World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access
Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc
Journal website http://www.wjon.org

Review

Volume 6, Number 1, February 2015, pages 243-261

Prognostic Value of Molecular Markers and Implication for Molecular Targeted Therapies in Nasopharyngeal Carcinoma: An Update in an Era of New Targeted Molecules Development

Figure

Figure 1.
Figure 1. Overview of the signaling pathways involved in nasopharyngeal carcinoma (NPC) development. Initiation of upstream signaling proteins in the NPC development begins with LMP1. Subsequent induced activity of downstream proteins in several pathways such as β-catenin, NF-κB, and AP-1 leads to dysregulation of cell proliferation (CDK/cyclin protein), increase in angiogenesis (VEGF, IL-8), metastasis (E-cadherin, MMPs), cell transformation (TERT), and inhibition of apoptosis (survivin, Bcl-2). ——►: stimulatory effect; ——●: inhibitory effect; AP-1: activator protein 1; EGFR: epidermal growth factor receptor; ERK: extracellular signal related kinase; JNK: c-Jun N-terminal kinase; LMP1: latent membrane protein 1; MMP: matrix metalloproteinase; PTEN: phosphatase and tensin homolog; PI3K: phosphoinositol-3-kinase; RASSF: Ras association domain family; TERT: telomerase reverse transcriptase; VEGF: vascular endothelial growth factor; WIF: Wnt inhibitory factor.

Tables

Table 1. Molecular Pathways and Targeted Therapeutic Agents Involved in Nasopharyngeal Cancer
 
MechanismPathwayTargeted therapeutic agent or strategyClinical applicationIn development
Abnormal signaling pathwaysEGFRCetuximab: anti-EGFR antibody+
PI3K/AKT and PTENPI3K inhibitor: Y294002+
RKIPRKIP: alter radiosensitivity+
RASSFDemethylation of RASSF2A+
Wnt/β-cateninYC-1: anti-invasion activity+
Receptor-mediated aberrationVEGFBevacizumab: monoclonal antibody against VEGF+
c-METc-MET inhibitor: SU11274, BAY 853474, PF-04217903+
Intra-cellular mitogenic signals aberrationHIF-1αHIF-1α inhibitor: NSC-134754, pantoprazole+
Cell cycle aberrationCyclin-dependent kinase (CDK), cyclin D1, ECyclin-dependent kinase inhibitor: seliciclib+
c-Mycc-Myc inhibitor+
MicroRNAsmiRNAs of let-7 family: suppress cell proliferation+
Cell adhesion aberrationE-cadherinDNA demethylating agent: 5-aza-dC+
Matrix metalloproteinases (MMPs)Synthetic inhibitors: marimastat, tanomastat (BAY12-9666), prinomastat (AG3340)+
Recombinant human endostatin: endosatr+
Off-target inhibitors: bisphosphonates+
Natural inhibitors: neovastat (AE-941)+

 

Table 2. Clinical Trials of Molecular Targeted Therapy in Nasopharyngeal Cancer
 
AgentPhaseTreatmentNumber of patientsORR (%)CR (%)SD (%)TTP (mo)PFS (mo)OS (mo)Reference
ORR: overall response rate; CR: complete response; SD: stable disease; SD: stable disease; TTP (mo): time to progression (month); PFS (mo): progression-free survival (month); OS (mo): overall survival (month).
Single or combination therapy in metastatic/recurrent disease
  CetuximabIICetuximab 250 mg/m2 weekly (400 mg/m2 loading dose) + carboplatin6011.7048.32.7-7.8Chan et al, 2005 [16]
  GefitinibIIGefitinib 250 mg daily190010.54-16Chua et al, 2008 [17]
  GefitinibIIGefitinib 500 mg daily16 (15 evaluable)0018.82.7-12Ma et al, 2008 [18]
Single or concurrent therapy in locally advanced disease
  SeliciclibI800 mg or 400 mg twice daily on days 1 to 3 and 8 to 1220 (14 evaluable)00Seven patients had > 25% reduction of tumor size---Hsieh et al, 2009 [19]
  CetuximabIIAn initial dose of cetuximab (400 mg/m2) 7 - 10 days before receiving concurrent IMRT, weekly cisplatin (30 mg/m2/week) and cetuximab (250 mg/m2/week)309690--2-year PFS 86.5%2-year OS 89.9%Ma et al, 2012 [20]
  BevacizumabIIThree cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m2) both given on days 1, 22, and 43 of IMRT, then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m2), both given on days 64, 85, and 106 after IMRT, and three cycles of fluorouracil (1,000 mg/m2/day), given on days 64 - 67, 85 - 88, and 106 - 109 after IMRT46 (44 evaluable)91---2-year PFS 74.7%2-year OS 90.9%Lee et al, 2012 [21]