Biliary tract cancer patient-derived xenografts: Surgeon impact on individualized medicine

Leiting, Jennifer L.; Murphy, Stephen J.; Bergquist, John R.; Hernandez, Matthew C.; Ivanics, Tommy; Abdelrahman, Amro M.; Yang, Lin; Lynch, Isaac T.; Smadbeck, James B.; Cleary, Sean P.; Nagorney, David M.; Torbenson, Michael; Graham, Rondell P.; Roberts, Lewis R.; Gores, Gregory J.; Smoot, Rory L.; Truty, Mark J.

doi:10.1016/j.jhepr.2020.100068

Cited by 21 publications

(20 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, successful tumor engraftment is highly correlated with poorer overall survival of the patients. This has been a consistent observation across different tumor types including non-small cell lung, head and neck and bile duct cancers (34)(35)(36).…”

Section: Discussionsupporting

confidence: 65%

Patient-derived Tumor Xenograft and Organoid Models Established from Resected Pancreatic, Duodenal and Biliary Cancers

Pham

Radulovich

Ibrahimov

et al. 2021

Preprint

View full text Add to dashboard Cite

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 37% (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, which was effectively suppressed when using a combination of a pan-RAF inhibitor (LY3009120) and a MEK inhibitor (trametinib), and showed significant inhibition of growth in its XDO and corresponding PDX models. In conclusion, PDAC/duodenal adenocarcinoma have high success rates forming PDX/organoid and retain their phenotypic and genotypic features. These models may be effective tools to evaluate novel drug combinations therapies.

show abstract

Section: Discussionsupporting

confidence: 65%

Patient-derived Tumor Xenograft and Organoid Models Established from Resected Pancreatic, Duodenal and Biliary Cancers

Pham

Radulovich

Ibrahimov

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The potentially relevant clinical genes listed in Table 2 were additionally evaluated for their relevance in previously reported PDAC genomics studies (Table ). Sixteen of the 40 gene (40%) were similarly hit by DNA junctions in previously reported MPseq of 68 independent PDAC tumours 9,25 . Somatic variants were reported in all 40 of the genes from genomic sequencing of 324 PDAC tumours listed in public data from TCGA Firehouse Legacy and TCGA PanCancer Atlas studies on the cBioPortal 26 .…”

Section: Resultsmentioning

confidence: 82%

Theragnostic chromosomal rearrangements in treatment‐naive pancreatic ductal adenocarcinomas obtained via endoscopic ultrasound

Murphy

Levy

Smadbeck

et al. 2021

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

A crucial mutational mechanism in malignancy is structural variation, in which chromosomal rearrangements alter gene functions that drive cancer progression. Herein, the presence and pattern of structural variations were investigated in twelve prospectively acquired treatment‐naïve pancreatic cancers specimens obtained via endoscopic ultrasound (EUS). In many patients, this diagnostic biopsy procedure and specimen is the only opportunity to identify somatic clinically relevant actionable alterations that may impact their care and outcome. Specialized mate pair sequencing (MPseq) provided genome‐wide structural variance analysis (SVA) with a view to identifying prognostic markers and possible therapeutic targets. MPseq was successfully performed on all specimens, identifying highly rearranged genomes with complete SVA on all specimens with > 20% tumour content. SVA identified chimeric fusion proteins and potentially immunogenic readthrough transcripts, change of function truncations, gains and losses of key genes linked to tumour progression. Complex localized rearrangements, termed chromoanagenesis, with broad pattern heterogeneity were observed in 10 (83%) specimens, impacting multiple genes with diverse cellular functions that could influence theragnostic evaluation and responsiveness to immunotherapy regimens. This study indicates that genome‐wide MPseq can be successfully performed on very limited clinically EUS obtained specimens for chromosomal rearrangement detection and potential theragnostic targets.

show abstract

“…248,322 Collectively, all the data indicate that CDKN2A/B is a potential target for GBC therapy. It was also noted that Leiting et al 323 found that CDKN2A was not associated with the survival of BTC. Nonetheless, to date, no potential drug candidates have been explored to target CDKN2A/B in cancer treatment.…”

Section: Tp53mentioning

confidence: 95%

Overview of current targeted therapy in gallbladder cancer

Song

et al. 2020

Sig Transduct Target Ther

112

View full text Add to dashboard Cite

Gallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.

show abstract

Biliary tract cancer patient-derived xenografts: Surgeon impact on individualized medicine

Cited by 21 publications

References 53 publications

Patient-derived Tumor Xenograft and Organoid Models Established from Resected Pancreatic, Duodenal and Biliary Cancers

Patient-derived Tumor Xenograft and Organoid Models Established from Resected Pancreatic, Duodenal and Biliary Cancers

Theragnostic chromosomal rearrangements in treatment‐naive pancreatic ductal adenocarcinomas obtained via endoscopic ultrasound

Overview of current targeted therapy in gallbladder cancer

Contact Info

Product

Resources

About