Highlights
- •Chemotherapeutic agents result in modest efficacy in advanced urothelial cancer.
- •Improved knowledge of molecular signaling pathways helps to identify new targets.
- •Innovative drugs are currently evaluated in clinical trials with promising results.
Abstract
Metastatic urothelial cancer (UC) is associated with poor prognosis. In the first-line
setting, platinum-based chemotherapy is the standard of care but resistance rapidly
occurs. With no validated treatment proven to increase survival after platinum failure,
there is an urgent unmet medical need to develop new and efficacious cytotoxic agents.
A better understanding of the molecular signaling pathways regulating UC has led to
the development of new and innovative therapeutic strategies. Despite this, many recent
drugs show only modest activity as single agents, and combining them with standard
chemotherapy does not seem to enhance efficacy. Ongoing research is producing, however,
a generation of new drugs that are showing promising results in clinical trials.
This paper aims to review the most important mechanisms in bladder cancer tumorigenesis
and describe the new therapeutic options currently undergoing evaluation in clinical
trials.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Cancer Treatment ReviewsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90
- Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1054 patients.J Clin Oncol. 2001; 19: 666-675
- A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.J Clin Oncol. 1992; 10: 1066-1073
- Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.J Clin Oncol. 2000; 18: 3068-3077
- Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.J Clin Oncol. 2005; 23: 4602-4608
- Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987.J Clin Oncol. 2012; 30: 1107-1113
- Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours.Eur J Cancer. 2006; 42: 50-54
- Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924.J Clin Oncol. 2001; 19: 2638-2646
- Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma.Invest New Drugs. 2007; 25: 265-270
- Second line chemotherapy with ifosfamide as outpatient treatment for advanced bladder cancer.Am J Clin Oncol. 1997; 20: 519-521
- Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium.J Clin Oncol. 2006; 24: 3451-3457
- Eastern cooperative oncology group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma.J Clin Oncol. 1997; 15: 589-593
- An eastern cooperative oncology group phase II trial of trimetrexate in the treatment of advanced urothelial carcinoma.Cancer. 1994; 73: 688-691
- Topotecan in previously treated advanced urothelial carcinoma: an ECOG phase II trial.Invest New Drugs. 1998; 16: 191-195
- Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract.J Clin Oncol. 2009; 27: 4454-4461
- Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors.Am J Pathol. 2001; 158: 1955-1959
- Chromosome instability and progression in urothelial cell carcinoma of the bladder.Acta Oncol. 2003; 42: 169-173
- FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis.Clin Cancer Res. 2005; 11: 5444-5450
- Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy.Expert Opin Ther Targets. 2012; 16: 103-119
- MTOR signaling in growth control and disease.Cell. 2012; 149: 274-293
- Comprehensive molecular characterization of urothelial bladder carcinoma.Nature. 2014; 507: 315-322
- Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas.J Clin Oncol. 2006; 24: 3664-3671
- FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy.PLoS ONE. 2010; 5: e13821
- Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer.Clin Cancer Res. 2009; 15: 6008-6017
- Oncogenic FGFR3 gene fusions in bladder cancer.Hum Mol Genet. 2013; 22: 795-803
- FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer.J Pathol. 2007; 213: 91-98
- Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer.Cancer Res. 2009; 69: 4613-4620
- Altered splicing of FGFR1 is associated with high tumor grade and stage and leads to increased sensitivity to FGF1 in bladder cancer.Am J Pathol. 2010; 177: 2379-2386
- Protein networking in bladder cancer: immunoreactivity for FGFR3, EGFR, ERBB2, KAI1, PTEN, and RAS in normal and malignant urothelium.Histol Histopathol. 2007; 22: 349-363
- Molecular pathways in invasive bladder cancer: new insights into mechanisms, progression, and target identification.J Clin Oncol. 2006; 24: 5552-5564
- EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype.Science Transl Med. 2014; 6 (244ra91)
- Mutations within the kinase domain and truncations of the epidermal growth factor receptor are rare events in bladder cancer: implications for therapy.Clin Cancer Res. 2006; 12: 4671-4677
- Expression of epidermal growth factor receptor in invasive transitional cell carcinoma of the urinary bladder. A multivariate survival analysis.Am J Clin Pathol. 1994; 101: 166-176
