Identification of a Novel Modifier of Lineage Plasticity and Therapy Resistance in Prostate Cancer
Abstract
Background: Prostate cancer is the most commonly diagnosed cancer among American men, ultimately ending in the most lethal form of prostate cancer, metastatic castration-resistant prostate cancer, which has a 5-year survival rate of only 28%. One of the biggest challenges when managing this lethal disease is that the majority of patients will develop resistance to the current “standard-of-care” androgen receptor (AR)-targeted therapies within 2 years of initial treatment, which largely limits the ability for doctors to fight this deadly disease. Therefore, there is an overwhelming need to understand the biology of AR-targeted therapy resistance, develop new measurable biological markers to predict resistance, and create a new therapeutic approach to fight against the resistance. The successful completion of this proposal will tremendously improve the clinical outcome and survival for men with lethal prostate cancer. Rationale: One of the possible reasons for the resistance to current AR targeted therapy is that, when primary prostate cancer transforms into metastatic prostate cancer, many genes are lost, enabling the tumors to no longer respond to current therapy. We have found, through a cutting-edge technology called “library screening,” that the loss of a particular gene, called ZNF397, is a key factor leading to therapy resistance in a novel subtype of lethal prostate cancer. The tumor cells that have lost the gene ZNF397 manage to convert themselves away from their original cell identity to a new cell identity, which no longer depends on the drug target AR protein for survival. This recently discovered phenomenon driving therapy resistance is called lineage plasticity, or “identify fraud,” and has also been observed widely in various types of other cancers. Our preliminary finding not only identified the gene ZNF397 as a novel modifier of the tumor cell “identify fraud,” but also suggests that proper clinical intervention targeting the unknown resistance driver proteins regulated by ZNF397 may be an effective avenue to combat resistance and improve the clinical outcome and survival of patients with lethal prostate cancer. Objective/Aims: Therefore, we proposed to examine how AR-targeted therapy resistance occurs in this subtype of lethal prostate cancer featuring low levels of ZNF397 using cutting-edge technologies, including “organoid 3D culture,” “single cell RNA sequencing,” “NanoString,” and “Spatial Transcriptomics.” More importantly, through comprehensively dissecting the mechanisms causing the “identity fraud” and therapy resistance in these prostate cancers, we will identify new therapeutic targets to overcome the resistance in this type of lethal prostate cancer. Finally, we will develop an original and measurable biological marker, called the ZNF397low signature, to predict patients’ responses to current AR targeted therapies and to use this new tool to guide the doctors when they are determining the best treatment options before administering them to patients. The combined results of these experiments will provide the rationale and foundation for direct follow-up clinical trials testing the effectiveness of this new ZNF397low signature, as well as the potential therapeutic approaches targeting the downstream proteins of ZNF397 needed to fight the AR-targeted therapy resistance. Applicability: If successfully completed within the 3 years provided by the support from this award, the proposed study will significantly contribute to addressing two of the FY20 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.” For example, this study will clearly define the biology and mechanism of AR-targeted therapy resistance in a large subtype of lethal prostate cancer, which occurs in approximately 25-40% patients. The successful development of the innovative and measurable biolog
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110520
Entities
People
- Ping Mu
Organizations
- United States Army
- University of Texas Southwestern Medical Center