Molecular Characterization of Patient-Derived Human Pancreatic Tumor Xenograft Models for Preclinical and Translational Development of Cancer Therapeutics

Abstract

Preclinical evaluation of novel cancer agents requires models that accurately reflect the biology and molecular characteristics of human tumors. Molecular profiles of eight pancreatic ductal adenocarcinoma patient tumors were compared to corresponding passages of xenografts obtained by grafting tumor fragments into immunocompromised mice. Molecular characterization was performed by copy number analysis, gene expression and microRNA microarrays, mutation analysis, short tandem repeat (STR) profiling, and immunohistochemistry. Xenografts were found to be highly representative of their respective tumors, with a high degree of genetic stability observed by STR profiling and mutation analysis. Copy number variation (CNV) profiles of early and late xenograft passages were similar, with recurrent losses on chromosomes 1p, 3p, 4q, 6, 8p, 9, 10, 11q, 12p, 15q, 17, 18, 20p, and 21 and gains on 1q, 5p, 8q, 11q, 12q, 13q, 19q, and 20q. Pearson correlations of gene expression profiles of tumors and xenograft passages were above 0.88 for all models. Gene expression patterns between early and late passage xenografts were highly stable for each individual model. Changes observed in xenograft passages largely corresponded to human stromal compartment genes and inflammatory processes. While some differences exist between the primary tumors and corresponding xenografts, the molecular profiles remain stable after extensive passaging. Evidence for stability in molecular characteristics after several rounds of passaging lends confidence to clinical relevance and allows for expansion of models to generate the requisite number of animals required for cohorts used in drug screening and development studies.

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

“…The AG-Br7 xenograft model was derived from a specimen of a patient with triple-negative breast cancer. AG-Panc4 was established from a patient with moderately differentiated adenocarcinoma of the pancreas (17). NCI-H322M lung adenocarcinoma cell line was used as a lung cancer model.…”

Patient-Derived-Tumor-Xenograft: modeling cancer for basic and translational cancer research

“…Interestingly, these changes could not be reverted once the in vitro propagated cells were re-implanted into mice. Instead, PDTX retain the original tumor heterogeneity, thus allowing for clonal dynamic studies [6,25,30,[42][43][44][45][46]. Moreover, Eirew et al used deep genome and single cell sequencing methods to demonstrate an ongoing clonal selection in both primary and metastatic breast tumors, with the expansion of clones sharing recurrent patterns.…”

Animal models of pancreatic cancer and their application in clinical research

“…40 Further recent work using exome sequencing has shown that along with the tumor architecture, the genetic signature is maintained for at least three passages, giving scope for greater investigation of prognostic biomarkers to therapeutic response. 41 This would ultimately reduce the requirement to perform PDX model testing for every individual and instead only require analysis of the primary tumor to direct therapy.…”

“…PDX models are clearly showing promise as a valuable tool in evaluating the efficacy of novel treatments and have the advantage of recapitulating the natural genetic makeup of the original human patient tumor, even after passaging in vitro and in vivo, while allowing novel drug testing in an in vivo setting. 41,46 This provides valuable information that can go toward the design of more effective human clinical trials to further test novel treatments for cancers such as pancreatic cancer. 41 Although the use of PDX models in pancreatic cancer research is still relatively in its infancy, there are a number of studies that have utilized these models in testing the efficacy of novel drug leads against pancreatic cancer.…”

“…41,46 This provides valuable information that can go toward the design of more effective human clinical trials to further test novel treatments for cancers such as pancreatic cancer. 41 Although the use of PDX models in pancreatic cancer research is still relatively in its infancy, there are a number of studies that have utilized these models in testing the efficacy of novel drug leads against pancreatic cancer.…”