Disrupting Access to Intracellular Lipid Depots to Treat Advanced Prostate Cancer
Abstract
Rationale: Despite the development and approval of several new treatments for advanced prostate cancer, this stage of the disease remains largely incurable. Hence, there is a pressing need to identify novel therapeutic approaches. It is now known that a defining hallmark of prostate cancer is increased lipid metabolism. Accordingly, there is great interest in targeting lipid metabolism for the treatment of advanced prostate cancer. Current efforts to target lipid metabolism have centered on blocking the cancer cell’s ability to take up lipids from the environment (lipid uptake) or synthesize these molecules themselves from other building blocks (de novo lipogenesis). However, targeting lipid uptake or de novo lipogenesis has not yet led to any clinical benefit for men with prostate cancer. Further, there may be compensation between the two pathways, indicating that targeting either pathway may be insufficient. Alternatively, we have identified that inhibition of an enzyme called adipose triglyceride lipase (ATGL), which regulates the first step in the breakdown of all stored fats within cells, blocks the growth of advanced prostate cancer in cell culture and in animal models. Preliminary data suggest that blocking ATGL may also be effective for the treatment of metastatic disease and/or prostate cancers that are resistant to all androgen receptor (AR)-targeted therapies. These findings indicate that ATGL may represent a mechanistically alternative therapeutic target. To drive the development of new ATGL-directed therapies, several issues still need to be addressed. First, we need to identify which disease state would benefit the most and whether there would be potential side effects, if any, of systemic targeting of ATGL. Second, it is not clear why prostate tumors require ATGL. Third, a faithful biomarker of ATGL-targeted therapy is needed. These three issues (determining patient population and potential side effects, understanding the fundamental biology, establishing a biomarker of activity) need to be addressed to evaluate any mechanistically new therapy to determine whether it can be safely and effectively administered to the correct patient population. Objectives: The primary objective of this study is to rigorously test whether ATGL is a bona fide therapeutic target in diverse preclinical models of advanced prostate cancer. Further, we will characterize whether this approach enhances the efficacy of existing drugs and assess whether there are potential side effects (positive or negative). We will also determine how ATGL regulates lipid metabolism to promote prostate cancer progression. Finally, we will test whether a non-invasive imaging agent that is already FDA-approved for the detection of recurrent and metastatic prostate cancer can be used as a biomarker of drug effectiveness and potentially, future patient selection. Aims: Aim 1 will test whether inhibition of ATGL blocks disease progression in rigorous, preclinical animal models of advanced prostate cancer. We will use new and established mouse models that mimic different stages of the disease (castration-resistant prostate cancer, metastasis, AR-positive and AR-negative), and that will allow us to test whether genetic or pharmacological inhibition of ATGL blocks disease progression. These experiments will also enable the initial assessment of potential side effects that could result from ATGL inhibitors. Aim 2 will establish ATGL’s role in prostate cancer lipid metabolism. Hence, these experiments will provide a biological explanation for how this therapeutic approach works. Aim 3 will evaluate whether 11C-choline, an FDA-approved agent used for positron emission tomography imaging (PET) of advanced prostate cancer, can function as a biomarker of ATGL activity and thus, ATGL inhibitors. Applicability of the Research: Given the focus on developing novel therapies for the treatment of the advanced disease and defining the underly
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210686
Entities
People
- Daniel Frigo
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army