Mansi Arora1,2,3,4, James M Bogenberger1,2,3,4, Amro Abdelrahman5, Jennifer L Leiting5, Xianfeng Chen6, Jan B Egan3, Aradhana Kasimsetty1, Elzbieta Lenkiewicz1, Smriti Malasi1, Pedro Luiz Serrano Uson1, Bolni Marius Nagalo1,2,3,4, Yumei Zhou1,2,3,4, Marcela A Salomao7, Heidi E Kosiorek8, Esteban Braggio1,9,4, Michael T Barrett1, Mark J Truty5, Mitesh J Borad10,11,12,13. 1. Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA. 2. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA. 3. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. 4. Cancer Cell, Gene and Virus Therapy Lab, Mayo Clinic Cancer Center, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ, 85254, USA. 5. Department of Surgery, Mayo Clinic, Rochester, MN, USA. 6. Department of Informatics, Mayo Clinic, Scottsdale, AZ, USA. 7. Department of Lab Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA. 8. Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA. 9. Department of Cancer Biology, Mayo Clinic, Rochester, MN, USA. 10. Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA. Borad.Mitesh@mayo.edu. 11. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA. Borad.Mitesh@mayo.edu. 12. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. Borad.Mitesh@mayo.edu. 13. Cancer Cell, Gene and Virus Therapy Lab, Mayo Clinic Cancer Center, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ, 85254, USA. Borad.Mitesh@mayo.edu.
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.
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.
Authors: Juan Valle; Harpreet Wasan; Daniel H Palmer; David Cunningham; Alan Anthoney; Anthony Maraveyas; Srinivasan Madhusudan; Tim Iveson; Sharon Hughes; Stephen P Pereira; Michael Roughton; John Bridgewater Journal: N Engl J Med Date: 2010-04-08 Impact factor: 91.245
Authors: Alison L Van Dyke; Meredith S Shiels; Gieira S Jones; Ruth M Pfeiffer; Jessica L Petrick; Jennifer L Beebe-Dimmer; Jill Koshiol Journal: Cancer Date: 2019-01-15 Impact factor: 6.860
Authors: Raphael Mohr; Burcin Özdirik; Jana Knorr; Alexander Wree; Münevver Demir; Frank Tacke; Christoph Roderburg Journal: Int J Mol Sci Date: 2020-07-15 Impact factor: 5.923