Oncotarget

Research Papers:

Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites

Robert J. Allaway, Dawn A. Fischer, Francine B. de Abreu, Timothy B. Gardner, Stuart R. Gordon, Richard J. Barth, Thomas A. Colacchio, Matthew Wood, Balint Z. Kacsoh, Stephanie J. Bouley, Jingxuan Cui, Joanna Hamilton, Jungbin A. Choi, Joshua T. Lange, Jason D. Peterson, Vijayalakshmi Padmanabhan, Craig R. Tomlinson, Gregory J. Tsongalis, Arief A. Suriawinata, Casey S. Greene, Yolanda Sanchez and Kerrington D. Smith _

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Oncotarget. 2016; 7:17087-17102. https://doi.org/10.18632/oncotarget.7718

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Abstract

Robert J. Allaway1*, Dawn A. Fischer2*, Francine B. de Abreu3, Timothy B. Gardner4, Stuart R. Gordon4, Richard J. Barth2,5, Thomas A. Colacchio2,5, Matthew Wood1,9, Balint Z. Kacsoh6, Stephanie J. Bouley1, Jingxuan Cui6, Joanna Hamilton1,7, Jungbin A. Choi1, Joshua T. Lange1, Jason D. Peterson3, Vijayalakshmi Padmanabhan3, Craig R. Tomlinson1,5,7, Gregory J. Tsongalis3,5, Arief A. Suriawinata3, Casey S. Greene5,6,8*, Yolanda Sanchez1,5*, Kerrington D. Smith2,5

1Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA

2Department of Surgery, Division of Surgical Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA

3Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA

4Department of Medicine, Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA

5Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, USA

6Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH 03756, USA

7Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA

8Institute for Quantitative Biomedical Sciences, Dartmouth College, Hanover, NH 03755, USA

9Current location: Department of Pathology, University of California, San Francisco, CA 94143, USA

*These authors have contributed equally to this work

Correspondence to:

Kerrington Smith, e-mail: kerrington.d.smith@hitchcock.org

Keywords: patient-derived xenograft, fine needle aspirate biopsy, pancreatic ductal adenocarcinoma, KRAS, CDK9

Received: July 03, 2015    Accepted: January 13, 2016    Published: February 25, 2016

ABSTRACT

N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced phosphorylation of a marker of CDK9 activity (phospho-RNAPII CTD Ser2/5) and reduced viability/growth of explant cells derived from PDAC PDX models. Similarly, a CDK inhibitor reduced phospho-RNAPII CTD Ser2/5, increased apoptosis, and inhibited tumor growth in FNA-PDX and patient-matched metastatic-PDX models. In summary, PDX models can be constructed from FNA biopsies of PDAC which in turn can enable genomic characterization and identification of potential therapies.


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