TY - JOUR
T1 - AraC-FdUMP[10] is a next-generation fluoropyrimidine with potent antitumor activity in PDAC and synergy with PARG inhibition
AU - Haber, Alex O.
AU - Jain, Aditi
AU - Mani, Chinnadurai
AU - Nevler, Avinoam
AU - Agostini, Lebaron C.
AU - Golan, Talia
AU - Palle, Komaraiah
AU - Yeo, Charles J.
AU - Gmeiner, William H.
AU - Brody, Jonathan R.
N1 - Funding Information:
This work was supported by NIH-NCI R21CA218933 (to W.H. Gmeiner), R01CA212600-01 (to J.R. Brody), and in part by NIH U01CA224012 (to R.C. Sears), P30CA069533 (to B.J. Druker), and P30CA056036 (to K.E. Knudsen). J. R. Brody is also supported by funding from the Pancreatic Cancer Cure Foundation, Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant, grant ID 15-90-25-BROD (to J.R. Brody), and the Richard Alan Parry Pancreatic Cancer Research Fund.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-20-0985
DO - 10.1158/1541-7786.MCR-20-0985
M3 - Article
C2 - 33593942
AN - SCOPUS:85103863229
VL - 19
SP - 565
EP - 572
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 4
ER -