Integrative Analysis of Exitrons in Metastatic Prostate Cancer
Abstract
Prostate cancer is the most common cancer diagnosis made in men in the United States. Prostate cancer is most often found in early stages, which means the cancer cells remain in the prostate and the cancer is highly treatable with surgery or radiation therapy. However, after localized therapy, some patients progress to an aggressive disease where the cancer has spread beyond the original area to other parts of the body. Although there are tests available that can efficiently diagnose the early stage prostate cancer, these tests cannot predict whether the patients will progress to the advanced stage or not. On the other hand, patients with advanced stage prostate cancer will receive androgen deprivation therapy (ADT), which is the treatment to deprive the cancer of what feeds it—androgen hormones. However, most of the patients under ADT will eventually develop resistance to this therapy, which is called castration-resistant prostate cancer (CRPC), leaving doctors with no options to counteract the inevitable. Therefore, there is an urgent need to (1) find novel biomarkers that can be used to identify patients that will progress to advanced disease; (2) identify novel targets that are druggable for CRPC patients; and (3) identify effective treatment options to improve outcomes for men with lethal prostate cancer. Recent advances in high-throughput sequencing technologies have greatly enhanced our understanding of the alterations present in the cancer genome that may serve as molecular drivers to cause the disease. Nearly all of the efforts to identify alterations affecting proteins have been focused on identifying DNA mutations and characterizing their oncogenic effects. In CRPC patients, we have recently identified a novel class of alterations, termed exitrons, that occurs at the RNA level. In this proposal, we will systematically identify and characterize exitrons in CPRC patients and dissect their underlying functional mechanisms, clinical relevance, and therapeutic potential. While we have identified exitrons in localized tumors, exitrons are highly expressed in advanced-stage tumors, which underscores the importance of exitrons as potential diagnostic and prognostic biomarkers. Treatment of patients with advanced-stage disease relies on hormone-like drugs that target androgen receptor (AR), a key protein in the disease. We have discovered that exitrons play an important role in the development of resistance for these hormone-like drugs. Additionally, exitron alternations likely change the structure of some tumor-specific proteins such that they appear foreign or dangerous to the immune system, which in turn stimulates an anti-tumor immune response. We have found that patients with a high exitron burden benefit from immunotherapy in melanoma and kidney cancers. This proposal will utilize cutting-edge computational and experimental technologies and large-scale clinical data to study the following aspects of exitrons: (1) on a global scale, what genes are affected by exitrons and what are the functional consequences of exitrons in CRPC patients? (2) can exitrons be used for predicting drug resistance? and (3) is it possible to select a subset of patients who benefit from immunotherapy due to their particular exitron expression? Our goal in this proposal is to understand the role of exitrons in prostate cancer progression, investigate the potential use of exitron expression as a biomarker, and identify novel approaches for the treatment of CRPC patients. We anticipate that the detection of exitrons will benefit early-stage patients for diagnosis and that therapies targeting exitrons will benefit CRPC patients with advanced lethal disease. We anticipate that our work will be immediately helpful to understand the biology of prostate cancer and to evaluate the potential of exitrons as predictive or prognostic biomarkers. Ultimately, our goal is to translate our discoveries into personalized patient care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910161
Entities
People
- Rendong Yang
Organizations
- United States Army
- University of Minnesota