Clinical applications for targeted therapy in bladder cancer

Transitional cell carcinoma (TCC) of the bladder is the fourth most common solid-tumor malignancy in men in the United States. Approximately 17,060 men in the United States died from TCC of the bladder in 2004; most of the deaths were due to metastatic disease [1]. Metastatic TCC is usually treated with systemic chemotherapy, including regimens such as M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) (2-4]. However, despite systemic chemotherapy with even the most effective regimens, most patients with distant metastatic bladder cancer die of the disease after a median survival duration of 18 months [3,4]. Although considerable efforts have been made to escalate the dose of MNAC, to modulate the components of the regimens, and to use novel combination regimens that include active agents such as paclitaxel, gemcitabine, and ifosfamide, there has been no improvement in survival [5-10]. Although some of these newer regimens produce fewer toxic side effects than MNAC, there is yet no compelling evidence that they improve patient survival. In general, the treatment of metastatic TCC of the bladder by classic cytotoxic chemotherapy has reached a therapeutic plateau. Despite high rates of response to treatment, the disease is generally incurable. However, it is clear that cytotoxic chemotherapy has provided significant palliation for many patients, and has resulted in improved outcome, probability for cure, or both in the adjuvant setting of microscopic metastatic disease. Although chemotherapy is still an important component of combined therapy, the need for more effective treatment options exists. Fortunately, an improved understanding of the biology of malignancy is finally facilitating the design of novel therapeutic approaches to battle cancer. Urothelial transformation involves several cellular events including the deregulation of cellcycle and apoptotic pathways via mutation or altered expression of p53, p21/WAF-1, pRB, p27, and INK4A (p16). Progression of urothelial carcinoma has also been related to various members of the erbB family, vascular epidermal growth factor (VEGF), nerve factor-kappa B (NF kappa B), Akt, PTEN, and cyclooxygenase/2 (COX-2) [11]. All of these molecules are potential targets for novel therapies. The focus of this article is the aberrant signal transduction of members of the erbB family (ie, epidermal growth factor receptor [EGFR], and human epidermal growth factor receptors [HER]-2, -3, and -4) in TCC of the bladder. EGFR was sequenced and cloned by Ullrich in 1984 [12]. EGFR, HER1, or c-erbB1, is the prototype of the type I receptor tyrosine kinase (RTK) family, which also includes HER2 (cerbB2), HER3 (c-erbB-3), and HER4 (c-erbB-4) [13-15]. EGFR family members transmit the biologic effects of the EGF family of ligands, which includes EGF, transforming growth factor-alpha (TGF alpha), amphiregulin, heparin-binding (HB)-EGF, betacellulin, and epiregulin. Ligand binding induces the formation of homodimers or heterodimers between EGFR and other members of this family, autophosphorylation of tyrosine residues in its intracellular domain, and activation of downstream signaling pathways [13-15]. These phosphotyrosines, in turn, phosphorylate other intracellular proteins that contain src homologous domains (SH2 and SH3), such as ras-associated GTPase activating protein, phosphatidylinositol3-kinase, and phospholipase C gamma. The downstream signaling pathways activated by these intracellular proteins include the ras/raf MAPKinase, phosphatidylinositol-3-kinase, and protein kinase C pathways, which ultimately lead to increased nuclear transcription and subsequent cellular proliferation [15,16]. Overexpression of EGFR alone or accompanied by production of one or more of its ligands, such as TGF alpha, has been reported in a range of human malignancies and is often associated with poor prognosis [16,17]. Overexpression of EGFR in bladder cancer has been widely reported [1823]. The reports suggest the presence of erbB1 in 23% to 100% of TCC samples. Several studies have shown that EGFR is positively associated with advanced tumor stage, tumor progression, and poor clinical outcome [24]. Immunohistochemical analyses suggest that rather than actual overexpression of erbB1 in TCC is the actual change in the distribution of the molecule, from basal layer in normal urothelium to all layers in premalignant or malignant urotheliums [25,26]. Other studies have demonstrated that expression of erbB1 and of erbB2 is downregulated in TCC compared with the expression in normal urothelium [27]. Still other studies have demonstrated erbB3 in 20% to 56% and erbB4 in 11% to 30% of cases of TCC, but reduced expression of erbB3 and erbB4 in TCC compared with normal tissues [27]. Statistical analyses of erbB expression patterns and clinical parameters have resulted in varying conclusions about the prognostic significance of erbB expression in TCC [27-32]. However, in patients with muscle-invasive TCC of the bladder, a retrospective immunohistochemical study has shown erbB2 overexpression to be a independent predictor of reduced cancer-specific survival [33]. In contrast, another prospective study found that erbB2 overexpression in the context of paclitaxel-based chemotherapy significantly decreased the risk of death [34]. On the basis of discovery of variant isoforms of the erbB family members, a series of studies was initiated that focused on acquiring quantitative information about erbB status, which was considered critical for selecting patients for erbB inhibitor therapies, and for evaluating the potential use of erbBs as prognostic indicators for patients with cancer. A report by Juntilla et al [35] describing specific erbB4 cytoplasmic or juxtamembrane isoforms overexpressed in TCC compared with its expression in interstitial cystitis or normal bladder, is an example of such finding. Thus, preclinical evidence about the expression levels of specific erbBs in TCC tissues, although controversial at the moment, may be verified through a more refined investigation. Several erbB I variants, somatic mutations, deletions, or truncations have been described for erbB1 in epithelial cancers, including lung, colon, and breast cancers [36-39]. For example, the erbBvIII variant, which lacks the extracellular domain, has been shown to be specifically expressed in tumor tissues rather than in normal, adjacent tissues and to activate aberrant signaling pathways relevant for EGFR-targeted therapy [40,41]. However, there currently are no studies investigating this aspect in bladder cancer.