USC Urology

In addition to the already published research projects, our team continues to move the field forward. We are currently at the fore-front of developing novel, cutting-edge robotic and image-guided prostate biopsy and focal therapy treatments. Also we are helping develop a new treatment concept for prostate cancer: “male lumpectomy”. These newer treatments will allow us to provide cancer control, without any compromise of erections or urinary continence. Our near-term goal: advance prostate cancer surgery to a new level, wherein excellent cancer outcomes are provided while maintaining quality of life in terms of erections, and continence.

Basic Science Projects:
•    How Genetic Predisposition affects Prostate Cancer Risk:
This project seeks to unravel fundamental mechanisms of prostate cancer risk, one of the most wide spread cancers in the U.S and the world. Additionally, men from African ancestry have nearly twice the risk for prostate cancer development than men from other racial-ethnic groups and genetic factors probably significantly contribute to this increase. Recently, genetic variation in protein non-coding regions associated with prostate cancers has been shown by us to be involved in the regulation of other distant genes. In this project we will expose exactly how (mechanism) this is brought about, to reveal molecular targets for prophylactic measures in men at high risk.

•    Androgen Receptor and Advanced Prostate Cancer:
Too many prostate-cancer treatments, especially those relying on the suppression of the male sex hormone androgen, eventually fail to slow the advance of the disease. One explanation for this is the absence of any systematic knowledge on the role and function of the androgen receptor in the course of prostate cancer development. Recent findings from us and others indicate that the androgen receptor is the key master regulator that determines disease progression to androgen independence and ultimately contributes to death from prostate cancer.

•    A novel transcription factor, Runx2 and Prostate Cancer Progression:
Building on our recent findings of strong physical and functional interactions between the androgen receptor and Runx2, two transcription factors with pivotal roles in prostate cancer, we are now investigating how this interaction affects expression of genes that may drive advanced disease and why the outcome of the interaction varies between different genes. This will provide novel insight into molecular mechanisms of prostate cancer progression, opening new research avenues towards improved prognosis, prevention and therapeutic approaches to metastatic disease.

•    The search of familial prostate cancer causing genes.
Prostate cancer is known to cluster in families. Several lines of evidence suggest that much of this clustering is due to inherited susceptibility. My laboratory has focused on finding the genes that predispose these families to a high incidence of prostate cancer. The National Institutes of Health has supported our laboratory for 16 years of this research. We are also one of the founding members of an international collaborative network with other prostate cancer research scientists from around the world, called the International Consortium on Prostate Cancer Genetics (ICPCG) that was established in 1996. Using the approach of genome-wide DNA marker scan followed by a powerful statistical analysis, we identified two chromosomal regions of 0.4% of the genome that may harbor the prostate causing genes. We are taking a combination approach of candidate-gene analysis and genomic sequencing to discover the prostate cancer-causing gene among the genes that reside in this 0.4% of the human genome. The ICPCG has been a very successful consortium that identified five DNA regions of interest, including one of the regions discovered by our troup, for prostate cancer. By working together with our colleagues around the world, we will ultimately identify prostate cancer causing genes in these regions and eventually pave the way for therapeutic steps forward.

•    Conduct a clinical trial with a new, non-toxic and very promising anti-cancer drug
Many men with prostate cancer cannot be treated with surgery or radiation. For these patients, the search for safe and effective treatments is of the utmost importance. The initial treatment will be a form of hormone therapy, and while this is usually effective, the duration of response is of limited duration. At that point, options are extremely limited. Clearly, we can do better. Researchers are diligently looking for more active agents in the battle against advanced prostate cancer but as of now, there is only one FDA approved chemotherapy agent available. The difficulty is finding a way to target the cancer without damaging other parts of the body. Working with Nobel Prize winner, Dr. Andrew Schally, we discovered a unique protein on the surface of prostate cancer cells. Using this protein as a gateway into the cancer cell, we can deliver chemotherapy exactly where it is needed, sparing the rest of the body. This project received significant funding from the NIH. We are planning to start this exciting new drug treatment in September of this year as part of a clinical trial and hope it will revolutionize the treatment of advanced prostate cancer. This trial will also use several new techniques to ensure the treatment is working. We will measure actual cancer cells in the blood with a simple blood test, giving patients quick progress reports on their treatment. With innovative drugs that work in different ways and using the latest in cancer monitoring, we hope this study will start a new chapter in the treatment of prostate cancer.

