Reference Detail

Ref Type

Journal Article

PMID

(34011980)

Authors

Pham NA, Radulovich N, Ibrahimov E, Martins-Filho SN, Li Q, Pintilie M, Weiss J, Raghavan V, Cabanero M, Denroche RE, Wilson JM, Metran-Nascente C, Borgida A, Hutchinson S, Dodd A, Begora M, Chadwick D, Serra S, Knox JJ, Gallinger S, Hedley DW, Muthuswamy L, Tsao MS

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Scientific reports	11	1	2021 May 19	10619	Sci Rep

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF N486_P490del	pancreatic ductal adenocarcinoma	predicted - sensitive	LY3009120	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, a patient-derived xenograft (PDX) model with pancreatic ductal adenocarcinoma harboring BRAF N486_P490del demonstrated partial inhibition of Erk phosphorylation and moderate inhibition of tumor growth when treated with LY3009120 (PMID: 34011980).	34011980
BRAF N486_P490del	pancreatic ductal adenocarcinoma	sensitive	LY3009120 + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, a patient-derived xenograft (PDX) model with pancreatic ductal adenocarcinoma harboring BRAF N486_P490del demonstrated inhibition of Erk phosphorylation and greater inhibition of tumor growth when treated with the combination of Mekinist (trametinib) and LY3009120 compared to either agent alone (PMID: 34011980).	34011980
BRAF N486_P490del	pancreatic ductal adenocarcinoma	sensitive	Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, a patient-derived xenograft (PDX) model with pancreatic ductal adenocarcinoma harboring BRAF N486_P490del demonstrated partial inhibition of Erk phosphorylation and moderate inhibition of tumor growth when treated with Mekinist (trametinib) (PMID: 34011980).	34011980