Dynamics of Epigenetic Mechanisms in the Akt Signaling Pathway and Its Influences on Drug Response in Advanced Prostate Cancer
Abstract
Scientific Objective and Rational: The androgen receptor (AR) is the most commonly altered gene in advanced prostate cancer (PCa). Recognition of this led to the development and approval of several AR-targeted therapies. Despite this, most patients develop resistance. Another common alteration in PCa is loss of PTEN, which is highly frequent in aggressive and advanced PCa. The AKT signaling pathway is essential for cell proliferation, metabolism, and survival and is negatively regulated by PTEN. Studies show a correlation of PTEN loss with a decrease in AR activity, which is associated with resistance to AR-targeted therapy. We have demonstrated that inhibition of the AKT signaling pathway leads to increased AR activity, but not increased survival. In breast cancer, another hormone receptor-driven cancer, inhibition of this pathway results in an overall increase in estrogen receptor (ER) activity, causing a change in where ER binds to chromatin and carries out its activity. This appears to be mediated by the epigenetic regulator KMT2D. In our preliminary studies, there are suggestions that the effect of AKT on AR in PCa is also mediated by epigenetic regulators. My proposed project seeks to characterize how inhibition of the AKT pathway alters where AR binds chromatin and carries out its activity and to identify the broader epigenetic effects from AKT inhibitors. I hypothesize that AKT pathway inhibition modulates AR chromatin binding and activity by disrupting regulation of KMT2D by AKT. To achieve this, I will be focused on (1) performing comprehensive analysis identifying changes in where AR binds chromatin and what cofactors bind with it, as well as the broader epigenetic landscape after exposure to AKT pathway-targeted therapies and (2) on performing mechanistic studies to test the hypothesis that AKT signaling alters AR activity and cofactor binding through KMT2D. Applicability of the Research: The majority of PCa-related deaths occur in men with advanced PCa who have developed resistance to current therapies. Understanding the underlying mechanisms of resistance and how to overcome them is paramount. Although the AKT pathway has long been a focus of PCa research, there is renewed interest due to encouraging preliminary clinical results with the AKT inhibitor ipatasertib. After PARP inhibitors, AKT inhibitors are potentially the next targeted therapy approved for PCa. This study will improve our understanding of the biological effects of this class of drugs and help optimize the use of these drugs in the clinic. In addition, it will improve our understanding of how regulation of specific genes by AR is connected to sensitivity or resistance to treatment. Career Goals: I aspire to be an independent researcher, running a multidisciplinary research laboratory focused on PCa and at the forefront of PCa research and making a substantive impact in our study of the disease. My immediate goal is to study the key role of epigenetic programming that links AKT signaling and resistance to AR blockade in advanced PCa. The proposed project is an excellent opportunity to provide me with the skills, expertise, and competence that I need to achieve that. While improving my technical skills, I plan to attend courses, seminars, and workshops to help prepare for running my own laboratory, as well as professional networking events to meet potential collaborators and get professional advice in an informal setting. My Mentors, Drs. Kathleen Kelly and David VanderWeele, are leading experts in the field of PCa, with a track record of producing quality basic and translational research, as well as mentoring successful research scientists. Dr. Kathleen Kelly is accomplished in the field of cancer biology, genetics, and genomics. Her laboratory pioneered the use of 3D organoid structures to study response to therapy, which I will use in this project, and she has extensive collaborations focused on drug discovery using
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910715
Entities
People
- Remi Adelaiye-Ogala
Organizations
- National Cancer Institute
- United States Army