Abstract
Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient–derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. SIGNIfICANCE: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 1112-1129 |
| Number of pages | 18 |
| Journal | Cancer Discovery |
| Volume | 8 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2018 |
Bibliographical note
Publisher Copyright:©2018 American Association for Cancer Research.
Funding
We would like to thank the patients, families, and clinicians who contributed to this work. This work was supported by the Lustgarten Foundation (D.A. Tuveson). D.A. Tuveson is a distinguished scholar of the Lustgarten Foundation and Director of the Lustgarten Foundation Dedicated Laboratory of Pancreatic Cancer Research. S. Gallinger is supported by the Ontario Institute for Cancer Research, charitable donations from the Canadian Friends of the Hebrew University (Alex U. Soyka) and the Pancreatic Cancer Canada Foundation, and the Leb-ovich Chair in Hepatobiliary/Pancreatic Surgical Oncology. This project was also supported in part by the NCI/LEIDOS Human Cancer Models Initiative (HHSN26100008; D.A. Tuveson, H. Clevers, and J.M. Crawford), NIH 5P50CA101955-07 (D.A. Tuveson), P20CA192996-03 (D.A. Tuveson), 1U10CA180944-04 (D.A. Tuveson), 5U01CA168409-5 (D.A. Tuveson), 1R01CA188134-01 (D.A. Tuveson), 1R01CA190092-04 (D.A. Tuveson), 5T32CA148056 (D.D. Engle), 5K99CA204725 (D.D. Engle), 5P01CA013106 (C.R. Vakoc), 5P30CA45508 (D.A. Tuve-son and P.A. Gilmoty), 1R01CA212600-01 (J.R. Brody and J.M. Winter), P20CA192994 (E. Li), R01CA202762 (K.H. Yu), P50CA127297 (M.A. Hollingsworth; UNMC RAP), U01CA210240 (M.A. Hollings-worth, D.A. Tuveson; UNMC RAP), and 5R50CA211462 (M.A. Hol-lingsworth; UNMC RAP), V Foundation Translational Grant (K.H. Yu and D.A. Tuveson), Cold Spring Harbor Laboratory Association (D.A. Tuveson), Stand Up To Cancer/AACRPS09 (D.A. Tuveson), Precision Medicine Research Associates (D.A. Tuveson), SWOG ITSC 5U10CA180944-04 (D.A. Tuveson, H. Tiriac, and E.J. Kim), Pancreatic Cancer Action Network-AACR 16-20-25-VAKO (C.R.Vakoc), State of New York C150158 (T.D.D. Somerville; the opinions, results, findings, and/or interpretation of data contained herein are the responsibility of the authors and do not necessarily represent the opinions, interpretations or policy of New York State), Concetta Greenberg in memory of Marvin S. Greenberg, MD (J.R. Brody and J.M. Winter), RAN grant from the AACR Pancreatic Cancer Action Network (J.R. Brody and J.M. Winter), ASGE Endoscopic Research Award 71040 (J.M. Buscaglia), Simons Foundation Award 415604 (E. Li), and Canadian Cancer Society Research Institute grant 702316 (S. Gall-inger). We acknowledge the Cold Spring Harbor Laboratory Tissue Culture and Next Generation Sequencing Shared Resources, which are funded by NIH Cancer Center Support Grant 5P30CA045508. We also acknowledge the contributions of Production Sequencing, Genome Sequencing Informatics and Tissue Portal (Diagnostic Development) at the Ontario Institute for Cancer Research, as well as the University Health Network BioBank. The pancreatic cancer patient study (ICGC-CA, COMPASS) was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario. We would like to thank the patients, families, and clinicians who contributed to this work. This work was supported by the Lustgarten Foundation (D.A. Tuveson). D.A. Tuveson is a distinguished scholar of the Lustgarten Foundation and Director of the Lustgarten Foundation Dedicated Laboratory of Pancreatic Cancer Research. S. Gallinger is supported by the Ontario Institute for Cancer Research, charitable donations from the Canadian Friends of the Hebrew University (Alex U. Soyka) and the Pancreatic Cancer Canada Foundation, and the Lebovich Chair in Hepatobiliary/Pancreatic Surgical Oncology. This project was also supported in part by the NCI/LEIDOS Human Cancer Models Initiative (HHSN26100008; D.A. Tuveson, H. Clevers, and J.M. Crawford), NIH5P50CA101955-07 (D.A. Tuveson), P20CA192996-03 (D.A. Tuveson), 1U10CA180944-04 (D.A. Tuveson), 5U01CA168409-5 (D.A. Tuveson), 1R01CA188134-01 (D.A. Tuveson), 1R01CA190092-04 (D.A. Tuveson), 5T32CA148056 (D.D. Engle), 5K99CA204725 (D.D. Engle), 5P01CA013106 (C.R. Vakoc), 5P30CA45508 (D.A. Tuveson and P.A. Gilmoty), 1R01CA212600-01 (J.R. Brody and J.M. Winter), P20CA192994 (E. Li), R01CA202762 (K.H. Yu), P50CA127297 (M.A. Hollingsworth; UNMC RAP), U01CA210240 (M.A. Hollingsworth, D.A. Tuveson; UNMC RAP), and 5R50CA211462 (M.A. Hollingsworth; UNMC RAP), V Foundation Translational Grant (K.H. Yu and D.A. Tuveson), Cold Spring Harbor Laboratory Association (D.A. Tuveson), Stand Up To Cancer/AACRPS09 (D.A. Tuveson), Precision Medicine Research Associates (D.A. Tuveson), SWOG ITSC 5U10CA180944-04 (D.A. Tuveson, H. Tiriac, and E.J. Kim), Pancreatic Cancer Action Network-AACR 16-20-25-VAKO (C.R.Vakoc), State of New York C150158 (T.D.D. Somerville; the opinions, results, findings, and/or interpretation of data contained herein are the responsibility of the authors and do not necessarily represent the opinions, interpretations or policy of New York State), Concetta Greenberg in memory of Marvin S. Greenberg, MD (J.R. Brody and J.M. Winter), RAN grant from the AACRPancreatic Cancer Action Network (J.R. Brody and J.M. Winter), ASGE Endoscopic Research Award 71040 (J.M. Buscaglia), Simons Foundation Award 415604 (E. Li), and Canadian Cancer Society Research Institute grant 702316 (S. Gallinger). We acknowledge the Cold Spring Harbor Laboratory Tissue Culture and Next Generation Sequencing Shared Resources, which are funded by NIH Cancer Center Support Grant 5P30CA045508. We also acknowledge the contributions of Production Sequencing, Genome Sequencing Informatics and Tissue Portal (Diagnostic Development) at the Ontario Institute for Cancer Research, as well as the University Health Network BioBank. The pancreatic cancer patient study (ICGC-CA, COMPASS) was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario. L.D. Wood is a consultant/advisory board member for Personal Genome Diagnostics. R.H. Hruban is a board member for MyDiag-nostics and reports receiving royalties from UpToDate. B.M. Wolpin reports receiving a commercial research grant from Celgene. A. Sasson has ownership interest (including patents) in Sanguine Diagnostics and Therapeutics. C.R. Vakoc reports receiving a commercial research grant from Boehringer Ingelheim and is a consultant/advisory board member for KSQ Therapeutics. No potential conflicts of interest were disclosed by the other authors.
| Funders | Funder number |
|---|---|
| Canadian Friends of the Hebrew University | |
| ICGC-CA | |
| NCI/LEIDOS | |
| State of New York C150158 | |
| National Institutes of Health (NIH) | 1R01CA212600-01, P20CA192996-03, 1R01CA188134-01, 5P30CA045508, 5R50CA211462, 1R01CA190092-04, 1U10CA180944-04, 5U01CA168409-5, 5K99CA204725, 5P01CA013106, 5P50CA101955-07 |
| National Institutes of Health (NIH) | |
| American Association for Cancer Research | |
| National Childhood Cancer Registry – National Cancer Institute | R01CA202762, HHSN26100008, P20CA192994, U01CA210240, P50CA127297, T32CA148056 |
| National Childhood Cancer Registry – National Cancer Institute | |
| Simons Foundation | 415604 |
| Simons Foundation | |
| V Foundation for Cancer Research | |
| Pancreatic Cancer Action Network | 16-20-25-VAKO |
| Pancreatic Cancer Action Network | |
| American Society for Gastrointestinal Endoscopy | 71040 |
| American Society for Gastrointestinal Endoscopy | |
| Lustgarten Foundation | |
| Celgene | |
| University of Nebraska Medical Center | |
| Boehringer-Ingelheim | |
| Stand Up To Cancer-Prostate Cancer Dream Team Translational Research | SWOG ITSC 5U10CA180944-04 |
| Stand Up To Cancer-Prostate Cancer Dream Team Translational Research | |
| Ontario Institute for Cancer Research | |
| Cold Spring Harbor Laboratory | |
| Government of Ontario | |
| Pancreatic Cancer Canada Foundation | |
| Canadian Cancer Society Research Institute | 702316 |
| Canadian Cancer Society Research Institute | |
| Ontario Institute for Cancer Research |
ASJC Scopus subject areas
- Oncology
