title: Small molecule-based chemotherapeutic approach in p16-positive and -negative HNSCC in vitro.
abstract: BACKGROUND
  Incidence of oropharyngeal head and neck squamous cell carcinoma (HNSCC) induced by the human papilloma virus (HPV) is rising. HNSCC is the sixth most common neoplasia worldwide. The survival rate remains poor, thus innovative therapy approaches are necessary. Everolimus, an inhibitor of the mammalian target of rapamycin, as well as the multi-tyrosine kinase inhibitors sorafenib (targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor and RAF) and sunitinib (targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, stem cell factor receptor, RET proto-oncogene and colony-stimulating factor), have shown a remarkable antitumor effect against various tumor entities, with moderate side-effects. These drugs are administered orally, which should lead to higher patient compliance and less hospitalisation.
  
  
  OBJECTIVE
  This study sought to evaluate the expression of PDGFR α/β and hypoxia-inducible factor-1α (HIF-1α) and their alterations induced by everolimus, sorafenib and sunitinib in chemonaïve HPV-positive and HPV-negative HNSCC. To our knowledge, this is the first in vitro study to investigate such cases.
  
  
  METHODS
  We incubated HPV-positive CERV196 and HPV-negative HNSCC 11A and 14C cells for 2 to 8 days with increasing concentration of drugs. Expression of PDGFR α/β and HIF-1α was measured by enzyme-linked immunosorbent assay and compared to a chemonaïve controls.
  
  
  RESULTS
  Our study showed that PDGFR α/β and HIF-1α were expressed in all three cell lines. Incubation with everolimus, sorafenib or sunitinib led to a decrease in PDGFR α/β and HIF-1α expression, depending on the HPV status. A statistically significant alteration of PDGFR α/β was detected in CERV196 only. Thus, HPV-positive HNSCC exhibited a higher sensitivity to the drugs used compared to HPV-negative HNSCC 11A and 14C tumor cells. A significant reduction of HIF-1α was measured for HNSCC 11A and 14C only. An escalation of drug concentration had no significant effect.
  
  
  CONCLUSIONS
  We showed that these novel agents led to a significant reduction of PDGFR and HIF-1α, depending on the HPV status. HPV positivity is associated with increased chemosensitivity and may be associated with better locoregional control and overall patient survival compared to HPV negativity. Further studies are necessary to investigate the efficacy and safety of these agents in the treatment of HPV-positive and -negative HNSCC in vivo.
authors: Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. christoph.aderhold@umm.de.
authors: Christoph
authors: C
authors: Aderhold
authors: Anne
authors: A
authors: Faber
authors: Guido Manuel
authors: GM
authors: Grobschmidt
authors: Anja
authors: A
authors: Chakraborty
authors: Andre
authors: A
authors: Bockmayer
authors: Claudia
authors: C
authors: Umbreit
authors: Richard
authors: R
authors: Birk
authors: Jens
authors: J
authors: Stern-Straeter
authors: Karl
authors: K
authors: Hörmann
authors: Johannes David
authors: JD
authors: Schultz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology* / Q000821:virology; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D052162:Human papillomavirus 16 / Q000302:isolation & purification*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000473:pathology* / Q000821:virology; D000090063:Proto-Oncogene Mas; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D054852:Small Molecule Libraries; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: HIF; PDGFR; Tyrosine kinase inhibitor; everolimus; head and neck squamous cell carcinoma; mTOR; sorafenib; sunitinib