Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer
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RESEArCH ArTICLE Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer Hervé Tiriac1, Pascal Belleau1, Dannielle D. Engle1, Dennis Plenker1, Astrid Deschênes1, Tim D. D. Somerville1, Fieke E. M. Froeling1, Richard A. Burkhart2, Robert E. Denroche3, Gun-Ho Jang3, Koji Miyabayashi1, C. Megan Young1,4, Hardik Patel1, Michelle Ma1, Joseph F. LaComb5, Randze Lerie D. Palmaira6, Ammar A. Javed2, Jasmine C. Huynh7, Molly Johnson8, Kanika Arora8, Nicolas Robine8, Minita Shah8, Rashesh Sanghvi8, Austin B. Goetz9, Cinthya Y. Lowder9, Laura Martello10, Else Driehuis11,12, Nicolas LeComte6, Gokce Askan6, Christine A. Iacobuzio-Donahue6, Hans Clevers11,12,13, Laura D. Wood14, Ralph H. Hruban14, Elizabeth Thompson14, Andrew J. Aguirre15, Brian M. Wolpin15, Aaron Sasson16, Joseph Kim16, Maoxin Wu17, Juan Carlos Bucobo5, Peter Allen6, Divyesh V. Sejpal18, William Nealon19, James D. Sullivan19, Jordan M. Winter9, Phyllis A. Gimotty20, Jean L. Grem21, Dominick J. DiMaio22, Jonathan M. Buscaglia5, Paul M. Grandgenett23, Jonathan R. Brody9, Michael A. Hollingsworth23, Grainne M. O’Kane24, Faiyaz Notta3, Edward Kim7, James M. Crawford25, Craig Devoe26, Allyson Ocean27, Christopher L. Wolfgang2, Kenneth H. Yu6, Ellen Li5, Christopher R. Vakoc1, Benjamin Hubert8, Sandra E. Fischer28,29, Julie M. Wilson3, Richard Moffitt16,30, Jennifer Knox24, Alexander Krasnitz1, Steven Gallinger3,24,31,32, and David A. Tuveson1 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 onco- genes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited hetero- geneous 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 thera- peutic 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. Cancer Discov; 8(9); 1–18. ©2018 AACR. 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. 2Johns Philadelphia, Pennsylvania. 10SUNY Downstate Medical Center, Depart- Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, ment of Medicine, New York, New York. 11Hubrecht Institute, Royal Neth- Baltimore, Maryland. 3PanCuRx Translational Research Initiative, Ontario erlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands. Institute for Cancer Research, Toronto, Ontario, Canada. 4Swiss Fed- 12University Medical Center (UMC), Utrecht, the Netherlands. 13Princess eral Institute of Technology Lausanne (EPFL), School of Life Sciences, Maxime Center (PMC), Utrecht, the Netherlands. 14Department of Pathol- Swiss Institute for Experimental Cancer Research (ISREC), Laboratory ogy, Johns Hopkins University, Baltimore, Maryland. 15Dana-Farber Can- of Tumor Heterogeneity and Stemness in Cancer, Lausanne, Switzerland. cer Institute, Broad Institute, Boston, Massachusetts. 16Department of 5Department of Medicine, Stony Brook University, Stony Brook, New York. Surgery, Stony Brook University, Stony Brook, New York. 17Department 6Memorial Sloan Kettering Cancer Center, New York, New York. 7University of Pathology, Stony Brook University, Stony Brook, New York. 18Donald of California, Davis, Comprehensive Cancer Center, Division of Hematol- and Barbara Zucker School of Medicine at Hofstra/Northwell, Division ogy and Oncology, Sacramento, California. 8New York Genome Center, New of Gastroenterology, Hempstead, New York. 19Department of Surgery, York, New York. 9Department of Surgery, Thomas Jefferson University, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, OF1 | CANCER DISCOVERY SEPTEMBER 2018 www.aacrjournals.org Pancreatic Cancer Organoids Parallel Patient Response RESEARCH ARTICLE is used in conjunction with oncologic resection but adds INTRODUCTION only a modest benefit in survival (4, 5). Most patients are not Pancreatic ductal adenocarcinoma (PDAC) is a deadly surgical candidates and are diagnosed with locally advanced malignancy often diagnosed at advanced stages. Fifteen to or metastatic disease. Therapeutic options for these patients thirty percent of patients with PDAC are diagnosed with include the combination chemotherapy regimens gemcit- clinically localized disease that is amenable to potentially abine/nab-paclitaxel (6) or FOLFIRINOX (5-fluorouracil, curative surgical resection (1, 2). Following surgical resec- leucovorin, irinotecan, and oxaliplatin; ref. 7). Despite thera- tion, the majority of patients will have local or distant recur- peutic intervention, the median overall survival (OS) is 6.7 rence (3) and succumb to the disease. Systemic treatment, in to 11.1 months [progression-free survival (PFS) = 3.3–6.4] the form of neoadjuvant or adjuvant cytotoxic chemotherapy, for advanced disease (6, 7), compared with 25 to 28 months Hempstead, New York. 20Department of Biostatistics, Epidemiology and 30Department of Biomedical Informatics, Stony Brook University, Stony Informatics, University of Pennsylvania, Philadelphia, Pennsylvania. Brook, New York. 31Lunenfeld-Tanenbaum Research Institute, Mount 21Department of Medicine, University of Nebraska Medical Center, Omaha, Sinai Hospital, Toronto, Ontario, Canada. 32Hepatobiliary/Pancreatic Nebraska. 22Department of Pathology and Microbiology, University of Surgical Oncology Program, University Health Network, Toronto, Ontario, Nebraska Medical Center, Omaha, Nebraska. 23University of Nebraska Canada. Medical Center, Eppley Institute for Research in Cancer and Allied Dis- Note: Supplementary data for this article are available at Cancer Discovery eases, Fred & Pamela Buffet Cancer Center, Omaha, Nebraska. 24Wallace Online (http://cancerdiscovery.aacrjournals.org/). McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Univer- P. Belleau and D.D. Engle contributed equally to this article. 25 sity of Toronto, Toronto, Ontario, Canada. Department of Pathology and Corresponding Authors: David A. Tuveson, Cold Spring Harbor Laboratory, Laboratory Medicine, Donald and Barbara Zucker School of Medicine at 1 Bungtown Road, Cold Spring Harbor, NY 11724. Phone: 516-367-5246; 26 Hofstra/Northwell, Hempstead, New York. Division of Medical Oncology, Fax: 516-367-8353; E-mail: [email protected]; and Steven Gallinger, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Toronto General Hospital, 200 Elizabeth Street, 10EN, Room 206, Toronto, 27 Hempstead, New York. Weill Cornell Medical College, New York, New Ontario M5G 2C4, Canada. E-mail: [email protected] York. 28Department of Pathology, University Health Network, University doi: 10.1158/2159-8290.CD-18-0349 of Toronto, Toronto, Ontario, Canada. 29Department of Laboratory Medi- cine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. ©2018 American Association for Cancer Research. SEPTEMBER 2018 CANCER DISCOVERY | OF2 RESEARCH ARTICLE Tiriac et al. (PFS = 13.1–13.9) in surgically resected patients (4). Many tome, we identify the expected hallmarks of PDAC. In addi- patients with PDAC have chemorefractory disease, but a tion, we find high concordance between the primary tumor smaller subset exhibits significant response to chemotherapy. and paired PDO samples when sufficient neoplastic cellularity Current therapeutic selection for patients with both local was observed in the patient specimen. We establish a PDAC- and metastatic pancreatic cancer is often based on patient specific PDO drug-testing pipeline, termed “pharmacotyp- performance status and comorbidities. Altogether, this high- ing,” and demonstrate that drug-sensitivity profiles can be lights the unmet clinical need to define responsive subgroups generated for each PDO within a clinically meaningful time- to inform treatment selection and to nominate alternative frame. In a retrospective analysis of a small subset of patients treatment options for patients who are resistant to currently with advanced PDAC from whom the PDOs were generated, approved treatment regimens. Therefore, approaches that the PDO chemotherapy sensitivity profile reflected patient predict the most effective chemotherapeutic regimen should response to therapy. These studies suggest that drug testing in improve patient care. To date, PDAC driver mutations have PDO cultures may be used to inform treatment selection. In been hard to target