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Evaluation of NUC-1031: a first-in-class ProTide in biliary tract cancer

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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.

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Abbreviations

BTC:

Biliary tract cancer

CCA:

Cholangiocarcinoma

hENT1:

Human equilibrative nucleoside transporters

CDA:

Deoxycytidine deaminase

dCK:

Deoxycytidine kinase

RRM1:

Ribonucleotide reductase catalytic subunit M1

FOLFOX:

Folinic acid fluorouracil oxaloplatin

DDR:

Drug dose response

EC50 :

Half-maximal effective concentration

H&E:

Hematoxylin and eosin stain

NOD:

Non-obese diabetic

PDX:

Patient-derived xenograft

IP:

Intraperitoneal

PI:

Propidium iodide

TUNEL:

Terminal deoxynucleotide transferase dUTP nick-end labelling

R 2 :

Linear regression

KMT2D:

Lysine methyltransferase 2D

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Acknowledgements

We would like to thank Asha A. Nair and Mrunal K. Dehankar (Department of Informatics, Mayo Clinic, Rochester, MN) for their contributions to the secondary analysis of RNA sequencing data.

Funding

This work was supported by Mayo Clinic institutional funding.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA

    Mansi Arora, James M. Bogenberger, Aradhana Kasimsetty, Elzbieta Lenkiewicz, Smriti Malasi, Pedro Luiz Serrano Uson, Bolni Marius Nagalo, Yumei Zhou, Esteban Braggio, Michael T. Barrett & Mitesh J. Borad

  2. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA

    Mansi Arora, James M. Bogenberger, Bolni Marius Nagalo, Yumei Zhou & Mitesh J. Borad

  3. Department of Surgery, Mayo Clinic, Rochester, MN, USA

    Amro Abdelrahman, Jennifer L. Leiting & Mark J. Truty

  4. Department of Informatics, Mayo Clinic, Scottsdale, AZ, USA

    Xianfeng Chen

  5. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA

    Mansi Arora, James M. Bogenberger, Jan B. Egan, Bolni Marius Nagalo, Yumei Zhou & Mitesh J. Borad

  6. Department of Lab Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA

    Marcela A. Salomao

  7. Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA

    Heidi E. Kosiorek

  8. Department of Cancer Biology, Mayo Clinic, Rochester, MN, USA

    Esteban Braggio

  9. Cancer Cell, Gene and Virus Therapy Lab, Mayo Clinic Cancer Center, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ, 85254, USA

    Mansi Arora, James M. Bogenberger, Bolni Marius Nagalo, Yumei Zhou, Esteban Braggio & Mitesh J. Borad

Authors
  1. Mansi Arora
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  2. James M. Bogenberger
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  3. Amro Abdelrahman
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  4. Jennifer L. Leiting
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  5. Xianfeng Chen
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  6. Jan B. Egan
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Contributions

MA performed experiments, analyzed data and wrote the manuscript. JMB analyzed data and wrote the manuscript. AA and JLL performed animal experiments and analyzed data. XC, JBE, AK, EL, SM, PLSUJ, BMN, YZ, MAS, and HEK analyzed data. EB performed the targeted sequencing experiments and analyzed data. MTB conceived and directed the aCGH studies and analyzed data. MJT and MJB conceived and directed the study. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Mitesh J. Borad.

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Conflict of interest

JMB owns purchased stock of Clovis Oncology. MJB has received grant to institution from Senhwa Pharmaceuticals, Adaptimmune, Agios Pharmaceuticals, Halozyme Pharmaceuticals, Celgene Pharmaceuticals, EMD Merck Serono, Toray, Dicerna, Taiho Pharmaceuticals, Sun Biopharma, Isis Pharmaceuticals, Redhill Pharmaceuticals, Boston Biomed, Basilea, Incyte Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Bioline, Sillajen, ARIAD Pharmaceuticals, PUMA Pharmaceuticals, Novartis Pharmaceuticals, QED Pharmaceuticals, Pieris Pharmaceuticals, consultancy from ADC Therapeutics, Exelixis Pharmaceuticals, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharmaceuticals, Western Oncolytics, Lynx Group, and travel support from Astra Zeneca. The remaining authors have no conflicts of interest to declare.

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Arora, M., Bogenberger, J.M., Abdelrahman, A. et al. Evaluation of NUC-1031: a first-in-class ProTide in biliary tract cancer. Cancer Chemother Pharmacol 85, 1063–1078 (2020). https://doi.org/10.1007/s00280-020-04079-z

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