TY - JOUR
T1 - Evaluation of NUC-1031
T2 - a first-in-class ProTide in biliary tract cancer
AU - Arora, Mansi
AU - Bogenberger, James M.
AU - Abdelrahman, Amro
AU - Leiting, Jennifer L.
AU - Chen, Xianfeng
AU - Egan, Jan B.
AU - Kasimsetty, Aradhana
AU - Lenkiewicz, Elzbieta
AU - Malasi, Smriti
AU - Uson, Pedro Luiz Serrano
AU - Nagalo, Bolni Marius
AU - Zhou, Yumei
AU - Salomao, Marcela A.
AU - Kosiorek, Heidi E.
AU - Braggio, Esteban
AU - Barrett, Michael T.
AU - Truty, Mark J.
AU - Borad, Mitesh J.
N1 - Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Purpose: NUC1031 is a first-in-class ProTide, that is a gemcitabine pro-drug designed to overcome putative mechanisms of resistance, including decreased expression of hENT/hCNT transporters, absence of activating enzymes such as deoxycytidine kinase (dCK) and presence of degrading enzymes such as cytidine deaminase (CDA). We undertook comprehensive pre-clinical evaluation of NUC1031 in biliary tract cancer (BTC) models, given that gemcitabine/cisplatin is a standard first-line therapy in advanced BTC. Methods: Here, we compared the in vitro activity of NUC1031 in comparison to gemcitabine, validate putative mechanism(s) of action, assessed potential biomarkers of sensitivity or resistance, and performed combination studies with cisplatin. We also evaluated the in vivo efficacy of NUC1031 and gemcitabine using a CDA-high cholangiocarcinoma patient-derived xenograft (PDX) model. Results: In a panel of BTC cell lines (N = 10), NUC1031 had less potency than gemcitabine in multiple cellular assays. NUC1031 did not demonstrate evidence of greater synergy over gemcitabine in combination with cisplatin. Surprisingly, efficacy of both gemcitabine and NUC1031 was not found to be correlated with hENT/hCTN, dCK or CDA transcript levels. Gemcitabine and NUC1031 showed equivalent efficacy in a CDA-high PDX model in vivo contradicting the primary rationale of NUC1031 design. Conclusion: NUC1031 did not exhibit evidence of superior activity over gemcitabine, as a single-agent, or in combination with cisplatin, in either our in vivo or in vitro BTC models. Given that the largest Phase 3 study (ClinicalTrials.gov: NCT0314666) to date in BTC is underway (N = 828) comparing NUC1031/cisplatin to gemcitabine/cisplatin, our results suggest that a more conservative clinical evaluation path would be more appropriate.
AB - Purpose: NUC1031 is a first-in-class ProTide, that is a gemcitabine pro-drug designed to overcome putative mechanisms of resistance, including decreased expression of hENT/hCNT transporters, absence of activating enzymes such as deoxycytidine kinase (dCK) and presence of degrading enzymes such as cytidine deaminase (CDA). We undertook comprehensive pre-clinical evaluation of NUC1031 in biliary tract cancer (BTC) models, given that gemcitabine/cisplatin is a standard first-line therapy in advanced BTC. Methods: Here, we compared the in vitro activity of NUC1031 in comparison to gemcitabine, validate putative mechanism(s) of action, assessed potential biomarkers of sensitivity or resistance, and performed combination studies with cisplatin. We also evaluated the in vivo efficacy of NUC1031 and gemcitabine using a CDA-high cholangiocarcinoma patient-derived xenograft (PDX) model. Results: In a panel of BTC cell lines (N = 10), NUC1031 had less potency than gemcitabine in multiple cellular assays. NUC1031 did not demonstrate evidence of greater synergy over gemcitabine in combination with cisplatin. Surprisingly, efficacy of both gemcitabine and NUC1031 was not found to be correlated with hENT/hCTN, dCK or CDA transcript levels. Gemcitabine and NUC1031 showed equivalent efficacy in a CDA-high PDX model in vivo contradicting the primary rationale of NUC1031 design. Conclusion: NUC1031 did not exhibit evidence of superior activity over gemcitabine, as a single-agent, or in combination with cisplatin, in either our in vivo or in vitro BTC models. Given that the largest Phase 3 study (ClinicalTrials.gov: NCT0314666) to date in BTC is underway (N = 828) comparing NUC1031/cisplatin to gemcitabine/cisplatin, our results suggest that a more conservative clinical evaluation path would be more appropriate.
KW - Cholangiocarcinoma
KW - Cisplatin
KW - Gemcitabine
KW - Phosphoramidate
KW - Pro-drug
UR - http://www.scopus.com/inward/record.url?scp=85085005198&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085005198&partnerID=8YFLogxK
U2 - 10.1007/s00280-020-04079-z
DO - 10.1007/s00280-020-04079-z
M3 - Article
C2 - 32440762
AN - SCOPUS:85085005198
SN - 0344-5704
VL - 85
SP - 1063
EP - 1078
JO - Cancer chemotherapy and pharmacology
JF - Cancer chemotherapy and pharmacology
IS - 6
ER -