title: Predicting drug responsiveness in human cancers using genetically engineered mice.
abstract: OBJECTIVE
  To use genetically engineered mouse models (GEMM) and orthotopic syngeneic murine transplants (OST) to develop gene expression-based predictors of response to anticancer drugs in human tumors. These mouse models offer advantages including precise genetics and an intact microenvironment/immune system.
  
  
  METHODS
  We examined the efficacy of 4 chemotherapeutic or targeted anticancer drugs, alone and in combination, using mouse models representing 3 distinct breast cancer subtypes: Basal-like (C3(1)-T-antigen GEMM), Luminal B (MMTV-Neu GEMM), and Claudin-low (T11/TP53-/- OST). We expression-profiled tumors to develop signatures that corresponded to treatment and response, and then tested their predictive potential using human patient data.
  
  
  RESULTS
  Although a single agent exhibited exceptional efficacy (i.e., lapatinib in the Neu-driven model), generally single-agent activity was modest, whereas some combination therapies were more active and life prolonging. Through analysis of RNA expression in this large set of chemotherapy-treated murine tumors, we identified a pair of gene expression signatures that predicted pathologic complete response to neoadjuvant anthracycline/taxane therapy in human patients with breast cancer.
  
  
  CONCLUSIONS
  These results show that murine-derived gene signatures can predict response even after accounting for common clinical variables and other predictive genomic signatures, suggesting that mice can be used to identify new biomarkers for human patients with cancer.
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Genetics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Usary
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: David
authors.initials: D
authors.lastname: Darr
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Roberts
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Lorraine
authors.initials: L
authors.lastname: Balletta
authors.forename: Olga
authors.initials: O
authors.lastname: Karginova
authors.forename: Jamie
authors.initials: J
authors.lastname: Jordan
authors.forename: Austin
authors.initials: A
authors.lastname: Combest
authors.forename: Arlene
authors.initials: A
authors.lastname: Bridges
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Maggie C U
authors.initials: MC
authors.lastname: Cheang
authors.forename: Jason I
authors.initials: JI
authors.lastname: Herschkowitz
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Rosen
authors.forename: William
authors.initials: W
authors.lastname: Zamboni
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D000069347:Erlotinib Hydrochloride; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: D054316:Biomarkers, Pharmacological; D011799:Quinazolines; D000077341:Lapatinib; D004317:Doxorubicin; D003520:Cyclophosphamide; D016190:Carboplatin; D000069347:Erlotinib Hydrochloride; D017239:Paclitaxel