated, which is the CMS-3 subtype, have shown resistance to BO-2762. Conclusion: BO-2762 functions as an angiogenesis inhibitor by inhibiting the phosphorylation of VEGFR2 and inhibits the DNA synthesis by cross-linking the DNA. Consequently, BO-2762 was shown to profoundly suppress the growth of CRC xenografts of CMS-1 and 4 subtypes but not that of CMS-2 and 3. Accordingly, BO-2762 has great potential for further development as a specific anti-CRC agent against CMS-1 and 4 subtypes and lead the further investigation on how to overcome the resistance of metabolic dysregulated CMS-3 subtype as a fundamental question that warrants our investigation. References: 1. J Med Chem, 2019. 62(5): p. 2404-2418. 2. Clin Cancer Res, 2018. 24(4): p. 794-806. 3. Neoplasia, 2020. 22(9): p. 365-375 Citation Format: Vaikar Navakanth Rao, Ramajayam Kuppuswamy, Kuo Chu Lai, Tsann-Long Su, Te-Chang Lee. A dual functional agent inhibits the angiogenesis and DNA synthesis resulting in the growth suppression of consensus molecular subtypes 1 and 4 in colorectal cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2648.