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- Randomized study of the Studer vs. T-pouch urinary diversion
- Lymph node mapping studies
- Use of MRI to pre-operative stage muscle-invasive bladder cancer
- Subsequent survival in patients with recurrence following radical cystectomy and extended pelvic lymph node dissection
- Effect of urinary diversion on renal function
- Factors affecting choice of urinary diversion in patients undergoing radical cystectomy
- Continence as a function of age in orthotopic ileal neobladder
- Continence in obese patients following radical cystectomy and orthotopic ileal neobladder
- Outcomes of cystectomy in patients who have undergone prior radiation therapy.
Basic Science Projects
Cancer Epigenetics and Epigenetic Therapy
It is becoming increasingly clear that epigenetic changes cooperate with genetic changes to drive the formation of human tumors. Our laboratory focuses on determining why epigenetic changes occur in urological tumors, particularly bladder cancer, and in the development of drugs which can target these changes. We hope to develop new therapeutic options for the management of urological diseases. Recently we have used high-throughput scans to determine the extent of DNA hypermethylation and hypomethylation events in cancer of the bladder. We are developing new strategies to develop epigenetic therapies for the treatment of hematological and solid tumors using hypomethylating drugs such as 5-azacytidine.
Epigenetic Field Defect and Bladder Cancer:
This is an NIH funded project, which focuses on epigenetic changes in malignant and pre-malignant bladders. Especially we have revealed that hypomethylation of specific LINE-1 promoters can alter the transcriptome, including activating an alternate transcript of the MET oncogene, not only in primary bladder tumors but also in the premalignant urothelium across entire bladders with tumors. Our study has important implications for tumor biology, cancer detection, and treatment. It also answers the long-standing question of whether hypomethylation of retrotransposons induces ectopic gene expression and influences bladder cancer susceptibility, particularly in the recurrence of bladder cancer.
Determining the Mechanistic and Theraputic Roles of MicroRNAs in Bladder Cancer:
Our results indicate that miRNA misexpression has major impact on TCC tumorigenesis because some miRNAs may be tumor suppressors or oncogenes. Our study also shows that some silenced tumor suppressor miRNAs can be reactivated by epigenetic treatments. Furthermore, we have developed a flexible platform using the CMV promoter to restore expression of multiple tumor suppressor miRNAs from a single engineered transcript. This novel expression vector can inhibit tumor cell growth by targeting multiple oncogenes or oncogenic pathways. Completion of these projects will provide a foundation for the clinical application of using miRNAs as diagnostic and/or prognostic markers and as therapeutic targets in bladder cancer patients.
Bladder Cancer Molecular Pathology
The overarching goal of the following projects is to better define the molecular biology of bladder cancer in an effort to individualize patient management.
Molecular Pathogenesis: Projects under this realm aim to determine molecular abnormalities associated with bladder cancer development. These studies are examining molecular changes in the bladder associated with smoking (the most common risk factor of bladder cancer in the western world) and bladder fluke infection (a common risk factor for bladder cancer in the Middle East), and the course of these diseases.
Prognosis: Bladder cancer is a disease of molecular heterogeneity, and such alterations are responsible for differences in patient outcome. Current clinical and histopathologic metrics are limited in their ability to predict the outcome of an individual patient. Our gene- and protein-level investigations are utilizing molecular profiling strategies to identify determinants that can better predict patient prognosis.
Response to Therapy: We are employing molecular strategies to define marker panels that can potentially predict the ability and degree of a patient to respond to current chemotherapeutic regimens. A major arena of investigation in this regard is the molecular profiling of patients from the international multi-center p53 targeted-therapy trial. This prospective, randomized therapy trial was recently closed for accrual, and current analyses are focused on the molecular determinants of response to MVAC chemotherapy.
Systems Biology and Therapeutic Target Discovery: A pathway-driven approach is being adopted to understand biologic interactions at the molecular level that contribute to bladder cancer progression. Using combinatorial approaches that include molecular pathology, molecular epidemiology, biostatistics bioinformatics, and computational biology, we are trying to identify molecular subclasses of the disease that may be amenable to treatment with novel targeted therapeutics.
