Targeting non-coding RNA Regulated Lineage Plasticity to Overcome Antiandrogen Resistance in Advanced Prostate Cancer
Abstract
Background: Prostate cancer (PCa) is the most common cancer among American men, with 161,360 estimated new cases in 2017. Despite the clinical success of targeted therapies for advanced PCa, such as next-generation hormone therapies, many patients have a very limited response and will eventually develop resistance to treatment. Understanding mechanisms of drug resistance will not only advance our understanding of PCa pathogenesis, but may also lead to new therapeutic approaches to preventing and overcoming resistance. During my postdoctoral training at the Memorial Sloan Kettering Cancer Center, I identified a novel mechanism of hormone therapy resistance in advanced PCa mediated by lineage plasticity, or “identity fraud.” PCa cells that have genetic alterations in two tumor suppressor genes, TP53 and RB1, can become resistant to treatment by changing their tumor cell identity to a different cell type that is not responsive to the therapy that was targeting their original identity. I have demonstrated that the therapy resistance caused by this identity fraud can be reversed by inhibition of a gene named SOX2. This work not only provides critical new insights into the mechanisms of drug resistance, but also sheds light on potential therapeutic strategies to overcome therapy resistance by interruption of this SOX2-driven lineage plasticity. Scientific Objective: Although my efforts to inhibit the SOX2 gene in preclinical models have shown promising results at reversing therapy resistance, direct therapeutic inhibition of the SOX2 gene in PCa patients is not currently feasible. Therefore, the goal of this study is to characterize the downstream targets of the SOX2 gene, as well as the exact mechanism by which the SOX2 gene becomes activated in these tumor cells. Clear elucidation of the mechanism of this SOX2 gene-mediated identity fraud will identify druggable targets and provide us with the opportunity to develop novel therapy to prevent or overcome therapy resistance. Furthermore, there is a type of RNA, called long non-coding RNAs (lncRNAs), in the human body that is not transcribed into proteins. These lncRNAs are widely involved in the regulation of many physiological functions and tumor progression. My preliminary results revealed a connection between this new class of lncRNAs and therapy resistance driven by identify fraud. Therefore, I will identify how lncRNAs regulate identity fraud and explore the utilization of these lncRNAs as biomarkers, ultimately benefiting clinical practice by way of precision medicine. Applicability of the Research: The clinical success of targeted therapy in PCa, including second-generation anti-androgen enzalutamide (Xtandi), has reformed the treatment of advanced PCa. However, the disparity in responses and acquired resistance to targeted therapy largely limit the clinical benefit of treatment. My previous work, published in Science, has revealed that the tumor cells are able to escape the targeted therapy by changing their identities to a different cell type that is not dependent on the original drug target. This identity fraud-mediated resistance is driven by a gene called SOX2. My proposed study will focus on elucidating the detailed mechanism of this identity fraud and identifying novel druggable targets to develop therapy that may prevent or overcome resistance and benefit patients with advanced Pa. Another challenge of treating advanced PCa is the varying response to current target therapy and the lack of biomarkers to predict patients’ responses. Thus, the second aim of this proposed study will elucidate how a new class of RNA, called lncRNAs, promotes lineage plasticity and resistance to treatment and will validate the utility of using lncRNAs as biomarkers. Eventually, the identification of a new class of biomarkers will empower clinical practice by way of precision medicine and greatly benefit patients with advanced PCa. Expected Contributions of the S
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810411
Entities
People
- Ping Mu
Organizations
- United States Army
- University of Texas Southwestern Medical Center