title: Comparison of genomics and functional imaging from canine sarcomas treated with thermoradiotherapy predicts therapeutic response and identifies combination therapeutics.
abstract: OBJECTIVE
  While hyperthermia is an effective adjuvant treatment to radiotherapy, we do not completely understand the nature of the response heterogeneity.
  
  
  METHODS
  We performed gene expression analysis of 22 spontaneous canine sarcomas before and after the first hyperthermia treatment administered as an adjuvant to radiotherapy. In parallel, diffusion-weighted MRI (DWI) was done prior to the treatment course and at the end of therapy.
  
  
  RESULTS
  From the integrative analysis of gene expression and DWI, we identified significant correlation between tumor responses with genes involved in VEGF signaling, telomerase, DNA repair, and inflammation. The treatment-induced changes in gene expression identified 2 distinct tumor subtypes with significant differences in their gene expression and treatment response, as defined by changes in DWI. The 2 tumor subtypes could also be readily identified by pretreatment gene expression. The tumor subtypes, with stronger expression response and DWI increase, had higher levels of HSP70, POT1, and centrosomal proteins, and lower levels of CD31, vWF, and transferrin. Such differential gene expression between the 2 subtypes was used to interrogate connectivity map and identify linkages to an HSP90 inhibitor, geldanamycin. We further validated the ability of geldanamycin to enhance cell killing of human tumor cells with hyperthermia and radiotherapy in clonogenic assays.
  
  
  CONCLUSIONS
  To our knowledge, this is one of the first successful attempts to link changes in gene expression and functional imaging to understand the response heterogeneity and identify compounds enhancing thermoradiotherapy. This study also demonstrates the value of canine tumors to provide information generalizable to human tumors.
authors.affiliation: Institute for Genome Sciences & Policy, Department of Molecular Genetics & Microbiology, Duke University, Durham, NC 27708, USA. jentsan.chi@duke.edu
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
authors.forename: Donald E
authors.initials: DE
authors.lastname: Thrall
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.forename: Stacey
authors.initials: S
authors.lastname: Snyder
authors.forename: Diane
authors.initials: D
authors.lastname: Fels
authors.forename: Chelsea
authors.initials: C
authors.lastname: Landon
authors.forename: Linda
authors.initials: L
authors.lastname: McCall
authors.forename: Lan
authors.initials: L
authors.lastname: Lan
authors.forename: Marlene
authors.initials: M
authors.lastname: Hauck
authors.forename: James R
authors.initials: JR
authors.lastname: MacFall
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Viglianti
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D003131:Combined Modality Therapy; D004285:Dogs; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D006801:Humans; D006979:Hyperthermia, Induced; D008279:Magnetic Resonance Imaging / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D011878:Radiotherapy / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000235:genetics* / Q000628:therapy*