AraC-FdUMP[10] is a next-generation fluoropyrimidine with potent antitumor activity in PDAC and synergy with PARG inhibition

Alex O. Haber, Aditi Jain, Chinnadurai Mani, Avinoam Nevler, Lebaron C. Agostini, Talia Golan, Komaraiah Palle, Charles J. Yeo, William H. Gmeiner, Jonathan R. Brody

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

AraC-FdUMP[10] (CF10) is a second-generation polymeric fluoropyrimidine that targets both thymidylate synthase (TS), the target of 5-fluorouracil (5-FU), and DNA topoisomerase 1 (Top1), the target of irinotecan, two drugs that are key components of FOLFIRNOX, a standard-of-care regimen for pancreatic ductal adenocarcinoma (PDAC). We demonstrated that F10 and CF10 are potent inhibitors of PDAC cell survival (in multiple cell lines including patient-derived lines) with IC50s in the nanomolar range and are nearly 1,000-fold more potent than 5-FU. The increased potency of CF10 relative to 5-FU correlated with enhanced TS inhibition and strong Top1 cleavage complex formation. Furthermore, CF10 displayed single-agent activity in PDAC murine xenografts without inducing weight loss. Through a focused drug synergy screen, we identified that combining CF10 with targeting the DNA repair enzyme, poly (ADP-ribose) glycohydrolase, induces substantial DNA damage and apoptosis. This work moves CF10 closer to a clinical trial for the treatment of PDAC.

Original languageEnglish (US)
Pages (from-to)565-572
Number of pages8
JournalMolecular Cancer Research
Volume19
Issue number4
DOIs
StatePublished - Apr 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'AraC-FdUMP[10] is a next-generation fluoropyrimidine with potent antitumor activity in PDAC and synergy with PARG inhibition'. Together they form a unique fingerprint.

Cite this