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. GreeneYolanda Sanchez, Kerrington D. Smith

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)17087-17102
Number of pages16
JournalOncotarget
Volume7
Issue number13
DOIs
StatePublished - Mar 29 2016
Externally publishedYes

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Fine Needle Biopsy
Heterografts
Adenocarcinoma
Mutation
Neoplasms
Therapeutics
Growth
Phosphorylation
Apoptosis

Keywords

  • CDK9
  • Fine needle aspirate biopsy
  • KRAS
  • Pancreatic ductal adenocarcinoma
  • Patient-derived xenograft

ASJC Scopus subject areas

  • Oncology

Cite this

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

In: Oncotarget, Vol. 7, No. 13, 29.03.2016, p. 17087-17102.

Research output: Contribution to journalArticle

Allaway, RJ, Fischer, DA, De Abreu, FB, Gardner, TB, Gordon, SR, Barth, RJ, Colacchio, TA, Wood, M, Kacsoh, BZ, Bouley, SJ, Cui, J, Hamilton, J, Choi, JA, Lange, JT, Peterson, JD, Padmanabhan, V, Tomlinson, CR, Tsongalis, GJ, Suriawinata, AA, Greene, CS, Sanchez, Y & Smith, KD 2016, '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', Oncotarget, vol. 7, no. 13, pp. 17087-17102. https://doi.org/10.18632/oncotarget.7718
Allaway, Robert J. ; Fischer, Dawn A. ; De Abreu, Francine B. ; Gardner, Timothy B. ; Gordon, Stuart R. ; Barth, Richard J. ; Colacchio, Thomas A. ; Wood, Matthew ; Kacsoh, Balint Z. ; Bouley, Stephanie J. ; Cui, Jingxuan ; Hamilton, Joanna ; Choi, Jungbin A. ; Lange, Joshua T. ; Peterson, Jason D. ; Padmanabhan, Vijayalakshmi ; Tomlinson, Craig R. ; Tsongalis, Gregory J. ; Suriawinata, Arief A. ; Greene, Casey S. ; Sanchez, Yolanda ; Smith, Kerrington D. / 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. In: Oncotarget. 2016 ; Vol. 7, No. 13. pp. 17087-17102.
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AU - Allaway, Robert J.

AU - Fischer, Dawn A.

AU - De Abreu, Francine B.

AU - Gardner, Timothy B.

AU - Gordon, Stuart R.

AU - Barth, Richard J.

AU - Colacchio, Thomas A.

AU - Wood, Matthew

AU - Kacsoh, Balint Z.

AU - Bouley, Stephanie J.

AU - Cui, Jingxuan

AU - Hamilton, Joanna

AU - Choi, Jungbin A.

AU - Lange, Joshua T.

AU - Peterson, Jason D.

AU - Padmanabhan, Vijayalakshmi

AU - Tomlinson, Craig R.

AU - Tsongalis, Gregory J.

AU - Suriawinata, Arief A.

AU - Greene, Casey S.

AU - Sanchez, Yolanda

AU - Smith, Kerrington D.

PY - 2016/3/29

Y1 - 2016/3/29

N2 - 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.

AB - 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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