title: Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human tumor models.
abstract: OBJECTIVE
  ERBB3 is overexpressed in a broad spectrum of human cancers, and its aberrant activation is associated with tumor pathogenesis and therapeutic resistance to various anticancer agents. Neuregulin 1 (NRG1) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members, resulting in activation of multiple intracellular signaling pathways. AV-203 is a humanized IgG1/κ ERBB3 inhibitory antibody that completed a first-in-human phase I clinical trial in patients with advanced solid tumors. The purpose of this preclinical study was to identify potential biomarker(s) that may predict response to AV-203 treatment in the clinic.
  
  
  METHODS
  We conducted in vivo efficacy studies using a broad panel of xenograft models representing a wide variety of human cancers. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models.
  
  
  RESULTS
  A significant correlation was observed between the levels of NRG1 expression and TGI by AV-203. In contrast, TGI was not correlated with ERBB3 expression. The correlation between the levels of NRG1 expression in tumors and their response to ERBB3 inhibition by AV-203 was further validated using patient-derived tumor explant models.
  
  
  CONCLUSIONS
  NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in preclinical human cancer models. NRG1 warrants further clinical evaluation and validation as a potential predictive biomarker of response to AV-203.
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Kristan
authors.initials: K
authors.lastname: Meetze
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Vincent
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Steven
authors.initials: S
authors.lastname: Tyler
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Mazsa
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Delpero
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Steve
authors.initials: S
authors.lastname: Bottega
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Donna
authors.initials: D
authors.lastname: McIntosh
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Nicoletti
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: William M
authors.initials: WM
authors.lastname: Winston
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Solly
authors.initials: S
authors.lastname: Weiler
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Jeno
authors.initials: J
authors.lastname: Gyuris
authors.affiliation: AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts. zweng@aveooncology.com.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Weng
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D015415:Biomarkers; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D008024:Ligands; D020890:Neuregulin-1; C000602877:AV-203; D020893:Receptor, ErbB-3