Molecular therapeutic targets for bladder cancer

There is often a considerable lapse in time between the definition of what causes a disease and the development of a successful therapy. Evidence-based medicine teaches us that scientific knowledge of a disease is essential prior to the performance of any kind of treatment.

The successful treatment of bladder cancer remains a challenge for urologists, as it is the second most common urologic malignancy in the Western world [101]. The current treatment options for bladder cancer include surgery, immunotherapy, chemotherapy and radiotherapy. Superficial tumors and carcinoma in situ are treated by transurethral resection, adjuvant intravesical instillations of chemotherapeutic or immunotherapeutic agents and surveillance. Various chemotherapeutic agents, such as mitomycin C, doxorubicin and valrubicin, which have been used intravesically for superficial bladder cancer, have limited efficacy [1]. New chemotherapeutic drugs, including gemcitabine, paclitaxel, docetaxel and ifosfamide, with single-agent activity, have been tested in clinical trials with some improved outcomes compared with the previous agents [1]. The difficulty with intravesically instillated chemotherapy is either minimal efficacy of the agent against bladder cancer cells or limited exposure of the agent to the bladder mucosa.

Immunotherapeutic strategies attempt to produce anticancer effects via either passive or active immunity. Immunotherapeutic agents, such as Bacillus Calmette–Guérin (BCG), IFN-α and bropirimine, have been instillated intravesically to enhance the host immune function against tumor cells [2]. Among these agents, BCG remains the most effective agent against superficial bladder cancer. However, the response is limited and a significant proportion of patients will have cancer progression.

Muscle-invasive bladder cancer is treated by radical treatment strategies, such as radical surgery (cystectomy), and less commonly radical radiotherapy. Neoadjuvant or adjuvant systemic chemotherapy have limited efficacy in this disease, although some promising work suggests a benefit [3]. The four-drug methotrexate, vinblastine, adriamycin and cisplatin regimen has been most widely used in locally invasive and metastatic disease; however, the gemcitabine regimen has shown promise [4].

Recently, there have been substantial changes in the therapeutic options for the management of both superficial and muscle-invasive bladder cancer. The exponential growth of information regarding the biology of bladder carcinogenesis, tumor progression and response at a molecular level has led to the development of potential therapeutic targets. Any of the features/pathways listed can be molecular targets (cancer cell self-sufficiency in growth, insensitivity to inhibition of growth, evasion of apoptosis, unlimited ability to replicate, as well as the ability for angiogenesis, tissue invasion and metastasis) [5].

The cascade of multiple genetic events gives rise to a tumor phenotype and clinical outcome for the patient. A major part of this relates to the balance between proto-oncogenes and tumor-suppressor genes. Mutation of a normal cellular gene can result in overexpression of the gene product or expression of an altered protein with transformed function. Tyrosine-specific protein kinases are products of the oncogenes C-erb B-1 and C-erb B-2, which encode the EGF receptor (EGFR) and human EGFR (HER)/neu, respectively. The degree of expression of these growth factor receptors has been associated with the progression of bladder cancer and a poor prognosis. An early Phase II trial has examined the response to the anti-HER-2/neu therapy monoclonal antibody, trastuzumab [6]. Promising results have also been obtained in preclinical models using EGFR-targeted agents (e.g., cetuximab, gefitinib, lapatinib and GW 572016) [7]. Other ongoing trials are examining gefitinib, an EGFR inhibitor, in combination with other chemotherapeutic agents, such as gemcitabine and cisplatin [8]. Furthermore, early studies focused on human cancer cell lines using bcl-2 antisense oligonucleitide gene therapy (e.g., oblimersen sodium) show promise, as this may augment the effects of radiotherapy and chemotherapy in patients with bladder cancer [9].

Preliminary results from studies focused on tumor-suppressor gene pathways are promising. Preclinical work on the use of adenoviral vectors as gene therapy has produced exciting results when investigating transduction of bladder cancer cell lines with the tumor-suppressor Rb gene and p53 gene [10].

It is very well known that the development of a proliferative tumor depends heavily upon revascularization promoted by growth factors. Consequently, current trials are focused on inhibition of these factors, developing either monoclonal antibodies (e.g., bevacizumab) against VEGF [11], antisense gene therapy for the inhibition of basic fibroblast growth factor [12] or inhibitors (e.g., piroxicam) against COX-2 [13]. Within the tumor, the balance between angiogenic stimulation and antiangiogenic inhibition on endothelium is firmly inclined towards the former and, therefore, promoting antiangiogenic factors provides a promising potential for future therapeutic mechanisms, as has been seen with the recent clinical use of tyrosine kinase inhibitors for renal cancers [14]. Many factors fall into this category, including angiostatin, endostatin, as well as collagen, laminin, fibronectin, tenascin and osteonectin [15]. In particular, Phase II trials have shown that trompospondin-1 reduces microvessel density and increases apoptosis in primary human bladder tumors in an orthotopic model in immune-deficient mice [16].

As evidence emerges that the mediators of cell adhesion, and proteases, which degrade extracellular matrix, are essential for the invasive and metastatic potential of cancer, novel agents may develop in this field. Recent studies have examined the effect of IFN-α by restoring the normal balance between matrix metalloproteinase (MMP) and E-cadherin, thus causing inhibition of tumor growth and metastasis [17]. Furthermore, de novo tumor models have shown that the tumor burden is reduced when MMP inhibitors (e.g., batimastat) are administered before the carcinoma becomes invasive [18].

It is expected that such molecularly targeted therapies will result in greater specificity, less toxicity and higher therapeutic indices. The ultimate goal of defining the molecular basis for bladder cancer progression is to refine individuals risk and response to new therapeutic strategies aimed at the specific defects that characterize bladder cancer. In particular, we should focus on genetic change and corresponding changes in translated proteins. Molecular therapeutic agents, such as trastuzumab, bevacizumab, cetuximab and other antiangiogenic agents, will improve survival rates for bladder cancer patients. However, larger randomized controlled trials are required to follow-up initial promising results from Phase II trials on these novel agents. COX-2 inhibitors may be important in the prevention of bladder cancer, although there is currently no direct evidence from long-term follow-up studies to demonstrate this. Furthermore, as gene therapy is developed, antisense oligonucleotide therapy directed against specific proto-oncogenes may offer novel methods of targeting bladder cancer cells. Interestingly, 3D molecular studies would be useful to understand the adhesion genes and molecules, with respect to spatial and temporal interaction in the progression of bladder cancer. Once this is established, agents directed against them can be evaluated in this ex vivo environment [15].

It is obvious that the successful development and optimal therapeutic use of molecularly targeted anticancer drugs will take a large effort. A side effect may be that these treatments cause treatment-resistant subclones [19], thus changing the outcome of a cancer into either cure or a more chronic condition, promoting salvage treatment. The latter may be less morbid to the patient, particularly with standardized laparoscopic salvage surgery. Synergism among agents targeting various pathways could be beneficial as a more aggressive management strategy for bladder cancer. This aim remains achievable as bladder cancer represents a unique model for implementation of multiple molecular therapies owing to the varied drug delivery options (intravesical, systemic and continuous administrator).

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.