Emerging therapeutic targets in bladder cancer

Cancer Treat Rev. 2015 Feb;41(2):170-8. doi: 10.1016/j.ctrv.2014.11.003. Epub 2014 Nov 24.

Abstract

Treatment of muscle invasive urothelial bladder carcinoma (BCa) remains a major challenge. Comprehensive genomic profiling of tumors and identification of driver mutations may reveal new therapeutic targets. This manuscript discusses relevant molecular drivers of the malignant phenotype and agents with therapeutic potential in BCa. Small molecule pan-FGFR inhibitors have shown encouraging efficacy and safety results especially among patients with activating FGFR mutations or translocations. mTOR inhibitors for patients with TSC1 mutations and concomitant targeting of PI3K and MEK represent strategies to block PI3K/AKT/mTOR pathway. Encouraging preclinical results with ado-trastuzumab emtansine (T-DM1) exemplifies a new potential treatment for HER2-positive BCa along with innovative bispecific antibodies. Inhibitors of cell cycle regulators (aurora kinase, polo-like kinase 1, and cyclin-dependent kinase 4) are being investigated in combination with chemotherapy. Early results of clinical studies with anti-CTLA4 and anti-PDL1 are propelling immune modulating drugs to the forefront of emerging treatments for BCa. Collectively, these novel therapeutic targets and treatment strategies hold promise to improve the outcome of patients afflicted with this malignancy.

Keywords: Bladder cancer; Immunotherapy; Targeted therapy; Treatment; Urothelial bladder carcinoma.

Publication types

  • Review

MeSH terms

  • Ado-Trastuzumab Emtansine
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Aurora Kinases / metabolism
  • B7-H1 Antigen / antagonists & inhibitors
  • Biomarkers, Tumor / metabolism
  • CTLA-4 Antigen / antagonists & inhibitors
  • Carcinoma, Transitional Cell / drug therapy*
  • Carcinoma, Transitional Cell / metabolism
  • Carcinoma, Transitional Cell / pathology
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Clinical Trials as Topic
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase 4 / metabolism
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunotherapy / methods*
  • Maytansine / analogs & derivatives
  • Maytansine / pharmacology
  • Molecular Targeted Therapy / methods*
  • Mutation
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-2 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism
  • Translocation, Genetic
  • Trastuzumab
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / genetics
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • CTLA-4 Antigen
  • Cell Cycle Proteins
  • Heat-Shock Proteins
  • Proto-Oncogene Proteins
  • TSC1 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • Cyclin D1
  • Maytansine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • ERBB2 protein, human
  • FGFR1 protein, human
  • Receptor, ErbB-2
  • Receptor, Fibroblast Growth Factor, Type 1
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • polo-like kinase 1
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • Trastuzumab
  • Ado-Trastuzumab Emtansine