Abstract 3058: Phenotype-based discovery and development of novel therapies for the treatment of colorectal cancer

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world. The treatment of late stage CRC using Bevacizumab®, a targeted anti-VEGF therapy, produces insufficient response rates among patients and inevitable acquired tumour resistance. There is a clinical need for improved treatment options. Methods: Previously, anti-angiogenic screens in Tg[fli1:EGFP] zebrafish identified quininib, a small molecule drug subsequently shown to be as effective as bevacizumab® at reducing tumour volume in vivo and which reduces tumour CD31 expression in xenografted mice. Here, structural analogues of quininib were synthesised to identify novel chemical entities with higher anti-angiogenic and anti-inflammatory efficacy. Analogues were examined for anti-angiogenic effects in the Tg[fli1:EGFP] zebrafish intersegmental-vessel assay. Hits were then progressed for safety analyses in cytotoxic assays, anti-angiogenic efficacy in aortic explants, and effects on cell proliferation and tubule formation using HT29_Luc2 and HMEC cells. Leads were then tested in ex vivo human CRC tumour explants to determine effects on angiogenic and inflammatory factor secretion. Following determination of the maximum tolerated dose (MTD) of the highest ranking analogues, CRC-specific murine xenograft models created by subcutaneous injection of HT29_Luc2 cells were assessed for anti-tumorigenic analysis. Results: Five out of 12 drug candidates (CC16_HCl, CC12_HCl, Z_HCl, CC8_HCl & OS_1) reduced developmental angiogenesis in Tg[fli1:EGFP] zebrafish significantly more than quininib (***P Conclusions: 5 analogues significantly more effective than quininib at reducing inflammation and angiogenesis were identified. The highest ranking analogue is tolerated by i/p injection in mice up to 50 mg/kg with no obvious adverse effects. The highest ranking analogue is currently being tested in murine xenografts with preliminary data suggests it is more effective than quininib at reducing tumour growth. Citation Format: Clare T. Butler, Breandan Kennedy, William M. Gallagher, Jacintha O’Sullivan. Phenotype-based discovery and development of novel therapies for the treatment of colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3058.