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

Abstract

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.

Establishment of Patient-derived Orthotopic Xenografts (PDX) as Models for Pancreatic Ductal Adenocarcinoma

“…Furthermore, NK cell checkpoint inhibitors have been developed, such as Lirilumab (IPH2102/BMS-986015), but its value in terms of survival endpoints has yet to be demonstrated in human trials (27). Unfortunately, we did not observe any distant metastasis in any of the PDOX developed in our lab, which is in agreement with a recently published work by Pham et al (28). However, we must underline a potential limitation of this study as we did not use fragments of tumor tissue but rather cell pellets to develop the PDAC-PDOX.…”

BRAF Δβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

“…The COMP-196 PDO was identified within a cohort of PDAC PDOs established at the Princess Margaret Cancer Centre Living Biobank (https://pmlivingbiobank.uhnresearch.ca/) from patients enrolled in the COMPASS trial ( 105 , 106 ) and using procedures previously described in detail for xenograft-derived organoids ( 107 ). In brief, percutaneous core biopsy tissue from a liver metastasis was minced and dissociated in 1 ml of advanced DMEM (adDMEM)/F12 with 100 μl of Liberase TH (Sigma-Aldrich) and 10 μM Y-27632 at 37°C for 15 min.…”

CT Radiomics and Whole Genome Sequencing in Patients with Pancreatic Ductal Adenocarcinoma: Predictive Radiogenomics Modeling

“…Multiple genes, that have been previously reported as altered in PDCA were collected from a web-based resource (cBioPortal.ca for Cancer Genomics [ 21 , 22 ]) and were categorized as follows: significantly mutated genes, oncogenes, DNA damage repair genes and chromatin modification genes [ 7 , 8 , 23 ]. The 4 most prevalent genes were then included for statistical analysis (KRAS, TP53, SMAD4, CDKN2A) ( Table 2 ).…”