title: Emerging therapeutic targets in bladder cancer.
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.
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, United States; Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States. Electronic address: benedito.carneiro@northwestern.edu.
authors.forename: Benedito A
authors.initials: BA
authors.lastname: Carneiro
authors.affiliation: Department of Urology, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Meeks
authors.affiliation: Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Kuzel
authors.affiliation: Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Scaranti
authors.affiliation: Department of Urology, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States.
authors.forename: Sarki A
authors.initials: SA
authors.lastname: Abdulkadir
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, United States; Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D064127:Aurora Kinases / Q000378:metabolism; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D014408:Biomarkers, Tumor / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002986:Clinical Trials as Topic; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008453:Maytansine / Q000031:analogs & derivatives / Q000494:pharmacology; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014178:Translocation, Genetic; D000068878:Trastuzumab; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000097869:Polo-Like Kinase 1
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D064127:Aurora Kinases; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D006360:Heat-Shock Proteins; D008453:Maytansine; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; C423236:CD274 protein, human; C000624650:TSC1 protein, human; C546842:MTOR protein, human; C508053:ERBB2 protein, human; C496348:FGFR1 protein, human; C495900:CDK4 protein, human
keywords: Bladder cancer; Immunotherapy; Targeted therapy; Treatment; Urothelial bladder carcinoma