Familial Nasopharyngeal Carcinoma 6

Drug Therapy for Nasopharyngeal Carcinoma: Cytotoxic and Targeted Therapy 155Increased expression of the MAD2 gene in MAD2-transfected NPC cells resulted in enhanced sensitivityto cisplatin, possibly via induction of mitotic arrestand activation of apoptosis (Cheung et al. 2005).Likewise, MAD2-induced sensitization of CNE2 cellsto the vinca alkaloid, vincristine, was associated withG2/M mitotic arrest (Wang and Wong 2003).The tumor suppressor p16 gene suppresses cellproliferation primarily by inhibiting G1 cell cycle progression,and is frequently inactivated via promotermethylation in NPC (Lo et al. 1996). Restoration ofp16 function via p16-transfection in CNE1 NPC cellsresulted in a modest increase in sensitivity to 5-fluorouraciland cisplatin in vitro (Chow et al. 2000).TWIST (or TWIST-1) is a basic helix–loop–helix(bHLH) protein implicated in carcinogenesis, thefunction of which is to interfere with p53-mediatedapoptosis and cell differentiation. Using an NPC cellline, HNE1-T3, upregulation of the gene encodingTWIST has been associated with increased resistanceto microtubule-disrupting agents such aspaclitaxel and vincristine (Wang et al. 2004), possiblyby suppressing paclitaxel-induced apoptosis(Zhang et al. 2007). Inactivation of the gene encodingTWIST via small RNA interference resulted insensitization to paclitaxel in HNE1-T3 cells (Zhanget al. 2007).P-glycoprotein (ABCB1, or MDR1) is a member ofthe ATP-binding cassette (ABC) superfamily of multidrugtransporters, and has been implicated in resistanceagainst platinum, paclitaxel, and anthracyclinesin a variety of cancers. MDR1 expression can be foundin up to 12% of NPC samples (Chen et al. 2001; Hsuet al. 2002), and has been associated with shorter survivalin metastatic NPC in two studies (Chen et al.2001; Hsu et al. 2002). No association with responseto doxorubicin-containing chemotherapy was foundin one study (Hsu et al. 2002).11.4The Clinical Development of TargetedTherapy for Nasopharyngeal Carcinoma11.4.1Molecular Abnormalities in NasopharyngealCarcinomaAdvances in the understanding of the molecularpathogenesis of NPC have led to the identification ofmany genetic and epigenetic aberrations that arecommon in NPC. Genome-wide microarray studiesof NPC tissues have revealed a high frequency ofaberrant expression of genes controlling apoptosis,cell cycle progression, cell migration and adhesion,growth, and differentiation (Sriuranpong et al.2004). Important oncogenes such as BCL2, CCND1,MDM2, MYC, H-RAS, N-RAS, RAF1, EGFR, andPIK3CA are frequently amplified in NPC tissues and/or cell lines (Hui et al. 2002; Or et al. 2006).Inactivation of tumor suppressor genes (TSGs) areparticularly prevalent in NPC, with chromosomaldeletions occurring in between 85 and 95% ofregions involving 9p21 and 3p (Tao and Chan2007). These regions contain TSGs such as p16 (Loet al. 1995), p15 (Kwong et al. 2002), p14ARF (Kwonget al. 2002), and RASSF1A (Lo et al. 2001), which areinactivated via mechanisms including promotermethylation, mutation, or deletions. EBV latentinfection and epigenetic silencing of immunodominantEBV genes may also contribute to the evasionof host-derived immunosurveillance, while the productionof oncogenic EBV proteins (e.g., latentmembrane protein-1, LMP-1) contributes to NPCcarcinogenesis (Young and Rickinson 2004). Formore comprehensive overview of the genetic andepigenetic abnormalities in NPC, readers may referto several excellent reviews (Tao and Chan 2007;Young and Rickinson 2004; Lo and Huang 2002).11.4.2Targeting Epidermal Growth FactorReceptor-Mediated SignalingInhibitors against the epidermal growth factor receptor(EGFR) were the first targeted therapy evaluatedclinically in recurrent and metastatic NPC. This isbased on the observation that the EGFR gene is amplifiedin 40% (Hui et al. 2002) and EGFR protein isoverexpressed in over 80% of NPC tumors. EGFRoverexpression is also associated with shorter survivalfollowing chemoradiotherapy in locoregionallyadvanced NPC (Ma et al. 2003). In NPC cells, the anti-EGFR monoclonal antibody, cetuximab (Sung et al.2005), and the EGFR tyrosine kinase inhibitor, gefitinib(Hsu et al. 2002), have been shown to inhibit cellgrowth, induce apoptosis, and exert an additive effectwhen combined with cisplatin. Based on these data,researchers at the Prince of Wales Hospital led a multicenterphase II study of cetuximab and carboplatinin 60 patients with metastatic NPC who had failedprevious platinum-based regimens (Chan et al.