- Overexpression of c-erbB-2 oncoprotein in muscle-invasive bladder carcinoma: relationship with gene amplification, clinicopathological parameters and prognostic outcome.Int J Oncol. 2002; 21: 981-987
- HER2 overexpression and amplification in urothelial carcinoma of the bladder is associated with MYC coamplification in a subset of cases.Am J Clin Pathol. 2008; 130: 274-281
- Genetic alterations in bladder cancer.Lancet. 1993; 342: 1184
- Evaluation of epidermal growth factor receptor, transforming growth factor alpha, epidermal growth factor and c-erbB2 in the progression of invasive bladder cancer.Urol Res. 1997; 25: 9-17
- The role of p53, MDM2 and c-erb B-2 oncoproteins, epidermal growth factor receptor and proliferation markers in the prognosis of urinary bladder cancer.Pathol Res Pract. 1997; 193: 767-775
- HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic implications.Int J Cancer. 2002; 102: 514-518
- Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.Cancer Cell. 2003; 3: 347-361
- Overexpression of c-met as a prognostic indicator for transitional cell carcinoma of the urinary bladder: a comparison with p53 nuclear accumulation.J Clin Oncol. 2002; 20: 1544-1550
- Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder.Br J Cancer. 2005; 92: 1906-1914
- Profiling bladder cancer using targeted antibody arrays.Am J Pathol. 2006; 168: 93-103
- FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma.Oncogene. 2005; 24: 5218-5225
- PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors.Cancer Res. 2006; 66: 7401-7404
- Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder.Eur Urol. 2014;
- PTEN deletions are related to disease progression and unfavourable prognosis in early bladder cancer.Histopathology. 2013; 63: 670-677
- Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder.Histopathology. 2011; 58: 1054-1063
- Somatic mutation of PTEN in bladder carcinoma.Br J Cancer. 1999; 80: 904-908
- Inactivation of p53 and Pten promotes invasive bladder cancer.Genes Dev. 2009; 23: 675-680
- Human bladder tumors with 2-hit mutations of tumor suppressor gene TSC1 and decreased expression of p27.J Urol. 2003; 170: 601-604
- Mutation of the 9q34 gene TSC1 in sporadic bladder cancer.Oncogene. 1999; 18: 2657-2661
- Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder.Cancer Res. 2003; 63: 7652-7656
- Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer.Cancer Metastasis Rev. 2009; 28: 305-316
- AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K.Oncogene. 2010; 29: 150-155
- A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1.PLoS ONE. 2011; 6: e18583
- P53 expression in patients with advanced urothelial cancer of the urinary bladder.BJU Int. 2010; 105: 489-495
- Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder.Urology. 2003; 61: 1140-1145
- P53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer.J Clin Oncol. 2004; 22: 1014-1024
- The spectrum of TP53 mutations in bladder carcinoma.Genes Chromosom Cancer. 1994; 9: 108-118
- Predictive value of cell cycle markers p53, MDM2, p21, and Ki-67 in superficial bladder tumor recurrence.Clin Cancer Res. 1999; 5: 4079-4084
- Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma.J Clin Oncol. 2004; 22: 1007-1013
- P53 and retinoblastoma pathways in bladder cancer.World J Urol. 2007; 25: 563-571
- Molecular biology of bladder cancer: prognostic and clinical implications.Clin Genitourinary Cancer. 2006; 5: 67-77
- Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis.J Natl Cancer Inst. 1995; 87: 1603-1612
- Molecular mechanisms and clinical applications of angiogenesis.Nature. 2011; 473: 298-307
- Vascular endothelial growth factor: an important angiogenic mediator in bladder cancer.Eur Urol. 1999; 35: 2-8
- Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer.Cancer Res. 1997; 57: 5281-5285
- Overexpression of hypoxia-inducible factor-1alpha predicts an unfavorable outcome in urothelial carcinoma of the upper urinary tract.Int J Urol. 2008; 15: 200-205
- Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology.Proc Natl Acad Sci USA. 2014; 111: 3110-3115
- Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.Cancer Cell. 2014; 25: 152-165
- Final results of a multicenter, open-label phase II trial of dovitinib (TKI258) in patients with advanced urothelial carcinoma with either mutated or nonmutated FGFR3.J Clin Oncol. 2013; 31
Dienstmann R, Bahleda R, Adamo B, et al. First in human study of JNJ-42756493, a potent pan fibroblast growth factor receptor (FGFR) inhibitor in patients with advanced solid tumors. In: 2014 AACR Annual Meeting. Abstract CT325. Presented April 8, 2014.
Sequist LV, Cassier P, Varga A, et al. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. In: 2014 AACR Annual Meeting. Abstract CT326. Presented April 8, 2014.
