title: Genetically engineered cancer models, but not xenografts, faithfully predict anticancer drug exposure in melanoma tumors.
abstract: BACKGROUND
  Rodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed.
  
  
  METHODS
  In this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs).
  
  
  RESULTS
  Using microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors.
  
  
  CONCLUSIONS
  The tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors.
authors.affiliation: University of North Carolina Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, 1013 Genetic Medicine Building, CB 7361, Chapel Hill, North Carolina 27599-7361, USA.
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Combest
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Roberts
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dillon
authors.forename: Katie
authors.initials: K
authors.lastname: Sandison
authors.forename: Suzan K
authors.initials: SK
authors.lastname: Hanna
authors.forename: Charlene
authors.initials: C
authors.lastname: Ross
authors.forename: Sohrab
authors.initials: S
authors.lastname: Habibi
authors.forename: Beth
authors.initials: B
authors.lastname: Zamboni
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Martin
authors.initials: M
authors.lastname: Brunner
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics; D016190:Carboplatin / Q000097:blood / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin