Investigating the Expression, Role, and Targeting of Collagen Modifying Prolyl 4-Hydroxylase P4HA1 in Prostate Cancer Progression and Metastasis
Abstract
Prostate cancer is a leading cause of cancer-related death in American men. Many molecular events are involved in prostate cancer initiation, unregulated growth, and metastasis to other organs such as bone, brain, and liver at an advanced stage. While effective surgical and radiation treatments exist for clinically localized prostate cancer, once prostate cancer spreads to other organs, it is essentially incurable, and most men diagnosed with metastatic disease will succumb over a period of months to years despite the standard anti-androgen therapies. Diagnosis of prostate cancer at an early stage, when it is still localized and curable, is essential to reduce the number of deaths from this disease. Therefore, we need to identify molecular markers of aggressive disease so that we can develop accurate clinical diagnostic and prognostic tests and effective therapies. Our previous studies led to the identification of many genes that were significantly elevated in prostate cancer compared to normal prostate. Those included AMACR, Gene fusion TMPRSS2-ERG, and histone methyltransferase EZH2. We went on to extensively characterize the mechanism by which EZH2 plays a role in tumor progression. Recently, EZH2 has been successfully targeted using compounds developed by several pharmaceutical companies. Another gene that we discovered to be highly expressed in aggressive prostate cancer is the extra cellular matrix modulating collagen modifier, prolyl collagen hydroxylase 1(P4HA1), which is also amenable to targeting with inhibitors. Our published study showed overexpression of this enzyme in aggressive PCa and a role for P4HA1 in prostate cancer growth. This gene encodes a key enzyme involved in processing collagen that is a structural protein known to play a role in tumor invasion and metastasis, and aggressive prostate cancer is known to mainly metastasize to bone. Thus, the aims of this proposal are: Aim 1. Evaluate the significance of P4HA1 expression in PCa. Aim 2. Investigate the functional role of P4HA1 in PCa metastasis. Aim 3. Target P4HA1 in PCa using specific small molecule inhibitor. Our published research shows that P4HA1 induces prostate cancer cells to proliferate and lead to invasion, tumor growth, and metastasis, which is the main cause of PCa-related death. Thus, in this proposal, we will aim to understand the mechanism by which P4HA1 causes prostate cancer progression to metastasis and whether it could be developed as a predictive biomarker for clinical use. Critically, we will use specific inhibitor targeting P4HA1 identified recently to test the effectiveness of blocking P4HA1 and in preventing PCa tumor growth and metastasis. Our group is well established in prostate cancer research and has been involved successfully in identifying novel therapeutic targets. We have assembled an expert team of pathologists, a prostate cancer bone metastasis researcher, and a biostatistician to complete the proposal successfully. The present proposal will combine cutting-edge technologies in cancer biology to discover genes that play a critical role in prostate cancer progression and cancer metastasis, as well as target them. The proposed study will elucidate the mechanism of action of P4HA1 and a strategy for therapeutic targeting using specific inhibitor. Our long-term goal is to target P4HA1 as a treatment option for aggressive prostate cancer with a specific drug.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910588
Entities
People
- Sooryanarayana Varambally
Organizations
- United States Army
- University of Alabama at Birmingham