- Results of the Southwest Oncology Group phase II evaluation (study S0031) of ZD1839 for advanced transitional cell carcinoma of the urothelium.BJU Int. 2010; 105: 317-321
- A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102.Ann Oncol. 2009; 20: 1074-1079
- Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma.J Clin Oncol. 2012; 30: 3545-3551
- A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.Cancer. 2014; 120: 2684-2693
- A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: clinical and pathological results.BJU Int. 2010; 106: 349-354
- Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial.J Clin Oncol. 2007; 25: 2218-2224
- A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma.Cancer. 2009; 115: 2881-2890
- Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.J Clin Oncol. 2002; 20: 719-726
- Phase I results from a study of lapatinib with gemcitabine and cisplatin (GC) in advanced/metastatic bladder cancer.J Clin Oncol. 2013; 31: 31
- Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers.Ann Oncol. 2012; 23: 2663-2670
- PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation.Br J Cancer. 2013; 109: 1586-1592
- Phase II study of everolimus in metastatic urothelial cancer.BJU Int. 2013; 112: 462-470
- Genome sequencing identifies a basis for everolimus sensitivity.Science. 2012; 338: 221
- Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.Cancer Discovery. 2014; 4: 546-553
- A phase II trial of temsirolimus in second-line metastatic urothelial cancer.Med Oncol. 2012; 29: 2870-2876
- Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04–75.J Clin Oncol. 2011; 29: 1525-1530
- Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer.J Clin Oncol. 2013; 31: 724-730
- Phase II study of Aflibercept (VEGF-Trap) in patients with recurrent or metastatic urothelial cancer, a California Cancer Consortium Trial.Urology. 2010; 76: 923-926
- Phase II study of sunitinib in patients with metastatic urothelial cancer.J Clin Oncol. 2010; 28: 1373-1379
- Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity.Ann Oncol. 2011; 22: 2646-2653
- Gemcitabine, cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer.Clin Genitourinary Cancer. 2013; 11: 175-181
- A phase II trial of sorafenib in first-line metastatic urothelial cancer: a study of the PMH phase II consortium.Invest New Drugs. 2011; 29: 1045-1049
- Phase 2 trial of sorafenib in patients with advanced urothelial cancer: a trial of the Eastern Cooperative Oncology Group.Cancer. 2009; 115: 4090-4095
- Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).BJU Int. 2014; 113: 429-436
- Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial.Lancet Oncol. 2012; 13: 810-816
- Combined treatment with pazopanib and vinflunine in patients with advanced urothelial carcinoma refractory after first-line therapy.Anticancer Drugs. 2013; 24: 422-425
- A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC).J Clin Oncol. 2014; 32
- A phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with advanced urothelial tract transitional cell carcinoma.Cancer. 2005; 103: 2035-2041
- MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.Nature. 2014; 515: 558-562
- A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (Pts) with advanced urothelial tract cancer.Annals of Oncology. 2014; 25: 25
- An open-label, single-arm, phase 2 trial of the Polo-like kinase inhibitor volasertib (BI 6727) in patients with locally advanced or metastatic urothelial cancer.Cancer. 2014; 120: 976-982
- Insulin-like growth factor-1 receptor overexpression is associated with outcome in invasive urothelial carcinoma of urinary bladder: a retrospective study of patients treated using radical cystectomy.Urology. 2014; 83: e1-e6
- Immunostimulatory monoclonal antibodies for cancer therapy.Nat Rev Cancer. 2007; 7: 95-106
- Targeting activity of a TCR/IL-2 fusion protein against established tumors.Cancer Immunol Immunother. 2008; 57: 1781-1794
- Phase I/II clinical trial of ALT-801, a T-cell receptor/IL-2 fusion protein, plus gemcitabine and cisplatin in urothelial cancer.J Clin Oncol. 2013; 31 (suppl 6; abstr 271)
- Raf1, Aurora-A/STK15 and E-cadherin biomarkers expression in patients with pTa/pT1 urothelial bladder carcinoma; a retrospective TMA study of 246 patients with long-term follow-up.Eur J Surg Oncol. 2006; 32: 439-444
- Gene expression study of Aurora-A reveals implication during bladder carcinogenesis and increasing values in invasive urothelial cancer.Urology. 2008; 72: 873-877
- The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell-cycle progression in malignant bladder cancer cells in vitro and in vivo.Clin Cancer Res. 2013; 19: 1717-1728
- The HSP90 inhibitor ganetespib has chemosensitizer and radiosensitizer activity in colorectal cancer.Invest New Drugs. 2014; 32: 577-586
- Targeted inhibition of Hsp90 by ganetespib is effective across a broad spectrum of breast cancer subtypes.Invest New Drugs. 2014; 321: 14-24
- Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has potent antitumor activity in in vitro and in vivo models of non-small cell lung cancer.Clin Cancer Res. 2012; 18: 4973-4985
- Discovery and molecular characterization of AGS-15/SLITRK6 as a novel target for antibody-mediated therapeutic development in bladder cancer.Cancer Res. 2013; 73 (abstract 2047)
- Normal stem cells and cancer stem cells: the niche matters.Cancer Res. 2006; 66: 4553-4557
- Chromatin targeting drugs in cancer and immunity.Genes Dev. 2013; 27: 1731-1738
- Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.Proc Natl Acad Sci USA. 2001; 98: 10869-10874
Article Info
Publication History
Published online: March 25, 2015
Accepted:
March 12,
2015
Received in revised form:
March 8,
2015
Received:
December 24,
2014
Identification
Copyright
© 2015 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
