Mutational landscapes of sequential prostate metastases and matched patient derived xenografts during enzalutamide therapy

Manish Kohli, Liguo Wang, Fang Xie, Hugues Sicotte, Ping Yin, Scott M. Dehm, Steven N. Hart, Peter T. Vedell, Poulami Barman, Rui Qin, Douglas W. Mahoney, Rachel E. Carlson, Jeanette E. Eckel-Passow, Thomas D. Atwell, Patrick W. Eiken, Brendan P. Mcmenomy, Eric D. Wieben, Gautam Jha, Rafael E. Jimenez, Richard WeinshilboumLiewei Wang

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Developing patient derived models from individual tumors that capture the biological heterogeneity and mutation landscape in advanced prostate cancer is challenging, but essential for understanding tumor progression and delivery of personalized therapy in metastatic castrate resistant prostate cancer stage. To demonstrate the feasibility of developing patient derived xenograft models in this stage, we present a case study wherein xenografts were derived from cancer metastases in a patient progressing on androgen deprivation therapy and prior to initiating pre-chemotherapy enzalutamide treatment. Tissue biopsies from a metastatic rib lesion were obtained for sequencing before and after initiating enzalutamide treatment over a twelve-week period and also implanted subcutaneously as well as under the renal capsule in immuno-deficient mice. The genome and transcriptome landscapes of xenografts and the original patient tumor tissues were compared by performing whole exome and transcriptome sequencing of the metastatic tumor tissues and the xenografts at both time points. After comparing the somatic mutations, copy number variations, gene fusions and gene expression we found that the patient's genomic and transcriptomic alterations were preserved in the patient derived xenografts with high fidelity. These xenograft models provide an opportunity for predicting efficacy of existing and potentially novel drugs that is based on individual metastatic tumor expression signature and molecular pharmacology for delivery of precision medicine.

Original languageEnglish (US)
Article number0145176
JournalPloS one
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2015

Bibliographical note

Funding Information:
The study is supported by the Mayo Clinic Centre for Individualized Medicine and the Pharmacogenomics Research Network (PGRN). This work was also supported by NIH grant R01CA174777 (to S.M.D.

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