In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1407-1407
Abstract:
Purpose: We have synthesized a bifunctional hybrid molecule BO-2762, which is able to induce DNA damage and inhibit angiogenesis simultaneously [1] as similar to first-line chemotherapy combination (FOLFOX + Bevacizumab). Recently, colorectal cancers (CRC) were classified into four consensus molecular types (CMS) [2] , CMS 1 to 4. We carried out a translational study to investigate the anti-CRC activity of BO-2762 to various CMS subtypes. Experimental Design: We performed in vitro and in vivo studies to determine the potency and selectivity of first-line combo like hybrid small molecule BO-2762 on a panel of CRC cell lines, which were classified into CMS-1 (LoVo & DLD-1), CMS-2 (LS1034 & SW116), CMS-3 (HT-29 & LS174T), CMS-4 (SW620 & CACO2) and several unclassified cell lines (HCT-116, RKO, & COLO205). Immunohistochemistry was adopted to determine the DNA damage marker (γH2AX) and blood vessel marker (CD31) in the tumor xenografts treated with BO-2762. Results: BO-2762 alone has bifunctional activity by lodging DNA crosslinking in CRC cells and inhibiting tube formation of HUVEC cells at IC50 of 0.50 to 3 μM range. Angiogenesis inhibition was possibly due to the suppression of VEGFR-2 phosphorylation in HUVEC cells and the depletion of VEGF-A in the conditioned media. As reported in previous studies [3], we did not observe non-subtype specific cytotoxicity in in vitro assay system. Intriguingly, animal models exhibited their selective suppression on xenografts of various CMS-1 subtypes, e.g., remarkable suppression in CMS-1 LoVo cells (85.8%) and CMS-4 SW620 cells (83.0%), moderate in CMS-2 LS1034 cells (75.4%), and poor in CMS-3 HT29 cells (44.8%). BO-2762 was administrated at 20 mg/kg via iv injection. Furthermore, by immunohistochemically staining of γH2AX and CD31, we found that BO-2762 was able to induce DNA damage in xenografts of all CMS subtypes but unable to suppress the angiogenesis in CMS-3 HT29 xenografts. Our preliminary results showed enriched VEGF-A and VEGFR2 in HT29 cells. Conclusion: CMS classification paves a medical platform to investigate the combination of anti-angiogenic and DNA crosslinking agents in the CRC selective treatment. BO-2762, a novel hybrid displaying anti-angiogenesis and induction of DNA damage, is functional similar to FOLFOX + Bevacizumab. CMS subtype-specific inhibition in xenografts was likely evented according to their expression levels of angiogenic signaling. Accordingly, BO-2762 has a great potential for further development as a potent and specific anti-CRC agent at least against CMS-1 and 4 subtypes. However, biomarker identification for selecting right patients warrants our further investigation. References:1) J Med Chem, 64 (2021) 12469-12486. 2) Nat Med, 21 (2015) 1350-1356. 3) Neoplasia, 22 (2020) 365-375. Citation Format: Vaikar Navakanth Rao, Kuo-Chu Lai, Chin-Huang Liu, Tsann-Long Su, Te-Chang Lee. A dual functional activity subdues the growth of consensus molecular subtypes 1 and 4 in colorectal cancer xenografts [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1407.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-1407
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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