The Urology Research Laboratory is a subdivision of the Department of Urology at KU Medical center. We are conducting basic and translational research related to Urological diseases, mainly focusing on human prostate cancers.
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer related deaths among American men. If treated during the time it is confined to the prostate, it is curable with definitive therapy. Currently, around fifty percent of men fail local therapy and develop metastatic cancer. There is no known cure for metastatic prostate cancer. Progression can be delayed but not halted or reversed. Presently, metastatic cancer can be treated by androgen suppression. Androgen suppression delays the time to progression, but eventually the cancer will become resistant and no longer respond to hormone treatment (so called hormone-refractory progression). Little is known about the biology at the molecular level for hormone-refractory progression. In particular, the event that triggers the change to the hormone-refractory stage is unknown.
The etiology of prostate tumorigenesis and hormone-refractory relapse may have various molecular causes, but in each scenario, the androgen receptor (AR) expression is maintained. Recent studies from our group and others demonstrated that AR-dependent signaling is required for prostate cancer development in early stage and androgen-independent progression in late stage. We also found that knocking down AR expression by small interference RNA (siRNA) technique caused a profound apoptotic cell death in AR-native prostate cancer cells regardless of their androgen dependency, demonstrating the essential role of the AR in cellular survival of prostate cancers. Recently we demonstrated that AR shRNA constructs systemically delivered by prostate cancer cell-specific-targeting nanoparticles eradicate prostate cancer xenografts in nude mice. Our study provided a new hope for advanced prostate cancer patients although further clinical testing is needed.
The ultimate goal of the laboratory is to uncover the mechanisms responsible for cancer development and progression at a molecular level, and subsequently to develop novel therapeutic approaches for treatment. In the past several years we have identified the PI3K/p110beta and its downstream targets AKT and SGK1 are involved in AR transactivation and prostate cancer progression. We are now developing a novel approach using nanocarriers to systemically deliver p110beta specific inhibitor TGX221 to prostate cancers. Currently the project is ongoing at the preclinical stage.
Epigenetic modifications of genomic DNA and histone proteins are major event in terms of gene expression. It has been shown that signal pathways like Her2 signaling and PI3K/p110beta are also critical for AR-mediated gene expression. We are currently working on the histone modifiers that are downstream of PI3K/p110beta in regulating AR transactivation.
Our research directions are