scholarly journals Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers

Aging ◽  
2021 ◽  
Author(s):  
Tianfeng Lan ◽  
Xia Xue ◽  
Louisa Chard Dunmall ◽  
Jinxin Miao ◽  
Yaohe Wang
Keyword(s):  
Therapeutic Targets ◽  
Esophageal Cancers ◽  
Patient Derived Xenograft

scholarly journals Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Alvaro Quintanal-Villalonga ◽  
Hirokazu Taniguchi ◽  
Yingqian A. Zhan ◽  
Maysun M. Hasan ◽  
Shweta S. Chavan ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Squamous Cell ◽  
Genetic Manipulation ◽  
Therapeutic Targets ◽  
Xenograft Model ◽  
Driver Mutations ◽  
Preclinical Models ◽  
Patient Derived Xenograft ◽  
Mixed Histology

Abstract Background Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% of EGFR-mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies. Methods We performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment. Results Our data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR-mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib. Conclusions Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.

Genetic alterations in esophageal cancers: Detection by next-generation sequencing and potential for therapeutic targets.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e22065-e22065
Author(s):  
Victoria Meucci Villaflor ◽  
Deric Wheeler ◽  
Mari Iida ◽  
Smruti Vidwans ◽  
Michelle Turski ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Next Generation ◽  
Esophageal Cancers ◽  
Generation Sequencing

scholarly journals Prioritizing therapeutic targets using patient-derived xenograft models

2015 ◽  
Vol 1855 (2) ◽  
pp. 223-234 ◽  
Author(s):  
K.A. Lodhia ◽  
A.M. Hadley ◽  
P. Haluska ◽  
C.L. Scott
Keyword(s):  
Therapeutic Targets ◽  
Patient Derived Xenograft ◽  
Xenograft Models

Cancer genomics-based screening of new therapeutic targets and biomarkers for esophageal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16514-e16514
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Esophageal Cancer ◽  
Cancer Patients ◽  
Mammalian Cells ◽  
Cancer Genomics ◽  
Profile Analysis ◽  
Gene Transfection ◽  
Objective Response ◽  
Therapeutic Targets ◽  
Immunohistochemical Analysis ◽  
Esophageal Cancers

e16514 Background: Since the number of esophageal cancer patients who show objective response to standard therapies is still small, development of new anti-cancer agents with minimum risk of adverse events and highly precise molecular biomarkers is eagerly awaited. Methods: We have been screening novel therapeutic targets and their companion diagnostics for esophageal cancers as follows; i) To identify up-regulated genes in esophageal cancers by the gene expression profile analysis, ii) To verify the candidate genes for their low expression in normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 265 esophageal cancers, and iv) To verify their function for the growth of the esophageal cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate oncoproteins and selected a metyltransferase ESOC1 (esophageal cancer-associated oncoprotein 1). Immunohistochemical analysis revealed that ESOC1 positivity was observed in 68.5% of esophageal cancers and associated with tumor size. Moreover ESOC1 expression was an independent prognostic factor for esophageal cancer patients. Suppression of ESOC1 expression by its siRNAs inhibited growth of esophageal cancer cell lines. Introduction of ESOC1 increased the growth activity of mammalian cells, suggesting that ESOC1 is likely to be a prognostic biomarker and therapeutic target for esophageal cancers. Conclusions: Cancer genomics-based approach could be useful for the development of new cancer biomarkers as well as therapeutic targets for small molecules, antibodies, nucleic acid drugs, and immunotherapies.

The use of patient-derived xenograft models for prioritizing therapeutic targets.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 5579-5579
Author(s):  
Clare L. Scott ◽  
Monique Topp ◽  
Alison Maree Hadley ◽  
Valerie Heong ◽  
Maria I Harrell ◽  
...  
Keyword(s):  
Therapeutic Targets ◽  
Patient Derived Xenograft ◽  
Xenograft Models

Combination therapy of the EZH2 inhibitor GSK126 and the PARP inhibitor Olaparib shows in vivo synergy in a patient-derived xenograft model of BRCA1-deficient breast cancer

2014 ◽  
Vol 74 (S 01) ◽  
Author(s):  
J Puppe ◽  
P ter Brugge ◽  
M Seressi ◽  
O van Tellingen ◽  
E van der Burg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Parp Inhibitor ◽  
Xenograft Model ◽  
Patient Derived Xenograft
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