Urologic Oncology: Seminars and Original Investigations
Review articleTargeted therapies in non-muscle-invasive bladder cancer according to the signaling pathways
Introduction
Each year, more than 300,000 new cases of urothelial-cell carcinoma of the bladder (UCCB) occur worldwide, indicating a critical international public health problem [1]. Approximately 70% to 80% of UCCB are non-muscle-invasive bladder cancers (NMIBCs), including 70% pTa, 20% pT1, and 10% carcinoma in situ (Cis), all of which do not invade the basement membrane [2]. The remaining 20% to 30% of UCCBs are muscle invasive (MIBC) from the outset, with a poor clinical outcome of less than 50% survival at 5 years [3], [4]. Almost 70% of NMIBCs recur even after optimal therapy (transurethral resection with intravesical chemotherapy [mitomycin] or immunotherapy [BCG]), and 10% to 20% will progress to a higher stage and/or grade, especially the high-risk pT1 high grade UCCB group [1], [5]. Despite significant improvements, NMIBC treatment remains disappointing in terms of oncologic results and morbidity. Indeed, NMIBC is characterized by economic impact (high rate of recurrence) and not by mortality, contrary to MIBC [6]. The most striking feature is that similar histopathologic UCCB may have a different clinical outcome, which probably reflects the diversity of molecular pathway alterations involved in bladder tumorigenesis and progression, and justifies the rationale for developing targeted therapy. The use of targeted treatment has the advantage of improving tolerance and also efficacy by attacking the cancer cells only. It may provide, in the near future, an additional efficient therapy.
Section snippets
Molecular characteristics of NMIBC tumorigenesis (Fig. 1)
Multiple altered molecular pathways are specifically involved in the development of NMIBC, suggesting a multiplicity of potential targets for the development of new therapeutic strategies. Cancer research has shown that NMIBC results from genetic and epigenetic abnormalities, which deregulate critical molecular pathways involved in cellular homeostasis. Some of the alterations take place very early in tumorigenesis, such as DNA repair mechanisms, reflecting the “addiction of tumors to certain
General molecular features
The tyrosine kinase receptor (RTK) family includes epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), which play a critical role in cellular growth, differentiation, adhesion, mobility, and apoptosis [8]. Activation of these RTKs by mutation or gene over-expression may lead to tumorigenesis.
Targeted therapy in NMIBC
Because the limits of current therapy in NMIBC (transurethral bladder tumor resection with chemo- or immunotherapy) have been reached, new approaches are urgently needed. The major issue in NMIBC is prediction of recurrence and progression by using biomarkers that could be potentially targeted in emerging therapies. Despite scientific advances, the potential application of targeted treatment is only just beginning in a few clinical trials and, unfortunately, is not yet ready for common clinical
Conclusion
The natural history of NMIBC is difficult to predict because of tumor heterogeneity. Although molecular markers do not have significant clinical application in treating UCCB at present, their use for predicting more aggressive tumors and influencing therapeutic decision is likely to be seen in the near future. A combination of various markers rather than a single agent will be more efficient in cancer diagnosis and prognosis. The new approaches using DNA micro-array or proteomic techniques,
References (71)
- et al.
Superficial bladder cancer: Progression and recurrence
J Urol
(1983) - et al.
Cytologic and histologic features of superficial bladder cancer
Urol Clin North Am
(1992) - et al.
Primary superficial bladder cancer risk groups according to progression, mortality, and recurrence
J Urol
(2000) - et al.
Cellular signaling by fibroblast growth factor receptors
Cytokine Growth Factor Rev
(2005) - et al.
Cell responses to FGFR3 signaling: Growth, differentiation, and apoptosis
Exp Cell Res
(2005) - et al.
Molecular profiling of bladder tumors based on the detection of FGFR3 and TP53 mutations
J Urol
(2006) - et al.
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomized, placebo-controlled, multicenter study (Iressa survival evaluation in lung cancer)
Lancet
(2005) - et al.
Neovascularization is a prognostic factor of early recurrence in T1/G2 urothelial bladder tumours
Ann Oncol
(2003) - et al.
Cellular ras activity and tumor cell proliferation
Exp Cell Res
(1987) - et al.
Use of an anti-ras ribozyme to alter the malignant phenotype of a human bladder cancer cell line
J Urol
(1996)
Farnesyltransferase inhibitors
Semin Oncol
Inhibition of SDC25 C-domain-induced guanine-nucleotide exchange by guanine ring binding domain mutants of v-H-ras
J Biol Chem
Activation of MAP kinase-kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells
Cell
Screening for bladder cancer: A perspective
World J Urol
Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese?
Carcinogenesis
Declining mortality from bladder cancer in Europe
BJU Int
Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction?
Nat Rev Cancer
Urothelial tumorigenesis: A tale of divergent pathways
Nat Rev Cancer
Chromosome 9 deletions are more frequent than FGFR3 mutations in flat urothelial hyperplasias of the bladder
Int J Cancer
Identification of fibroblast growth factor receptor 3 mutations in urine sediment DNA samples complements cytology in bladder tumor detection
Cancer
FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma
Cancer Res
FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder
Cancer Res
Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas
Nat Genet
The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3
Oncogene
Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4
Oncogene
Prospective study of FGFR3 mutations as a prognostic factor in non-muscle-invasive urothelial bladder carcinomas
J Clin Oncol
Accumulation of nuclear p53 and tumor progression in bladder cancer
N Engl J Med
Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer
Cancer Res
Ras genes
Annu Rev Biochem
Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation
Oncogene
Focus on bladder cancer
Cancer Cell
Molecular pathways in invasive bladder cancer: New insights into mechanisms, progression, and target identification
J Clin Oncol
FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma
Oncogene
The phosphatidylinositol-3 kinase pathway regulates bladder cancer cell invasion
BJU Int
Epidermal growth factor receptor-regulated human bladder cancer motility is in part a phosphatidylinositol 3-kinase-mediated process
Cell Growth Differ
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