Pharmacologic Inhibition of Lipogenesis Suppresses AR and Its Splice Variants to Inhibit Progression of Castration-Resistant Prostate Cancer
Abstract
Fats or lipids are the principal stored forms of energy in many organisms. Modified fats such as phospholipids are a major structural component of membranes of all cells. Other lipids are important for the function of many enzymes as well as for signaling within and between cells. Finally, fats are essential for the synthesis of hormones including male hormones. While normal cells rely on the availability of lipids from the diet and from the surrounding environment, for reasons that are not entirely clear, tumor cells need to make (or synthetize) fatty acids from scratch. They do so by massively stimulating the activity of enzymes that make fatty acids. The prototype of these enzymes is Fatty Acid Synthase, commonly abbreviated as FASN. Others and we have found increased amounts of this enzyme in prostate cancer and especially in advanced, castration-resistant metastatic disease, which is still fatal. More pointedly, we found that inhibition of this enzyme leads to the decrease of androgen receptor, the molecule through which male hormones exert their growth-promoting function on prostate cancer cells. When these cancers become castration-resistant, they produce an androgen receptor that functions independently of circulating male hormones, eluding the effects of castration. Importantly, inhibition of FASN markedly decreases the function and activity of this form of the androgen receptor as well. In this proposal, we will use a novel and powerful inhibitor of FASN to shut down the activity of androgen receptors in both murine and human models of castration-resistant prostate cancer. Since this inhibitor is powerful, safe, orally bioavailable and irreversible, results from our studies will provide the necessary data to move quickly into a clinical trial in patients with advanced, castration-resistant prostate cancer. In addition, the molecular mechanisms dissected in this study will form the basis for an entirely novel way of treating castration-resistant prostate cancer and tumor growth driven by constitutively active androgen receptor. By eliminating the androgen receptor in all its forms through blocking lipid synthesis by the cells rather than structurally interfering with it, we hope to be able to avoid resistance, which regularly happens with direct inhibitors of the androgen receptor.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710483
Entities
People
- Massimo Loda
Organizations
- Dana–Farber Cancer Institute
- United States Army