title: Platelet-derived growth factor receptor alpha (PDGFRα) targeting and relevant biomarkers in ovarian carcinoma.
abstract: OBJECTIVE
  Platelet-derived growth factor receptor alpha (PDGFRα) is believed to be associated with cell survival. We examined (i) whether PDGFRα blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFRα therapy.
  
  
  METHODS
  PDGFRα expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFRα (IMC-3G3) was used for in vitro and in vivo experiments with or without docetaxel. Gene microarrays and reverse-phase protein arrays with pathway analyses were performed to identify potential predictive biomarkers.
  
  
  RESULTS
  When compared to low or no PDGFRα expression, increased PDGFRα expression was associated with significantly poorer overall survival of patients with ovarian cancer (P=0.014). Although treatment with IMC-3G3 alone did not affect cell viability or increase apoptosis, concurrent use of IMC-3G3 with docetaxel significantly enhanced sensitization to docetaxel and apoptosis. In an orthotopic mouse model, IMC-3G3 monotherapy had no significant antitumor effects in SKOV3-ip1 (low PDGFRα expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFRα expression). Concurrent use of IMC-3G3 with docetaxel, compared with use of docetaxel alone, significantly reduced tumor weight in all tested cell lines. In protein ontology, the EGFR and AKT pathways were downregulated by IMC-3G3 therapy. MAPK and CCNB1 were downregulated only in the HeyA8-MDR model.
  
  
  CONCLUSIONS
  These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development.
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kakajan
authors.initials: K
authors.lastname: Komurov
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA.
authors.forename: Rouba
authors.initials: R
authors.lastname: Ali-Fehmi
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ju-Won
authors.initials: JW
authors.lastname: Roh
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Dianna D
authors.initials: DD
authors.lastname: Cody
authors.affiliation: Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Prahlad T
authors.initials: PT
authors.lastname: Ram
authors.affiliation: ImClone Systems Inc., New York, NY, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Loizos
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, Houston, TX, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, Houston, TX, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: asood@mdanderson.org.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D000077143:Docetaxel; D005260:Female; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D043823:Taxoids / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D043823:Taxoids; D000077143:Docetaxel; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; C000589393:olaratumab
keywords: EGFR; IMC-3G3; MAPK; Ovarian cancer; Platelet-derived growth factor receptor alpha