title: Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment.
abstract: BACKGROUND
  Current technology permits an unbiased massive analysis of somatic genetic alterations from tumor DNA as well as the generation of individualized mouse xenografts (Avatar models). This work aimed to evaluate our experience integrating these two strategies to personalize the treatment of patients with cancer.
  
  
  METHODS
  We performed whole-exome sequencing analysis of 25 patients with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. Avatar models were used as an in vivo platform to test proposed treatment strategies.
  
  
  RESULTS
  Successful exome sequencing analyses have been obtained for 23 patients. Tumor-specific mutations and copy-number variations were identified. All samples profiled contained relevant genomic alterations. Tumor was implanted to create an Avatar model from 14 patients and 10 succeeded. Occasionally, actionable alterations such as mutations in NF1, PI3KA, and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and, accordingly, treatment of the patients with these drugs was not effective. To date, 13 patients have received a personalized treatment and 6 achieved durable partial remissions. Prior testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in some patients with no actionable mutations.
  
  
  CONCLUSIONS
  The use of full genomic analysis for cancer care is encouraging but presents important challenges that will need to be solved for broad clinical application. Avatar models are a promising investigational platform for therapeutic decision making. While limitations still exist, this strategy should be further tested.
authors.affiliation: Authors' Affiliations: Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Champions Oncology, Baltimore, Maryland; Personal Genome Diagnostics, Inc., Baltimore, Maryland; Laboratorio Dianas Terapéuticas, Hospital Universitario Madrid-Sanchinarro, Madrid, Spain; Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid-Sanchinarro, Madrid, Spain; Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.
authors.forename: Elena
authors.initials: E
authors.lastname: Garralda
authors.forename: Keren
authors.initials: K
authors.lastname: Paz
authors.forename: Pedro P
authors.initials: PP
authors.lastname: López-Casas
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Amanda
authors.initials: A
authors.lastname: Katz
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kann
authors.forename: Fernando
authors.initials: F
authors.lastname: López-Rios
authors.forename: Francesca
authors.initials: F
authors.lastname: Sarno
authors.forename: Fátima
authors.initials: F
authors.lastname: Al-Shahrour
authors.forename: David
authors.initials: D
authors.lastname: Vasquez
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bruckheimer
authors.forename: Samuel V
authors.initials: SV
authors.lastname: Angiuoli
authors.forename: Antonio
authors.initials: A
authors.lastname: Calles
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D019295:Computational Biology; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D059472:Exome; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D005260:Female; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D057285:Precision Medicine; D011487:Protein Conformation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000737:chemistry; D012189:Retrospective Studies; D016896:Treatment Outcome; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt