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Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

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. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

SUBMITTER: Tiriac H

PROVIDER: S-EPMC6125219 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

Tiriac Hervé H Belleau Pascal P Engle Dannielle D DD Plenker Dennis D Deschênes Astrid A Somerville Tim D D TDD Froeling Fieke E M FEM Burkhart Richard A RA Denroche Robert E RE Jang Gun-Ho GH Miyabayashi Koji K Young C Megan CM Patel Hardik H Ma Michelle M LaComb Joseph F JF Palmaira Randze Lerie D RLD Javed Ammar A AA Huynh Jasmine C JC Johnson Molly M Arora Kanika K Robine Nicolas N Shah Minita M Sanghvi Rashesh R Goetz Austin B AB Lowder Cinthya Y CY Martello Laura L Driehuis Else E LeComte Nicolas N Askan Gokce G Iacobuzio-Donahue Christine A CA Clevers Hans H Wood Laura D LD Hruban Ralph H RH Thompson Elizabeth E Aguirre Andrew J AJ Wolpin Brian M BM Sasson Aaron A Kim Joseph J Wu Maoxin M Bucobo Juan Carlos JC Allen Peter P Sejpal Divyesh V DV Nealon William W Sullivan James D JD Winter Jordan M JM Gimotty Phyllis A PA Grem Jean L JL DiMaio Dominick J DJ Buscaglia Jonathan M JM Grandgenett Paul M PM Brody Jonathan R JR Hollingsworth Michael A MA O'Kane Grainne M GM Notta Faiyaz F Kim Edward E Crawford James M JM Devoe Craig C Ocean Allyson A Wolfgang Christopher L CL Yu Kenneth H KH Li Ellen E Vakoc Christopher R CR Hubert Benjamin B Fischer Sandra E SE Wilson Julie M JM Moffitt Richard R Knox Jennifer J Krasnitz Alexander A Gallinger Steven S Tuveson David A DA

Cancer discovery 20180531 9

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 chemoth ...[more]

PMID: 29853643

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Project description:BackgroundThe vast majority of metastatic cancers cannot be cured. Palliative treatment may relieve disease symptoms by stopping or slowing cancer growth and may prolong patients' lives, but almost all patients will inevitably develop disease progression after initial response. However, for reasons that are not fully understood, a very few patients will have extraordinary durable responses to standard anticancer treatments.Materials and methodsWe analyzed exceptional responders treated at Fox Chase Cancer Center between September 2009 and November 2017. An exceptional response was defined as a complete response lasting more than 1 year or a partial response or stable disease for more than 2 years. Tumor samples were analyzed using an Ambry Genetics test kit with a 142-gene panel. Messenger RNA expression was evaluated using NanoString's nCounter PanCancer Pathways Panel and Immune Profiling Panel and compared with matched controls for gender, age, and cancer type.ResultsTwenty-six exceptional responders with metastatic bladder, kidney, breast, lung, ovarian, uterine, and colon cancers were enrolled. Mutations were identified in 45 genes. The most common mutation was an EPHA5 nonsynonymous mutation detected in 87.5% of patients. Mutations in DNA damage repair pathway genes were also frequent, suggesting increased genome instability. We also found varying expression of 73 genes in the Pathways panel and 85 genes in the Immune Profiling panel, many of them responsible for improvement in tumor recognition and antitumor immune response.ConclusionsThe genomic instability detected in our exceptional responders, plus treatment with DNA damage compounds combined with favorable anticancer immunity, may have contributed to exceptional responses to standard anticancer therapies in the patients studied.Implications for practiceWith recent advances in the treatment of cancer, there is increased emphasis on the importance of identifying molecular markers to predict treatment outcomes, thereby allowing precision oncology. In this study, it was hypothesized that there is a "specific biologic signature" in the biology of the cancer in long-term survivors that allows sensitivity to systemic therapy and durability of response. Results showed that DNA damage repair pathway alterations, combined with favorable anticancer immunity, may have contributed to exceptional responses. It is very likely that an in-depth examination of outlier responses will become a standard component of drug development in the future.

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Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

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Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

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