Document Type
Article
Publication Date
11-8-2024
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease soon to become the second leading cause of cancer deaths in the US. Beside surgery, current therapies have narrow clinical benefits with systemic toxicities. FOLFIRINOX is the current standard of care, one component of which is 5- Fluorouracil (5-FU), which causes serious gastrointestinal and hematopoietic toxicities and is vulnerable to resistance mechanisms. Recently, we have developed polymeric fluoropyrimidines (F10, CF10) which unlike 5-FU, are, in principle, completely converted to the thymidylate synthase inhibitory metabolite FdUMP, without generating appreciable levels of ribonucleotides that cause systemic toxicities while displaying much stronger anti-cancer activity. Here, we confirm the potency of CF10 and investigate enhancement of its efficacy through combination with inhibitors in vitro targeting replication stress, a hallmark of PDAC cells. CF10 is 308-times more potent as a single agent than 5-FU and was effective in the nM range in primary patient derived models. Further, we find that activity of CF10, but not 5-FU, is enhanced through combination with inhibitors of ATR and Wee1 that regulate the S and G2 DNA damage checkpoints and can be reversed by addition of dNTPs indicative of CF10 acting, at least in part, through inducing replication stress. Our results indicate CF10 has the potential to supersede the established benefit of 5-FU in PDAC treatment and indicate novel combination approaches that should be validated in vivo and may be beneficial in established regimens that include 5-FU.
Recommended Citation
Finan, Jennifer M.; Di Niro, Roberto; Park, Soon Young; Jeong, Kang Jin; Hedberg, Madeline D.; Smith, Alexander; McCarthy, Grace A.; Haber, Alex O.; Muschler, John; Sears, Rosalie C.; Mills, Gordon B.; Gmeiner, William H.; and Brody, Jonathan R., "The Polymeric Fluoropyrimidine CF10 Overcomes Limitations of 5-FU in Pancreatic Ductal Adenocarcinoma Cells Through Increased Replication Stress" (2024). Department of Surgery Faculty Papers. Paper 279.
https://jdc.jefferson.edu/surgeryfp/279
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
39513592
Language
English
Comments
This article is the author's final published version in Cancer Biology and Therapy, Volume 25, Issue 1, November 2024, Article number 2421584.
The published version is available at https://doi.org/10.1080/15384047.2024.2421584.
Copyright © 2024 The Author(s).