title: Genomic profiling of a Hepatocyte growth factor-dependent signature for MET-targeted therapy in glioblastoma.
abstract: BACKGROUND
  Constitutive MET signaling promotes invasiveness in most primary and recurrent GBM. However, deployment of available MET-targeting agents is confounded by lack of effective biomarkers for selecting suitable patients for treatment. Because endogenous HGF overexpression often causes autocrine MET activation, and also indicates sensitivity to MET inhibitors, we investigated whether it drives the expression of distinct genes which could serve as a signature indicating vulnerability to MET-targeted therapy in GBM.
  
  
  METHODS
  Interrogation of genomic data from TCGA GBM (Student's t test, GBM patients with high and low HGF expression, p ≤ 0.00001) referenced against patient-derived xenograft (PDX) models (Student's t test, sensitive vs. insensitive models, p ≤ 0.005) was used to identify the HGF-dependent signature. Genomic analysis of GBM xenograft models using both human and mouse gene expression microarrays (Student's t test, treated vs. vehicle tumors, p ≤ 0.01) were performed to elucidate the tumor and microenvironment cross talk. A PDX model with EGFR(amp) was tested for MET activation as a mechanism of erlotinib resistance.
  
  
  RESULTS
  We identified a group of 20 genes highly associated with HGF overexpression in GBM and were up- or down-regulated only in tumors sensitive to MET inhibitor. The MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall impede tumor growth by inhibiting cell cycle progression. EGFR (amp) tumors undergo erlotinib resistance responded to a combination of MET and EGFR inhibitors.
  
  
  CONCLUSIONS
  Combining TCGA primary tumor datasets (human) and xenograft tumor model datasets (human tumor grown in mice) using therapeutic efficacy as an endpoint may serve as a useful approach to discover and develop molecular signatures as therapeutic biomarkers for targeted therapy. The HGF dependent signature may serve as a candidate predictive signature for patient enrollment in clinical trials using MET inhibitors. Human and mouse microarrays maybe used to dissect the tumor-host interactions. Targeting MET in EGFR (amp) GBM may delay the acquired resistance developed during treatment with erlotinib.
authors.affiliation: Molecular Oncogenesis and Targeted Therapy, Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick AVE NE, Grand Rapids, MI, 49503, USA. jennifer.johnson@vai.org.|Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI, USA. jennifer.johnson@vai.org.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Transfusion Medicine, Infectious Disease and Immunogenetics Section, Clinical Center, Trans-National Institutes of Health Center for Human Immunology, National Institutes of Health, Bethesda, MD, USA. asciertoml@jhu.edu.|Department of Oncology, Johns Hopkins University, Baltimore, MD, USA. asciertoml@jhu.edu.
authors.forename: Maria Libera
authors.initials: ML
authors.lastname: Ascierto
authors.affiliation: Departments of Neurosurgery and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. smittal@med.wayne.edu.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Mittal
authors.affiliation: Vertex Pharmaceutical Inc., Boston, MA, USA. david_newsone@vrtx.com.
authors.forename: David
authors.initials: D
authors.lastname: Newsome
authors.affiliation: Molecular Oncogenesis and Targeted Therapy, Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick AVE NE, Grand Rapids, MI, 49503, USA. liang.kang@vai.org.|Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI, USA. liang.kang@vai.org.
authors.forename: Liang
authors.initials: L
authors.lastname: Kang
authors.affiliation: Woodland Pharmaceuticals, Shrewsbury, MA, USA. mbriggs@woodlandpharma.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Briggs
authors.affiliation: Vertex Pharmaceutical Inc., Boston, MA, USA. kirk_tanner@vrtx.com.
authors.forename: Kirk
authors.initials: K
authors.lastname: Tanner
authors.affiliation: Department of Transfusion Medicine, Infectious Disease and Immunogenetics Section, Clinical Center, Trans-National Institutes of Health Center for Human Immunology, National Institutes of Health, Bethesda, MD, USA. fmarincola@sidra.org.|Research Branch, Sidra Medical and Research Center, Doha, Qatar. fmarincola@sidra.org.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ, USA. mberens@tgen.org.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI, USA. george.vandewoude@vai.org.
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
authors.affiliation: Molecular Oncogenesis and Targeted Therapy, Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick AVE NE, Grand Rapids, MI, 49503, USA. qian.xie@vai.org.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xie
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C066855:HGF protein, human; D047428:Protein Kinase Inhibitors; D017228:Hepatocyte Growth Factor; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met