title: Bridging tumor genomics to patient outcomes through an integrated patient-derived xenograft platform.
abstract: New approaches to optimization of cancer drug development in the laboratory and the clinic will be required to fully achieve the goal of individualized, precision cancer therapy. Improved preclinical models that more closely reflect the now recognized genomic complexity of human cancers are needed. Here we describe a collaborative research project that integrates core resources of The Jackson Laboratory Basic Science Cancer Center with genomics and clinical research facilities at the UC Davis Comprehensive Cancer Center to establish a clinically and genomically annotated patient-derived xenograft (PDX) platform designed to enhance new drug development and strategies for targeted therapies. Advanced stage non-small-cell lung cancer (NSCLC) was selected for initial studies because of emergence of a number of "druggable" molecular targets, and recent recognition of substantial inter- and intrapatient tumor heterogeneity. Additionally, clonal evolution after targeted therapy interventions make this tumor type ideal for investigation of this platform. Using the immunodeficient NOD scid gamma mouse, > 200 NSCLC tumor biopsies have been xenotransplanted. During the annotation process, patient tumors and subsequent PDXs are compared at multiple levels, including histomorphology, clinically applicable molecular biomarkers, global gene expression patterns, gene copy number variations, and DNA/chromosomal alterations. NSCLC PDXs are grouped into panels of interest according to oncogene subtype and/or histologic subtype. Multiregimen drug testing, paired with next-generation sequencing before and after therapy and timed tumor pharmacodynamics enables determination of efficacy, signaling pathway alterations, and mechanisms of sensitivity-resistance in individual models. This approach should facilitate derivation of new therapeutic strategies and the transition to individualized therapy.
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA. Electronic address: david.gandara@ucdmc.ucdavis.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME and Sacramento, CA.
authors.forename: Carol
authors.initials: C
authors.lastname: Bult
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Li
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Riess
authors.affiliation: Response Genetics, Inc, Los Angeles, CA.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Astrow
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Regina
authors.initials: R
authors.lastname: Gandour-Edwards
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: David T
authors.initials: DT
authors.lastname: Cooke
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Ken Y
authors.initials: KY
authors.lastname: Yoneda
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Moore
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Chong-Xian
authors.initials: CX
authors.lastname: Pan
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Rebekah A
authors.initials: RA
authors.lastname: Burich
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: David
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME and Sacramento, CA.
authors.forename: James G
authors.initials: JG
authors.lastname: Keck
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME and Sacramento, CA.
authors.forename: Susan
authors.initials: S
authors.lastname: Airhart
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME and Sacramento, CA.
authors.forename: Neal
authors.initials: N
authors.lastname: Goodwin
authors.affiliation: University of California, Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Ralph W
authors.initials: RW
authors.lastname: de Vere White
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME and Sacramento, CA.
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents
keywords: Clinical trials; Lung cancer; Mouse model; Patient derived xenograft
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