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Integrative Pharmacogenomics Analysis of Patient-Derived Xenografts
- Source :
- Cancer Research. 79:4539-4550
- Publication Year :
- 2019
- Publisher :
- American Association for Cancer Research (AACR), 2019.
-
Abstract
- Identifying robust biomarkers of drug response constitutes a key challenge in precision medicine. Patient-derived tumor xenografts (PDX) have emerged as reliable preclinical models that more accurately recapitulate tumor response to chemo- and targeted therapies. However, the lack of computational tools makes it difficult to analyze high-throughput molecular and pharmacologic profiles of PDX. We have developed Xenograft Visualization & Analysis (Xeva), an open-source software package for in vivo pharmacogenomic datasets that allows for quantification of variability in gene expression and pathway activity across PDX passages. We found that only a few genes and pathways exhibited passage-specific alterations and were therefore not suitable for biomarker discovery. Using the largest PDX pharmacogenomic dataset to date, we identified 87 pathways that are significantly associated with response to 51 drugs (FDR < 0.05). We found novel biomarkers based on gene expressions, copy number aberrations, and mutations predictive of drug response (concordance index > 0.60; FDR < 0.05). Our study demonstrates that Xeva provides a flexible platform for integrative analysis of preclinical in vivo pharmacogenomics data to identify biomarkers predictive of drug response, representing a major step forward in precision oncology. Significance: A computational platform for PDX data analysis reveals consistent gene and pathway activity across passages and confirms drug response prediction biomarkers in PDX. See related commentary by Meehan, p. 4324
- Subjects :
- 0301 basic medicine
Cancer Research
Computational biology
Biology
Tumor response
Precision medicine
Xenograft Model Antitumor Assays
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Oncology
Pharmacogenetics
In vivo
Neoplasms
030220 oncology & carcinogenesis
Pharmacogenomics
Drug response
Animals
Heterografts
Humans
Precision Medicine
Biomarker discovery
Pathway activity
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 79
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....8a3a7fc3222a8424db188f884d06126f