Full Project 1 – SMARCA1 Signaling in Prostate Cancer
Title: The functional role of SMARCA1 signaling in prostate cancer progression and drug resistance
Project Leads:
- Guoliang Li, PhD – Vanderbilt University Medical Center
- Paula J. Hurley, PhD – Vanderbilt-Ingram Cancer Center
- Zhenbang Chen, PhD – Meharry Medical College
- Ho-Jin Koh, PhD – Tennessee State University
Project Summary:
Prostate cancer (PCa) is the second leading cause of cancer-related deaths among American men. The mortality rate for PCa is 2.5 times higher in African American (AA) men compared to their Caucasian American (CA) counterparts. Various therapies, including surgery, radiation, and androgen deprivation, have been developed to manage PCa at different stages. However, many PCa patients ultimately succumb to relapse due to the recurring growth of cancer cells that result in castration-resistant prostate cancer (CRPC). Emerging evidence revealed that CRPC tumors eventually develop resistance to drugs targeting the androgen receptor (AR). Therefore, a detailed understanding of the mechanisms involved in PCa progression and drug resistance is essential for developing novel and effective therapeutics.
SNF2L (encoded by the SMARCA1 gene) is a ubiquitously expressed transcription regulator, and its elevation is associated with the development of human cancers including PCa. Literature and our data support that SMARCA1 is elevated in advanced PCa and SMARCA1 inactivation resulted in a significant decrease on the growth of cancer cells, suggesting that the selective inhibition of SMARCA1 could be a viable therapy for cancers. In addition, AA normal prostate cells display higher levels of SMARCA1 as compared to CA normal prostate cells, indicating an association between SMARCA1 and PCa disparities among AA and CA men. Importantly, our preliminary studies revealed that SMARCA1 expression was increased ~900 times in the drug-resistant cells (LNCaP-MDV) compared with androgen-sensitive cells (LNCaP). Based on the literature and our preliminary data, we propose a novel concept and approach to suppress PCa progression and reduce drug resistance through SMARCA1 inactivation. Specifically, we hypothesize that SMARCA1 upregulation drives PCa malignancy and therapy resistance, and targeting SMARCA1 can re-sensitize AR signaling and efficiently suppress CRPC growth to reduce cancer disparity. We plan to test this hypothesis by evaluating the anti-proliferation effects of SMARCA1 ablation in PCa cells in vitro and its efficacy on the suppression of prostate tumors and the restoration of sensitivity to AR inhibitors in mice in vivo.
Results from this proposal can provide a novel and efficient therapeutic regimen to suppress PCa growth and reduce cancer disparity and will further allow us to generate publications necessary to apply for extramural funds including an R01 grant.
Specific Aims:
1) Investigate the essential role of SMARCA1 signaling in prostate cancer progression.
2) Determine the anticancer effects of targeting SMARCA1 in drug resistance prostate cancer in vivo.
3) Elucidate the molecular mechanism of SMARCA1 signaling in drug resistance prostate cancer cells.