Novel therapeutics in the treatment of bladder cancer.
ABSTRACT The successful treatment of bladder cancer remains a challenge for urologists and oncologists. There have been substantial changes in the therapeutic options for the management of both superficial and muscle-invasive bladder cancer in the last 5 years. Here we review the preclinical and clinical developments over the last year in bladder cancer therapeutics.
There is a growing trend toward the use of multimodal treatments for all bladder cancers. For superficial disease, intravesical instillation of chemotherapeutic agents after transurethral resection is quickly becoming the standard of care. Novel therapeutic modalities under investigation include DNA vaccines, magnetically targeted carriers, bio-adhesive microspheres and antisense oligodeoxynucleotides. For muscle-invasive bladder cancer, systemic perioperative chemotherapy is being used with increasing frequency and the latest preclinical research efforts are focused on the inhibition of angiogenesis and other processes predisposing to metastatic disease.
Treatment goals for bladder cancer of any stage are complete removal of the initial tumor, prevention of disease recurrence and effective inhibition of progression to advanced disease with the ultimate aim of reducing mortality. The myriad novel therapeutic modalities currently being explored suggest that these goals may perhaps be achievable within our lifetime.
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ABSTRACT: Early-stage bladder cancer occurs as two distinct forms: namely, low-grade superficial disease and high-grade carcinoma in situ (CIS), which is the major precursor of muscle-invasive bladder cancer. Although the low-grade form is readily treatable, few, if any, effective treatments are currently available for preventing progression of nonmuscle-invasive CIS to invasive bladder cancer. Based on our previous findings that the mammalian target of Rapamycin (mTOR) signaling pathway is activated in muscle-invasive bladder cancer, but not superficial disease, we reasoned that suppression of this pathway might block cancer progression. To test this idea, we performed in vivo preclinical studies using a genetically engineered mouse model that we now show recapitulates progression from nonmuscle-invasive CIS to muscle-invasive bladder tumors. We find that delivery of Rapamycin, an mTOR inhibitor, subsequent to the occurrence of CIS effectively prevents progression to invasive bladder cancer. Furthermore, we show that intravesical delivery of Rapamycin directly into the bladder lumen is highly effective for suppressing bladder tumorigenesis. Thus, our findings show the potential therapeutic benefit of inhibiting mTOR signaling for treatment of patients at high risk of developing invasive bladder cancer. More broadly, our findings support a more widespread use of intravesical delivery of therapeutic agents for treatment of high-risk bladder cancer patients, and provide a mouse model for effective preclinical testing of potential novel agents.Cancer Prevention Research 12/2009; 2(12):1008-14. · 4.89 Impact Factor
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ABSTRACT: Bladder cancer is the ninth most common malignancy in the world featuring very high gender variability in occurrence. Current options for bladder cancer therapy include surgery, immunotherapy, chemotherapy and radiotherapy with a trend towards multimodal treatments. However, successful management remains a challenge for urologists and oncologists because of the high risk for recurrence and progression. Particularly in the field of bladder cancer chemotherapy, efficacy of treatment might be improved by advanced drug delivery strategies aimed at prolonged residence time within the bladder cavity and increased permeability of the bladder wall during intravesical instillation. Moreover, a deeper understanding of the biology of bladder carcinogenesis and malignant progression stimulated the development of a new generation of anticancer drugs for targeted therapies that might result in increased treatment specificity together with lower toxic potential and higher therapeutic indices. This review discusses the available strategies for 'targeted therapy', focusing on molecular targets, and for 'controlled delivery', comprising all other approaches towards improved drug delivery.Expert Opinion on Drug Delivery 08/2009; 6(7):727-44. · 4.87 Impact Factor
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ABSTRACT: There is little information on pulmonary metastasectomy of urinary tract transitional cell carcinoma (TCC). In this study, we examined the long-term outcome and the factors associated with long-term survival after pulmonary metastasectomy of urinary tract TCC based on a 20-year single center experience. Between 1984 and 2005, 18 patients (12 men, six women) underwent pulmonary metastasectomy of the urinary tract TCC in our hospital. The clinicopathological and surgical data of these patients obtained from the medical records were analyzed in this retrospective study. The time interval between lung resection and death, or latest follow-up ranged from two to 200 months (median 52). Survival analysis was conducted by the Kaplan-Meier method and log-rank test. The cumulative three- and five-year survival rates were 59.8% and 46.5%, respectively. The number of resected metastatic tumors (solitary vs. multiple) was associated with long-term survival (P<0.05). The five-year survival rate of patients with solitary metastasis was 85.7% while that of patients with multiple metastases was 20.0%. Pulmonary metastasectomy of urinary tract TCC is associated with a favorable outcome, and solitary metastasis is associated with long-term survival. Aggressive management of solitary pulmonary metastasis from a urinary tract TCC is feasible in selected patients.Interactive Cardiovascular and Thoracic Surgery 07/2010; 11(1):60-4. · 1.11 Impact Factor