Prognostic and Therapeutic Significance of COP9 Signalosome Subunit CSN5 in Prostate Cancer
Abstract
Prostate cancer is the third leading cause of cancer death in American men, with approximately one in nine men being diagnosed with prostate cancer during his lifetime. Some therapies that are used to treat men with prostate cancer may not be effective after several years of treatment, suggesting that new medicines to treat these patients are urgently needed. Because proteins perform a wide range of functions in cells, their activity needs to be tightly controlled; one way this occurs is through the regulated breakdown of proteins. COP9 signalosome subunit 5—or CSN5—has an important function to control the way other proteins are broken down. The amount of CSN5 that is expressed in cancer cells can be different from the amount that is expressed in normal cells and tissues, with some cancer cells having higher levels of CSN5 than normal cells. Research in other cancer types has shown that changes in CSN5 can affect a diverse set of functions that are important to the normal functioning of cells and can contribute to tumor development. Although we know that CSN5 affects the activity of two specific proteins that are very important in prostate cancer—one called the androgen receptor and one called MYC—our understanding of how CSN5 functions in prostate cancer is minimal. The objective of our work is to better understand the function of CSN5 in prostate cancer, with the ultimate goal of determining whether a drug that decreases CSN5 activity can be used alone or in combination with other medications to treat men with prostate cancer. Aim 1: To determine whether patients with prostate cancer who have changes in CSN5 have different survival and outcomes from patients with prostate cancer who do not have changes in CSN5. We will use a large set of existing patient samples to determine whether patients who have changes in CSN5 have differences in tumor aggression or survival. Aim 2: To characterize how CSN5 affects the activity of the androgen receptor and MYC and to identify other proteins that CSN5 regulates in prostate cancer. We will expand upon the data that demonstrate that CSN5 affects androgen receptor and MYC activity. We will also identify a wider set of proteins that are regulated by CSN5 in prostate cancer. Aim 3: To examine whether a new drug that decreases CSN5 activity is effective in different models of prostate cancer. We will test a new drug that decreases CSN5 activity in different prostate cancer models to determine whether it may be an effective treatment. We will also test this new drug in combination with other drugs that can be used to treat patients with prostate cancer. This work addresses two FY19 PCRP Overarching Challenges: develop treatments that improve outcomes for men with lethal prostate cancer and define the biology of lethal prostate cancer to reduce death. Our work has the potential to help patients with prostate cancer who have changes in CSN5 or patients with prostate cancer for whom other existing treatments have stopped working. The drug that targets CSN5 that we will test may be effective alone or in combination with other medications, which would allow physicians to find the best treatment plan for individual patients. The clinical significance of this project lies in the advancement of our understanding of the role of CSN5 in prostate cancer and the assessment of the potential of drugs that target CSN5 as treatment for men with prostate cancer. The benefit will be the potential identification of a new way to treat certain patients with prostate cancer and improve their survival. There is a chance that decreasing CSN5 activity may not be an effective way to treat prostate cancer, but this is also critical information that is needed to advance our understanding of the disease and how to help men who have it. It will likely be approximately 2 years after the successful completion of our research before we can test in men with prostate cancer whether
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010114
Entities
People
- Philip W. Kantoff
Organizations
- Sloan-Kettering Institute
- United States Army