Abstract B010: A novel hybrid with anti-angiogenic and DNA crosslinking activities potently suppresses the growth of colorectal cancer cells and patient-derived organoids in mice


 Background: Colorectal cancer (CRC) is the second-leading death of all cancers in the world. Metastasis is the basis for cause of death in patients with CRC. Currently, combination of anti-VEGF therapy and DNA damaging agents, such as Bevacizumab + FOLFOX, has become the first-line therapy in managing colorectal cancer progression. To mimic the first-line therapy, we have conjugated the angiogenesis inhibitory and the DNA damaging moieties to form a bifunctional hybrid molecule. The purpose of this study is to prove the efficacy and safety of the novel hybrid molecule in treatment of CRC cells in mouse models. Materials and methods: The novel hybrid molecule, designated as BO-2762, was synthesized as previously reported. The anti-proliferative activity was analyzed by PrestoBlue® assay in a variety of CRC cell lines and CRC patient derived organoids (PDO). DNA damage was analyzed by alkaline gel electrophoresis and comet assay. Antiangiogenic property was assessed using the docking model, in vitro tube formation, and in vivo angiogenesis methods. Anti-tumor efficacy of BO-2762 was determined using xenografts of CRC cell lines and PDOs at 20 mg/kg via tail vein injection. For safety profiling and toxicology study, the ICR mice model was adopted for various pathological analyses. Results: The values of anti-proliferative IC50 of BO-2762 against a panel of 11 CRC and 10 PDO cell lines were ranged between 0.5 to 4.5 µM. Subsequently, we demonstrated that BO-2762 induced DNA inter-strand cross-linking (ICL) by alkaline agarose gel electrophoresis. Apparently, ICLs caused significant cell cycle arrest at the S phase, and subsequently triggered apoptosis. The angiogenesis inhibition by BO-2762 was also confirmed by in vitro tube formation assay and Direct In Vivo Angiogenesis Assay. The anti-CRC activity of BO-2762 was assessed using xenografts of CRC cells, derived from metastatic sites (LoVo and SW620 cells) and from primary sites (LS1034 and HT-29 cells). Via tail vein injection of BO-2762 at 20 mg/kg for 10 times, the growth of LoVo, SW620, LS1034, and HT-29 cells was suppressed by 85.8%, 83.0%, 75.4%, and 44.8% respectively. In addition, BO-2762 also significantly suppressed the growth of metastatic PDOs (T53 and T112) by 90%. Biosafety analysis showed promising safety parameters in blood chemistry and major organs. Conclusions: Our present results have shown that conjugated hybrid molecule with DNA cross-linking and anti-angiogenic activity is likely a novel approach to treat patients with CRC.
 Citation Format: Vaikar Navakanth Rao, Kuo-Chu Lai, Chin-Hung Liu, Shung-Haur Yang, Jeou-Yuan Chang, Tsann-Long Su, Te-Chang Lee. A novel hybrid with anti-angiogenic and DNA crosslinking activities potently suppresses the growth of colorectal cancer cells and patient-derived organoids in mice [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B010.