Mutational Landscape of the Y Chromosome and Prostate Cancer
Abstract
This project is focused on developing better therapies for patients with aggressive prostate cancer. Recently, it has been observed that the loss of the male-specific Y chromosome is associated with increased risk for disease and mortality in men. Recently, our team has found that the loss of a specific gene, KDM5D, on the Y chromosome predicts poor prognosis in men with prostate cancer. Further, loss of KDM5D expression is associated with resistance to androgen-deprivation therapy and docetaxel treatment. We have also developed preliminary evidence that a related gene, UTY, is also involved in processes that lead to the development of aggressive prostate cancer. Together, these studies indicate that one or more genes on the Y chromosome most likely play an important role in prostate cancer progression. We hypothesize that alterations of the Y chromosome, particularly mutations or loss of these two specific genes, may significantly affect the expression of other genes and lead to aggressive, treatment-resistant prostate cancer. Our objective is to study changes to the Y chromosome in order to identify and reveal the role of specific Y chromosome genes that are of importance for developing aggressive, therapy-resistant prostate cancer. Our specific aims are to determine the scope and prevalence of Y chromosome changes in men with PC who have contributed tumor tissue to tumor repositories to which we have access, including the Stand Up To Cancer/Prostate Cancer Foundation Dream Team “Precision Therapy for Advanced Prostate Cancer,” the Cancer Genome Atlas, and others. Second, we will use gene-editing technology in established prostate cancer cell lines to identify specific genes on the Y chromosome that may play a role in the emergence of aggressive and treatment-resistant prostate cancer. Last, in cellular and animal studies, we will investigate the role of KDM5D, UTY, and other genes we discover through our first two aims by evaluating how the expression of these genes in various cell lines and human tumors is associated with other genetic changes involved in the emergence of aggressive and treatment-resistant prostate cancer. The central potential clinical application of this work is to identify patients who have a high risk of aggressive disease based on their Y chromosome. This will provide guidance for physicians to match the best treatment plan to an individual patient, including the type of treatment, the best drug, combination, or sequence and timing of drugs. The patients most likely to benefit from this research are those with aggressive prostate cancer who have Y chromosome alterations and who will potentially receive treatment regimens more likely to benefit them (and less likely to receive treatments unlikely to benefit them) and who ultimately may benefit from new treatments developed specifically for such patients. The longer-term contribution of this study is likely to advance the field of prostate cancer research. We anticipate that we will characterize specific mechanisms underlying the aggressive, treatment-resistant prostate cancer caused by the alteration of Y chromosome genes. These mechanisms could potentially serve as markers to disease progression and drug sensitivity, but more importantly, they could serve as targets for the discovery of new drug therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810200
Entities
People
- Nikolaus Schultz
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army