Patient-derived cell models as preclinical tools for genome-directed targeted therapy

Abstract

BackgroundIn this study, we established patient-derived tumor cell (PDC) models using tissues collected from patients with metastatic cancer and assessed whether these models could be used as a tool for genome-based cancer treatment.MethodsPDCs were isolated and cultured from malignant effusions including ascites and pleural fluid. Pathological examination, immunohistochemical analysis, and genomic profiling were performed to compare the histological and genomic features of primary tumors, PDCs. An exploratory gene expression profiling assay was performed to further characterize PDCs.ResultsFrom January 2012 to May 2013, 176 samples from patients with metastatic cancer were collected. PDC models were successfully established in 130 (73.6%) samples. The median time from specimen collection to passage 1 (P1) was 3 weeks (range, 0.5–4 weeks), while that from P1 to P2 was 2.5 weeks (range, 0.5–5 weeks). Sixteen paired samples of genomic alterations were highly concordant between each primary tumor and progeny PDCs, with an average variant allele frequency (VAF) correlation of 0.878. We compared genomic profiles of the primary tumor (P0), P1 cells, P2 cells, and patient-derived xenografts (PDXs) derived from P2 cells and found that three samples (P0, P1, and P2 cells) were highly correlated (0.99–1.00). Moreover, PDXs showed more than 100 variants, with correlations of only 0.6–0.8 for the other samples. Drug responses of PDCs were reflective of the clinical response to targeted agents in selected patient PDC lines.Conclusion(s)Our results provided evidence that our PDC model was a promising model for preclinical experiments and closely resembled the patient tumor genome and clinical response.

MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

“…Based on that the MCT4 isoform was very strongly expressed in malignant ascites, development of a highly potent MCT4 inhibitor might be effective for treatment of GC with peritoneal carcinomatosis. Our group has previously shown that PDCs are reflective of genomic alterations in patient tumors and clinical phenotypes in response to targeted agents [56]. To the best of our knowledge, this is the first study to systematically investigate the role of MCT4 in malignant ascites using PDCs.…”

Hepatocellular carcinoma cell lines retain the genomic and transcriptomic landscapes of primary human cancers

“…In cell line factory project in Broad Institute (http://www.broadinstitute.org/cellfactory#home), cells through passage 5 were highlighted. In recent reports, passage 1–4 were analyzed as PDCs1012. These work also emphasized continuous culture to passage 10 to obtain enough cells for analysis.…”

“…There have been very few analyses of transcriptomic similarities between cell lines and matched primary cancers. Besides established cell lines, it has been proposed that cancer cells at early passages during cell line establishment (around passage 5, also called patient-derived cells, PDC) may faithfully represent primary cancers101112. Indeed, PDCs were found similar to those of the primary cancers in terms of key gene mutations, copy number profiles and drug responses11.…”

Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor–Resistant Clear Cell Renal Cell Carcinoma

“…PDC from malignant effusions has more than a few advantages over conventional cell lines [9]. First, PDC models faithfully recapitulated primary patient tumors, with the molecular and gross phenotypic characteristics of the primary tumor retained.…”