title: Identification of soluble candidate biomarkers of therapeutic response to sunitinib in medullary thyroid carcinoma in preclinical models.
abstract: OBJECTIVE
  Medullary thyroid carcinoma (MTC), an aggressive rare tumor due to activating mutations in the proto-oncogene RET, requires new therapeutic strategies. Sunitinib, a potent inhibitor of RET, VEGF receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor (PDGFR)α/β, has been reported as clinically effective in some patients with advanced MTC. In this study, we examine molecular mechanisms of action of sunitinib and identify candidate soluble biomarkers of response.
  
  
  METHODS
  Both in vitro and in vivo assays, using the human TT RET(C634W) MTC cell line, were done to assess the activity of sunitinib. Kinetic microarray studies were used to analyze molecular pathways modified by sunitinib and to identify candidate biomarkers that were subsequently investigated in the serum of patients.
  
  
  RESULTS
  Sunitinib displayed antiproliferative and antiangiogenic activities and inhibited RET autophosphorylation and activation of downstream signaling pathways. We showed that sunitinib treatment induced major changes in the expression of genes involved in tissue invasion and metastasis including vimentin (VIM), urokinase plasminogen (PLAU), tenascin-C (TN-C), SPARC, and CD44. Analyzing downregulated genes, we identified those encoding secreted proteins and, among them, interleukin (IL)-8 was found to be modulated in the serum of xenografted mice under sunitinib treatment. Furthermore, we demonstrated that metastatic MTC patients presented increased serum levels of IL-8 and TGF-β2.
  
  
  CONCLUSIONS
  Experimental models confirm the clinical efficacy of sunitinib observed in a few studies. Molecular pathways revealed by genomic signatures underline the impact of sunitinib on tissue invasion. Selected soluble candidate biomarkers could be of value for monitoring sunitinib response in metastatic MTC patients.
authors.affiliation: Unité CNRS UMR8200, Institut de Cancérologie Gustave Roussy and Univ Paris-Sud, Villejuif, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Broutin
authors.forename: Nabahet
authors.initials: N
authors.lastname: Ameur
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Thomas
authors.initials: T
authors.lastname: Robert
authors.forename: Benoit
authors.initials: B
authors.lastname: Petit
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
authors.forename: Monique
authors.initials: M
authors.lastname: Talbot
authors.forename: Bernard
authors.initials: B
authors.lastname: Caillou
authors.forename: Martin
authors.initials: M
authors.lastname: Schlumberger
authors.forename: Corinne
authors.initials: C
authors.lastname: Dupuy
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Bidart
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000097:blood; D018276:Carcinoma, Medullary / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000097:blood; D007211:Indoles / Q000494:pharmacology*; D016209:Interleukin-8 / Q000097:blood; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D000077210:Sunitinib; D019063:Tenascin / Q000097:blood; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D053781:Transforming Growth Factor beta2 / Q000097:blood; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D002272:Carcinoembryonic Antigen; D018960:Hyaluronan Receptors; D007211:Indoles; D016209:Interleukin-8; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011758:Pyrroles; D019063:Tenascin; D053781:Transforming Growth Factor beta2; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D000077210:Sunitinib