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01-06-2020 | Biomarkers | Editorial

NUC-1031 in biliary tract cancer: from bench to bedside and back?

Authors: Lenka N. C. Boyd, Godefridus J. Peters, Geert Kazemier, Elisa Giovannetti

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2020

Abstract

In preclinical models of biliary tract cancer, NUC-1031 showed less potency than gemcitabine, no correlation with potential biomarkers and only moderate additive interaction in combination with cisplatin. These findings should prompt further careful pharmacological and translational studies to better define the purported therapeutic advantage of NUC-1031 over gemcitabine. That would be a more cautious approach than the phase III clinical trial which is planning to enrol 828 patients with biliary tract tumours to compare gemcitabine/cisplatin “conventional” treatment with or without NUC-1031.

Kendall T, Verheij J, Gaudio E, Evert M, Guido M, Goeppert B, Carpino G (2019) Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver Int 39(Suppl 1):7–18. https://doi.org/10.1111/liv.14093 CrossRefPubMed

Esnaola NF, Meyer JE, Karachristos A, Maranki JL, Camp ER, Denlinger CS (2016) Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma. Cancer 122:1349–1369. https://doi.org/10.1002/cncr.29692 CrossRefPubMed

Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J, Investigators for the ABC-02 trial (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–1281. https://doi.org/10.1056/NEJMoa0908721 CrossRefPubMed

Park JO, Oh DY, Hsu C, Chen JS, Chen LT, Orlando M, Kim JS, Lim HY (2015) Gemcitabine plus cisplatin for advanced biliary tract cancer: a systematic review. Cancer Res Treat 47(3):343–361. https://doi.org/10.4143/crt.2014.308 CrossRefPubMedPubMedCentral

Arora M, Bogenberger JM, Abdelrahman A, Leiting JL, Chen X, Egan JB, Kasimsetty A, Lenkiewicz E, Malasi S, Luiz Serrano Uson Junior P, Marius Nagalo B, Zhou Y, Salomao MA, Kosiorek HE, Braggio E, Barrett MT, Truty MJ, Borad MJ (2020) Evaluation of NUC-1031: a first-in-class ProTide in biliary tract cancer. Cancer Chemother Pharmacol. https://doi.org/10.1007/s00280-020-04079-z CrossRefPubMed

Slusarczyk M, Lopez MH, Balzarini J, Mason M, Jiang WG, Blagden S, Thompson E, Ghazaly E, McGuigan C (2014) Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development. J Med Chem 57(4):1531–1542. https://doi.org/10.1021/jm401853a CrossRefPubMed

Elnaggar M, Giovannetti E, Peters GJ (2012) Molecular targets of gemcitabine action: rationale for development of novel drugs and drug combinations. Curr Pharm Des 18(19):2811–2829. https://doi.org/10.2174/138161212800626175 CrossRefPubMed

Ciccolini J, Serdjebi C, Peters GJ, Giovannetti E (2016) Pharmacokinetics and pharmacogenetics of gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective. Cancer Chemother Pharmacol 78:1–12. https://doi.org/10.1007/s00280-016-3003-0 CrossRefPubMedPubMedCentral

Brandi G, Deserti M, Vasuri F, Farioli A, Degiovanni A, Palloni A, Frega G, Barbera MA, de Lorenzo S, Garajova I, Di Marco M, Pinna AD, Cescon M, Cucchetti A, Ercolani G, D'Errico-Grigioni A, Pantaleo MA, Biasco G, Tavolari S, G.I.CO. (Gruppo Italiano Colangiocarcinoma) (2016) Membrane localization of human equilibrative nucleoside transporter 1 in tumor cells may predict response to adjuvant gemcitabine in resected cholangiocarcinoma patients. Oncologist 21(5):600–607. https://doi.org/10.1634/theoncologist.2015-0356 CrossRefPubMedPubMedCentral

10.

Meijer LL, Puik JR, Peters GJ, Kazemier G, Giovannetti E (2016) hENT-1 expression and localization predict outcome after adjuvant gemcitabine in resected cholangiocarcinoma patients. Oncologist 21(12):e4. https://doi.org/10.1634/theoncologist.2016-0262 CrossRefPubMedPubMedCentral

11.

Raffenne J, Nicolle R, Puleo F, Le Corre D, Boyez C, Marechal R, Emile JF, Demetter P, Bardier A, Laurent-Puig P, de Mestier L, Paradis V, Couvelard A, VanLathem JL, MacKey JR, Bachet JB, Svrcek M, Cros J (2019) hENT1 testing in pancreatic ductal adenocarcinoma: are we ready? A multimodal evaluation of hENT1 status. Cancers (Basel) 11(11):1808. https://doi.org/10.3390/cancers11111808 CrossRef

12.

Rizzuto I, Ghazaly E, Peters GJ (2017) Pharmacological factors affecting accumulation of gemcitabine’s active metabolite, gemcitabine triphosphate. Pharmacogenomics 18:911–925. https://doi.org/10.2217/pgs-2017-0034 CrossRefPubMed

13.

Blagden SP, Rizzuto I, Suppiah P, O'Shea D, Patel M, Spiers L, Sukumaran A, Bharwani N, Rockall A, Gabra H, El-Bahrawy M, Wasan H, Leonard R, Habib N, Ghazaly E (2018) Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study. Br J Cancer 119(7):815–822. https://doi.org/10.1038/s41416-018-0244-1 CrossRefPubMedPubMedCentral

14.

Knox JJ, McNamara MG, Palmer DH, Jeffry Evans TR, Goldstein D, Bridgewater JA, Valle JW (2019) NUC-1031 in combination with cisplatin for first-line treatment of advanced biliary tract cancer. JCO 37:TPS4156–TPS4156. https://doi.org/10.1200/JCO.2019.37.15_suppl.TPS4156 CrossRef

15.

McNamara MG, Bridgewater JA, Palmer DH, Singh Wasan H, Ryder D, Gnanaranjan C, Ghazaly E, Jeffry Evans TR, Valle JW (2018) ABC-08: A phase Ib, multi-centre, open-label study of a first-in-class nucleotide analogue NUC-1031 in combination with cisplatin in patients with locally advanced/metastatic biliary tract cancers. JCO 36:TPS544. https://doi.org/10.1200/JCO.2018.36.4_suppl.TPS544 CrossRef

16.

Roos E, Soer EC, Klompmaker S, Meijer LL, Besselink MG, Giovannetti E, Heger M, Kazemier G, Klumpen HJ, Takkenberg RB, Wilmink H, Wurdinger T, Dijk F, van Gulik TM, Verheij J, van de Vijver MJ (2019) Crossing borders: a systematic review with quantitative analysis of genetic mutations of carcinomas of the biliary tract. Crit Rev Oncol Hematol 140:8–16. https://doi.org/10.1016/j.critrevonc.2019.05.011 CrossRefPubMed

17.

Puik JR, Meijer LL, Le Large TY, Prado MM, Frampton AE, Kazemier G, Giovannetti E (2017) miRNA profiling for diagnosis, prognosis and stratification of cancer treatment in cholangiocarcinoma. Pharmacogenomics 18(14):1343–1358. https://doi.org/10.2217/pgs-2017-0010 CrossRefPubMed

Title: NUC-1031 in biliary tract cancer: from bench to bedside and back?
Authors: Lenka N. C. Boyd
Godefridus J. Peters
Geert Kazemier
Elisa Giovannetti
Publication date: 01-06-2020
Publisher: Springer Berlin Heidelberg
Keyword: Biomarkers
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04080-6

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