Abstract 1842: F10 and 5-fluorouracil: Chemotherapeutic potential of F10 in alleviating colon cancer racial health disparity
Authors: Shrey Thaker, William H. Gmeiner, Ping Ji, Jovanny Zabaleta, Tiana Reyes, Matthew DiGiovanni, Xuefeng Wang, Jennie L. Williams
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) is the second most lethal cancer in the United States, but underlying its incidence and mortality is a disproportionate burden in African Americans (AA). Compared to Caucasian Americans (CA), AA patients are 30% more likely to develop and 50% more likely to die from CRC. Socioeconomic factors contribute to racial health disparity. However, recent evidence suggests that biological factors may shape the AA patient predisposition. Clinical assessment has shown that AA CRC patients have a higher rate of chemoresistance, tumor recurrence post-resection, and lower 5-year survival rate post-resection as compared to CA CRC patients. 5-fluorouracil (5-FU) has been the standard of care against CRC for more than 50 years. However, high chemoresistance in AA patients has become apparent. Thus, the formulation of safer and more effective chemotherapeutic agents is paramount. Using the MTT proliferation assay, we evaluated the efficacy of the fluoropyrimidine polymer ‘F10' (a promising chemotherapeutic agent) against 3 novel AA CRC cell lines (SB501, SB521, and CHTN06) and compare its potential effectiveness against 5-FU. Additionally, we assessed the potential differential efficacy of F10 between the three novel AA CRC cell lines and three CA CRC cell lines (e.g., HT29 and a p53+/+ wild type and a p53-/- variant of HCT116). A high potency of F10 in inducing DNA-directed apoptosis was shown to be significant regardless of p53 status. Given that AA CRC patients have a higher rate of unique TP53 polymorphisms linked to chemoresponse and chemoresistance, this finding is important. In 4 out of 6 cell lines, the IC50 value significantly decreased for F10 as compared to 5-FU. HCT116 -/-, HCT116 +/+, HT29, and SB521 exhibited ~12-fold, ~150-fold, ~10-fold, and ~6850-fold decrease in IC50 value for F10 compared to 5-FU, respectively (Two-Sample T-Test: HCT116-/-: p = 0.0043, HCT116 +/+: p = 0.0483, HT29: p = 0.0386, SB521: p = 0.0122). The cell line with wild type p53 exhibited a strong benefit from F10. In general, cell lines with p53 mutations showed benefits, but to a lesser extent; suggesting that both p53-dependent and p53-independent mechanisms are responsible for F10 chemotherapeutic activity. In addition, RNAseq analysis of each cell line was assessed and differential expression compared. Several differences between and within racial cell lines were defined. Notably, in AA some of these were associated with drug absorption (e.g., SLC28A2 and CES1). Additionally, p53 mutations within the AA cell lines were identified. Identifying and understanding genetic variables affecting treatment response is critical in the development of effective chemotherapeutic agents. Overall, validation of F10 as a chemotherapeutic agent is needed to assist in the development of treatment modalities which are effective for all CRC patients regardless of race and ethnicity. Citation Format: Shrey Thaker, William H. Gmeiner, Ping Ji, Jovanny Zabaleta, Tiana Reyes, Matthew DiGiovanni, Xuefeng Wang, Jennie L. Williams. F10 and 5-fluorouracil: Chemotherapeutic potential of F10 in alleviating colon cancer racial health disparity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1842.