Rationale and Objective: Prostate cancer is the second leading cause of cancer death in American men. Androgen deprivation therapy causes a chemical castration and is the primary treatment for prostate cancer. However, this therapy is short-lived because prostate cancer progresses to a lethal and castration-resistant form and grows despite continued androgen deprivation therapy. Despite decades of investigations, the mechanisms causing prostate cancer progression to this advanced stage have remained largely unknown. This greatly hinders the effective treatment of these castration-resistant prostate cancer patients. Our recent studies identified a protein called P-Rex1 as a key molecule promoting prostate cancer progression. For example, P-Rex1 is markedly elevated in tumors of patients with aggressive castration-resistant cancer, and increased P-Rex1 in prostate cancer cells leads to an increase in growth of these cells in androgen deprivation conditions. More importantly, we are developing a novel drug that selectively targets castration-resistant prostate cancer and inhibits P-Rex1 protein. This provides an innovative therapeutic agent to treat castration-resistant prostate cancer patients by reducing P-Rex1 levels. In the present proposal, we will investigate the function and underlying mechanism of P-Rex1 in the castration resistance of prostate cancer cells. Our immediate objective is to fully define this novel mechanism that promotes prostate cancer progression to lethal castration-resistant disease. Our intermediate clinical objective is to determine if increased P-Rex1 can serve as a biomarker to distinguish lethal prostate tumors from treatable indolent disease. Our ultimate objective is to determine if our novel inhibitory drug will be the start of a new generation of therapeutics to treat lethal prostate cancer.
The Ultimate Applicability of the Research: Given that prostate cancer has many different forms, it is critical to identify reliable biomarkers to distinguish lethal from indolent prostate tumors to guide more effective therapeutic treatments. We will determine whether increased P-Rex1 levels can identify aggressive prostate cancer and predict the response to androgen deprivation therapy. The development of accurate progression risk biomarkers and accurate biomarkers for predicting response to castration therapy will allow caregivers to better manage prostate cancer. Thus, our proposal focuses on translational research with clinical applicability that will benefit prostate cancer patients of various stages. More importantly, toxicities due to effects of anticancer drugs on non-cancer cells and organs limit the therapeutic value of currently used drugs. Our new inhibitor drug combines a component reducing P-Rex1 with a tumor-targeting component. This combination will allow specific delivery of anticancer agents to tumor cells to destroy them with reduced toxicity in other cells and organs. Success in these studies would have a significant long-term clinical impact by changing treatment paradigms for castration-resistant prostate cancer. This could be a major step forward to eliminate suffering and death from prostate cancer. Therefore, the proposed work has clinical importance for risk assessment, early diagnosis, prognostic monitoring, and treatment of human prostate cancer. Within 3-5 years, our study will identify new biomarkers for predicting prostate cancer aggressiveness and the response to androgen deprivation therapy, and new tools for treatment of human prostate cancer.
The Likely Contributions of This Study to Advancing the Field of Prostate Cancer Research: Our research will make contributions towards identifying and targeting causes of castration-resistant prostate cancer progression. First, we will identify increased P-Rex1 protein as an important cause of castration-resistant prostate cancer progression. Understanding how P-Rex1 promotes prostate cancer progression will further contribute to identifying new molecules causing drug-resistant cell growth in androgen deprivation therapy. Second, development of our new inhibitor drug that selectively targets P-Rex1 in prostate cancer cells, but does not affect normal prostate cells, can also be applied to other molecules causing prostate cancer progression. Thus, our studies provide the prostate cancer research community with a new technology to investigate and selectively target various mechanisms of prostate cancer progression. Thus, our studies will guide future prostate cancer research from a novel perspective.
|Effective start/end date||1/1/12 → …|
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