title: Mutational Landscapes of Sequential Prostate Metastases and Matched Patient Derived Xenografts during Enzalutamide Therapy.
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.
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Manish
authors.initials: M
authors.lastname: Kohli
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Liguo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Hugues
authors.initials: H
authors.lastname: Sicotte
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.affiliation: Masonic Cancer Center and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dehm
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hart
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Vedell
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Poulami
authors.initials: P
authors.lastname: Barman
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Mahoney
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Carlson
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Atwell
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Eiken
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Brendan P
authors.initials: BP
authors.lastname: McMenomy
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieben
authors.affiliation: Division of Hematology-Oncology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Gautam
authors.initials: G
authors.lastname: Jha
authors.affiliation: Department of Pathology and Lab Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Rafael E
authors.initials: RE
authors.lastname: Jimenez
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Weinshilboum
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D001549:Benzamides; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide