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Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma.

ABSTRACT: Translation of the patient-derived xenograft (PDX) model into a method for practical personalized cancer treatment is prevented by the intense resources and time necessary to generate and test each tumorgraft. We aimed to develop a high-throughput ex vivo drug testing approach that can be used for personalized cancer treatment design.We developed a unique ex vivo live tissue sensitivity assay (LTSA), in which precision-cut and uniform small tissue slices derived from pancreatic ductal adenocarcinoma PDX tumors were arrayed in a 96-well plate and screened against clinically relevant regimens within 3 to 5 days. The correlation between the sensitivities of tissue slices to the regimens and patients' clinical responses and outcome were statistically analyzed. The results of LTSA assay were further confirmed with biochemical methods in vitro and animal PDX model in vivo RESULTS: The ex vivo tissue slices remain viable for at least 5 days, and the tumor parenchyma, including stroma, vascular structures, and signaling pathways, are all retained. The sensitivities of the ex vivo tissue slices to gemcitabine and irinotecan was consistent with the clinical responses and outcomes of the patients from whom the tumorgrafts were derived (r = 0.77; P = 0.0002). Retrospective analysis showed that the patients who received LTSA-sensitive regimens had remarkably longer progression-free survival than patients who received LTSA-resistant regimens (16.33 vs. 3.8 months; n = 18, P = 0.011).The results from these PDX and LTSA methods reflect clinical patients' responses and could be used as a personalized strategy for improving systemic therapy effectiveness in patients with pancreatic cancer. Clin Cancer Res; 22(24); 6021-30. ©2016 AACR.

SUBMITTER: Roife D

PROVIDER: S-EPMC5136340 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma.

Roife David D Dai Bingbing B Kang Ya'an Y Perez Mayrim V Rios MVR Pratt Michael M Li Xinqun X Fleming Jason B JB

Clinical cancer research : an official journal of the American Association for Cancer Research 20160603 24

<h4>Purpose</h4>Translation of the patient-derived xenograft (PDX) model into a method for practical personalized cancer treatment is prevented by the intense resources and time necessary to generate and test each tumorgraft. We aimed to develop a high-throughput ex vivo drug testing approach that can be used for personalized cancer treatment design.<h4>Experimental design</h4>We developed a unique ex vivo live tissue sensitivity assay (LTSA), in which precision-cut and uniform small tissue slic ...[more]

PMID: 27259561

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Project description:New methods of tumor ablation have shown exciting efficacy in pre-clinical models but often demonstrate limited success in the clinic. Due to a lack of quality or quantity in primary malignant tissue specimens, therapeutic development and optimization studies are typically conducted on healthy tissue or cell-line derived rodent tumors that don't allow for high resolution modeling of mechanical, chemical, and biological properties. These surrogates do not accurately recapitulate many critical components of the tumor microenvironment that can impact in situ treatment success. Here, we propose utilizing patient-derived xenograft (PDX) models to propagate clinically relevant tumor specimens for the optimization and development of novel tumor ablation modalities. Specimens from three individual pancreatic ductal adenocarcinoma (PDAC) patients were utilized to generate PDX models. This process generated 15-18 tumors that were allowed to expand to 1.5 cm in diameter over the course of 50-70 days. The PDX tumors were morphologically and pathologically identical to primary tumor tissue. Likewise, the PDX tumors were also found to be physiologically superior to other in vitro and ex vivo models based on immortalized cell lines. We utilized the PDX tumors to refine and optimize irreversible electroporation (IRE) treatment parameters. IRE, a novel, non-thermal tumor ablation modality, is being evaluated in a diverse range of cancer clinical trials including pancreatic cancer. The PDX tumors were compared against either Pan02 mouse derived tumors or resected tissue from human PDAC patients. The PDX tumors demonstrated similar changes in electrical conductivity and Joule heating following IRE treatment. Computational modeling revealed a high similarity in the predicted ablation size of the PDX tumors that closely correlate with the data generated with the primary human pancreatic tumor tissue. Gene expression analysis revealed that IRE treatment resulted in an increase in biological pathway signaling associated with interferon gamma signaling, necrosis and mitochondria dysfunction, suggesting potential co-therapy targets. Together, these findings highlight the utility of the PDX system in tumor ablation modeling for IRE and increasing clinical application efficacy. It is also feasible that the use of PDX models will significantly benefit other ablation modality testing beyond IRE.

Dataset Information

Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma.

Publications

Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma.

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