論文 - 詳細
| RRC ID | 63822 |
|---|---|
| 著者 | Arora M, Bogenberger JM, Abdelrahman A, Leiting JL, Chen X, Egan JB, Kasimsetty A, Lenkiewicz E, Malasi S, Uson PLS, Nagalo BM, Zhou Y, Salomao MA, Kosiorek HE, Braggio E, Barrett MT, Truty MJ, Borad MJ. |
| タイトル | Evaluation of NUC-1031: a first-in-class ProTide in biliary tract cancer. |
| ジャーナル | Cancer Chemother Pharmacol |
| Abstract |
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. |
| 巻・号 | 85(6) |
| ページ | 1063-1078 |
| 公開日 | 2020-6-1 |
| DOI | 10.1007/s00280-020-04079-z |
| PII | 10.1007/s00280-020-04079-z |
| PMID | 32440762 |
| MeSH | Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology* Apoptosis Biliary Tract Neoplasms / drug therapy* Biliary Tract Neoplasms / pathology Cell Proliferation Cisplatin / administration & dosage Cytidine Monophosphate / administration & dosage Cytidine Monophosphate / analogs & derivatives Deoxycytidine / administration & dosage Deoxycytidine / analogs & derivatives Drug Synergism* Female Gemcitabine Humans Mice Mice, Inbred NOD Mice, SCID Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| IF | 2.967 |
| リソース情報 | |
| ヒト・動物細胞 | RBE(RCB1292) TFK-1(RCB2537) |