Journal Article

Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers

Denroche, Robert E., Li, Quan, Hedley, David W., Ibrahimov, Emin, Cabanero, Michael, Begora, Michael, Pintilie, Melania, Pham, Nhu-An, Dodd, Anna, Hutchinson, Shawn, Martins-Filho, Sebastiao N., Wilson, Julie M., Gallinger, Steven, Tsao, Ming-Sound, Metran-Nascente, Cristiane, Chadwick, Dianne, Radulovich, Nikolina, Weiss, Jessica, Knox, Jennifer J., Muthuswamy, Lakshmi, Raghavan, Vibha, Serra, Stefano, Borgida, Ayelet

2021

Overview

Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and biliary cancer resections. Initial, passage 0 (P0) engraftment rates were 59% (118/199) for pancreatic, 86% (25/29) for duodenal, and 35% (17/48) for biliary ductal tumors. Pancreatic ductal adenocarcinoma (PDAC), had a P0 engraftment rate of 62% (105/169).  KRAS  mutant and wild-type PDAC models were molecularly profiled, and XDO models were generated to perform initial drug response evaluations. Subsets of PDAC PDX models showed global copy number variants and gene expression profiles that were retained with serial passaging, and they showed a spectrum of somatic mutations represented in patient tumors. PDAC XDO models were established, with a success rate of 71% (10/14). Pathway activation of KRAS-MAPK in PDXs was independent of  KRAS  mutational status. Four wild-type KRAS models were characterized by one with  EGFR  (L747-P753 del), two with BRAF alterations (N486_P490del or V600E), and one with triple negative  KRAS/EGFR/BRAF . Model OCIP256, characterized by BRAF (N486-P490 del), had activated phospho-ERK. A combination treatment of a pan-RAF inhibitor (LY3009120) and a MEK inhibitor (trametinib) effectively suppressed phospho-ERK and inhibited growth of OCIP256 XDO and PDX models. PDAC/duodenal adenocarcinoma have high success rates forming PDX/organoid and retaining their phenotypic and genotypic features. These models may be effective tools to evaluate novel drug combination therapies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/67 / 631/67/1504/1329 / 631/67/1504/1713 / 631/67/70 / 692/4028 / Adenocarcinoma / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biliary Tract Neoplasms - drug therapy / Biliary Tract Neoplasms - pathology / Cell Proliferation - drug effects / Copy number / Dose-Response Relationship, Drug / Duodenal Neoplasms - drug therapy / Duodenal Neoplasms - pathology / Epidermal growth factor receptors / Gene expression / Humanities and Social Sciences / Humans / Inhibitor drugs / MAP kinase / MEK inhibitors / Mice / Mice, Inbred NOD / Mice, SCID / multidisciplinary / Mutation - genetics / Organoids / Organoids - drug effects / Organoids - pathology / Pancreas / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - pathology / Patients / Raf protein / Science / Science (multidisciplinary) / Tumors / Xenograft Model Antitumor Assays / Xenografts