Androgen Deprivation Therapy Resistance, Fatty Acid Oxidation, and the Role of Beta Hydroxybutyrate
Abstract
Rationale: With one in every four deaths, cancer is one of the most severe diseases that affect our society. Out of all types of cancers, prostate cancer affects one in every six American men. Prostate cancer is often treated with androgen deprivation therapy, like enzalutamide. This type of treatment focuses on blocking hormonal signals that promote prostate growth. Even though this line of treatment is initially effective, most patients develop resistance. This means, their prostate cancer no longer depends on hormones, and it is described as castration-resistant disease. Unfortunately, this stage of disease is often incurable, and the changes that occur to promote resistance are unclear. There is evidence that metabolism changes are associated with prostate cancer progression. We have observed that metabolites, like ketone bodies (and specifically beta hydroxybutyrate), are correlated to androgen deprivation therapy response. Beta hydroxybutyrate has been studied in different types of cancer, and it has been shown to change gene expression patterns, act in cell-cell communication, and be a source of energy. In this proposal, we will focus on the cells surrounding the tumor (stromal cells), also referred to as the tumor microenvironment. We want to understand the role of beta hydroxybutyrate released by these stromal cells and the role they have in androgen-targeted therapy resistance. To do so, we will study the levels of beta hydroxybutyrate and the enzymes that produce and utilize this metabolite. In prostate cancer patients, we see that, under androgen-targeted therapy, beta hydroxybutyrate is readily consumed by the cancer cells for energy to thwart therapy-induced death. Preliminary work demonstrates that prostate cancer cells treated with enzalutamide can be rescued by a biologically active form of beta hydroxybutyrate (R-enantiomer). Therefore, we will evaluate the use of a non-metabolizable form of beta hydroxybutyrate (S-enantiomer) to limit therapy resistance. Objective: Our overall objective in this proposal is to understand the metabolic changes that occur in the tumor microenvironment and how they promote therapy resistance. We will accomplish this by (1) characterizing stromal cell metabolism under enzalutamide treatment and different nutrient conditions, (2) evaluating prostate cancer cells under enzalutamide treatment and in conjunction with stromal cells, and (3) studying prostate cancer cell response to enzalutamide in conditions where the production of beta hydroxybutyrate is inhibited. Clinical Relevance: This work focuses on the role of beta hydroxybutyrate in castrate-resistant prostate cancer. Preliminary results show a correlation between serum beta hydroxybutyrate and response to androgen deprivation therapy. Patient Focus: The results of this work will help prostate cancer patients that undergo androgen deprivation therapy like enzalutamide and cease to respond. In addition, we will study beta hydroxybutyrate as a possible predictor of biochemical recurrence. Clinical applicability: We aim to understand the biology of castrate-resistant prostate cancer. For future applications, beta hydroxybutyrate could be easily measured in serum. The potential of S-enantiomer of beta hydroxybutyrate can be investigated as a treatment option. Also, the enzymes that process beta-hydroxybutyrate can be studied as potential targets for treatment in combination with enzalutamide. Career Goals: My advancement as an independent prostate cancer researcher and the development of this project has been closely supported by my mentor. I have been given freedom to design and progress this project as my own. I believe this is a very important and positive factor for an effective postdoctoral training. In addition, we have assembled the appropriate collaborators with expertise in fatty acid metabolism, genitourinary oncology, and signaling pathways in prostate cancer progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910387
Entities
People
- Krizia Rohena-rivera
Organizations
- Cedars-Sinai Medical Center
- United States Army