•    Design and test a new class of anti-cancer drugs
This project is designed to develop a class of agents (called MAPs) that have been shown to block aggressive behavior of prostate cancer cells thereby exerting anti-metastatic activities. We plan to develop MAPs that can be easily used as both diagnostic imaging agents as well as therapeutic agents in men with prostate cancer. The proposed agents will be radiolabeled to enable imaging with positron emission tomography (PET) that provides noninvasive, highly sensitive and quantitative assessment of tumor. The same unlabeled agents can provide therapy to the targeted tumor. This investigation will have an important impact on the care of men with advanced prostate cancer through development of useful dual functional agents that can serve both as an accurate diagnostic imaging probe as well as an effective therapeutic agent against advanced prostate cancer. On broader terms our approach may have an important role as an imaging tracer to study the extent of this disease and response to treatment in other cancers.

•    Understand the regulation of testosterone (male hormone) production in prostate cancer cells
Recently, it has been shown that prostate cancer cells can produce testosterone from cholesterol similar to testicular cells. This process may make prostate cancer cells resistant to hormonal therapy. Very recently, we discovered a unique molecular pathway which regulates testosterone production in prostate cancer cells. Presently, we are conducting experiments to better understand this pathway, which, if shut down, could result in inhibition of prostate cancer cell growth in patients who fail current hormonal treatments. We are also in the process of developing new anti-cancer drugs to inhibit this molecular pathway in castration resistant prostate cancer.

•    Identify patients who are at high risk of prostate cancer recurrence after surgery or radiation therapy using a genetic fingerprint
The cancer recurrence among patients diagnosed with localized tumors (limited to the prostate) can be as high as 30%. The clinical indicators currently available to physicians cannot accurately identify which patients will remain cancer-free after removal of the localized tumor, and which patients might have a recurrence within the next ten years. This often results in over-treatment, with its associated morbidity, of many ‘low-risk’ patients who would have remained indolent, and under-treatment of ‘high-risk’ patients who would benefit from earlier institution of more aggressive therapy. Therefore, it is of critical importance to more accurately determine which patients have better prognosis than others, as this may have implications for the choice of treatment and the timing of available therapies. There is evidence that subsets of patients diagnosed with localized prostate cancer already contain specific alterations in their cancer cells that will predispose them to the recurrence of more aggressive disease. The analyses of gene expression patterns in the entire genome of prostate cancer cells offer the possibility to identify these alterations, which is a necessary first step towards reliably identify patients at high-risk of worse clinical outcomes. We plan to conduct a rigorous large-scale gene expression profiling study that characterizes prostate cancer localized tumors from a population cohort of 1,200 patients for whom long-term clinical follow-up data are available. At the conclusion of our study, we will have identified novel biomarkers of localized prostate cancer clinical outcomes. Overall, the development and clinical application of novel prognostic biomarkers would reduce the morbidity associated with over-treatment of indolent patients, and allow the identification of those patients diagnosed with localized prostate cancer that might benefit the most from more aggressive treatments.

•    Role of EphB4 and EphrinB2 in tumor development and Progression and development of novel therapy for prostate cancer.
We have discovered that prostate cancer cells have a pair of unique proteins on their cell surface which are lacking in the normal prostate gland. Second, when we target these proteins with very specific antibodies, the tumor cells die. We are thus conducting detailed studies as to how these proteins are turned on in prostate cancer. Next we wish to determine if the absolute amounts of these proteins predict for stage, grade and survival. Most importantly we plan to conduct human trials with the antibodies to EphB4-EphrinB2.