Familial Nasopharyngeal Carcinoma 6

156 B. B. Y. Ma and A. T. C. Chan2005). There were seven partial responses with anoverall response rate of 11.7%, and disease stabilizationrate was 48.3%. In this cohort where over 30% ofpatients had three or more lines of prior therapy, themedian time to progression and overall survival were2.6 and 7.7 months, respectively. Treatment was welltolerated, and grade 3–4 cetuximab-related rashoccurred in 12% of patients.Another EGFR inhibitor, gefitinib, was evaluatedin a phase II study at a dose of 500 mg daily inchemotherapy-refractory patients at the Prince ofWales Hospital (Ma et al. 2007). Three patients experienceddisease stabilization lasting up to 8 months, andthe study was terminated after 15 patients were accruedowing to a lack of response. This is probably due to theabsence of activating mutations of the EGFR tyrosinekinase in NPC tumors (Lee et al. 2006).11.4.3Targeting Tumor AngiogenesisHypoxia-inducible factor-1 alpha (HIF-1a) is a keyhypoxia-inducible transcriptional factor, which upregulatesthe expression of important mediators ofangiogenesis such as vascular endothelial growthfactor and its ligands, and of glucose metabolismsuch as carbonic anhydrase 9 (CA-9). Genome-wideexpression analysis of NPC cell lines has demonstratedthat expression of genes encoding HIF-1a,CA-9, VEGF, and other signaling proteins in NPC areupregulated under hypoxic conditions (Sung et al.2007). HIF-1a, CA-9, and VEGF are also overexpressedin over 50% of NPC tumors, while co-expressionof these hypoxic-angiogenic factors predictshorter survival following radiotherapy in patientswith locoregionally advanced NPC (Hui et al. 2002).Therefore, pharmacological inhibition of the downstreamsignaling mediators of HIF-1a may be usefulagainst NPC. Researchers have evaluated the clinicalactivity of several inhibitors of VEGF (e.g., bevacizumab)or its receptors (VEGFR-2 and -3), such assorafenib, sunitinib, and pazopanib in NPC patients.The only reported published to date is a phase IIstudy of sorafenib (400mg bd) in chemo-refractorypatients with either advanced NPC and non-NPChead and neck cancer (Elser et al. 2007). No responsewas reported among the 6 out of 27 who had NPC,and the study was terminated after the first stage ofaccrual. Phase II studies of sunitinib and pazopanibas single agent in patients with previously treatedadvanced NPC are either ongoing or completedaccrual. Results have not yet been reported. The anti-VEGF antibody, bevacizumab, is currently being evaluatedin combination with IMRT in patients withlocoregionally advanced NPC in a Radiation TherapyOncology Group (RTOG)-sponsored study involvingboth North American and Asian centers.The use of anti-angiogenesis agents is associatedwith an increased bleeding tendency. This is of theoreticalconcern in the clinical evaluation of suchagents in NPC; therefore, such agents should beavoided in patients with locally advanced tumorsinvading major blood vessels or venous plexus, andin those presenting with epistaxis.11.4.4Epigenetic ModulationThe EBV exist in a state of latency in undifferentiatedNPC cells where it evades the host’s immune responseby expressing a limited repertoire of EB latent genes,while expression of the more immunodominant EBVnuclear and lytic antigens are silenced. Epigeneticgene silencing via promoter methylation has beenfound to be one of the key mechanisms of silencedexpression of EBV nuclear and lytic antigens, as wellas host-derived tumor suppressor genes (Kwonget al. 2002; Ambinder et al. 1999). It has been postulatedthat pharmacological reversal of promotermethylation may result in re-expression of the EBVimmunodominant antigens, thereby attracting host’simmune response and/or providing target antigensfor cytotoxic T-cell therapy. Researchers of theChinese University of Hong Kong and Johns HopkinsUniversity (Singapore) were able to demonstrate forthe first time in humans that the demethylating agent,azacitadine, could induce expression of silenced EBVgenes in NPC tissues (Chan et al. 2004). In this study,patients with recurrent EBV-associated NPC andlymphoma who had exhausted all treatment optionshad paired tumor biopsies performed before andafter treatment with azacitdine. Treatment was welltolerated by the eight NPC patients, and expressionof the viral regulatory protein, Zta, was re-expressedin the posttreatment biopsy of a patient. Using methylation-specificpolymerase chain reaction andbisulfite genomic sequencing, the postbiopsies offour patients showed partial demethylation at the Cpand Wp promoter of the EBV genome (Chan et al.2004). A phase I study of combining azacitidine anda histone deacetylase inhibitor in NPC is ongoing.