Περίληψη:
Bladder cancer is a major cause of morbidity, mortality and health-related costs. Urothelial carcinoma is by far the most common histologic type of bladder cancer and may also arise from the upper urinary tract, e.g. renal pelvis and ureter, as well as from the proximal urethra. There have been no major advances in the development of new systemic therapies for urothelial carcinoma for over two decades, which may be related to prior lack of profound comprehension of biological pathogenetic mechanisms. However, in the last few years there has been a major shift in the development of new promising therapies that stem from improved molecular profiling of this malignancy. Developments in molecular biology, genomics, bioinformatics and immunology provide a solid foundation for therapeutic advances. A plethora of novel treatment targets and biomarkers are being evaluated, but there has been no molecular biomarker with established clinical utility so far. Genomic characterization of each patient's tumor has not been implemented due to the high cost, lack of validated standardized techniques that could be available in different laboratories, as well as absence of validated biomarkers and available therapeutic agents with clinically proven benefit. However, genomic characterization before treatment has now started to be implemented in novel clinical trial designs in order to contribute to proper patient selection based on biomarker-based enrichment strategies. Several "umbrella" or "basket" type, molecular biomarkers-based trials, in which patient eligibility and/or stratification is based on the presence of specific genetic alterations regardless of tissue of origin and/or histology, are being launched. Mathematical models and bioinformatics platforms that perform high level computational integrated pathway analysis may reveal clinical relevant signaling pathways amenable for targeting in individual patient tumors. Moreover, the high mutational burden of urothelial carcinoma may create numerous neo-antigens that may explain the very promising results with immune checkpoint inhibitors in early phase clinical trials. A combination of several, e.g. DNA, mRNA, miRNA, protein, and other molecular biomarkers merit further investigation, but this process has to be based on stringent criteria that test and prove clinical utility. © 2015 Elsevier Ltd.
Συγγραφείς:
Grivas, P.D.
Melas, M.
Papavassiliou, A.G.
Λέξεις-κλειδιά:
biological marker; cytokeratin 19 fragment; fibroblast growth factor receptor 3; K ras protein; mammalian target of rapamycin; messenger RNA; nuclear matrix protein 22; phosphatidylinositol 4,5 bisphosphate 3 kinase; protein inhibitor; protein kinase B; protein p53; survivin; biological marker; transcriptome, Akt gene; bioinformatics; bladder cancer; cancer growth; cancer prognosis; carcinogenesis; CTNNB1 gene; CYFRA 21 1 gene; DD23 gene; disease association; drug efficacy; exome; FGFR3 gene; gene expression profiling; gene mapping; gene mutation; gene sequence; high risk patient; human; marker gene; mTOR gene; oncogene K ras; PIK3CA gene; Review; signal transduction; survivin gene; transitional cell carcinoma; treatment planning; animal; carcinoma; cell transformation; disease course; gene expression regulation; metabolism; multimodality cancer therapy; prognosis; risk factor; treatment outcome; Urologic Neoplasms, Animals; Biomarkers; Carcinoma; Cell Transformation, Neoplastic; Combined Modality Therapy; Disease Progression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Prognosis; Risk Factors; Signal Transduction; Transcriptome; Treatment Outcome; Urologic Neoplasms
