De Novo Lipogenesis and Chemosensitivity of Prostate Cancer
Abstract
Rationale/Objective/Aims: Docetaxel is a key therapeutic approach for both hormone-sensitive and -resistant metastatic prostate cancer. Improving the effectiveness of docetaxel in metastatic disease is critical to increase the survival of prostate cancer patients. Docetaxel requires interaction with the cell membrane to enter a cell, which is a main barrier restricting its efficacy. Our recent study demonstrates that aggressive prostate cancer tends to produce lipid species that are linked to decreased membrane fluidity and permeability and that inhibition of lipid biosynthesis significantly enhances docetaxel-mediated killing of prostate cancer cells in petri dishes. We therefore hypothesize that lipid biosynthesis protects prostate cancer from docetaxel chemotherapy by decreasing member fluidity and permeability, and we propose that targeting lipid metabolism represents a promising approach to improve the effectiveness of docetaxel for the treatment of advanced prostate cancer. Our proposed research will test the combinatorial treatment of FGH10019 (an orally available chemical inhibitor that blocks lipid production) and docetaxel in mouse xenografts and in a robust genetically engineered mouse model that exhibits enhanced lipid biosynthesis. We also propose to assess the effects of lipids on cell membrane dynamics and docetaxel uptake. We aim to determine whether inhibition of lipid biosynthesis enhances the responsiveness of prostate cancer to chemotherapy to create powerful and long-lasting anti-tumor effects. In order to accomplish this, we will take a multidisciplinary approach that includes mouse genetics, preclinical studies, and well-established techniques in molecular and cell biology to achieve the following Specific Aims: Aim 1. To determine the therapeutic efficacy of docetaxel in combination with FGH10019 in cell line-derived xenograft models of prostate cancer. Aim 2. To determine the therapeutic efficacy of docetaxel in combination with FGH10019 in genetically engineered mouse models of prostate cancer. Aim 3. To elucidate the molecular mechanisms underlying the combinatorial anti-tumor activity of docetaxel and FGH10019 in prostate cancer. The Ultimate Applicability of the Research: This project has the potential to contribute to two PCRP Overarching Challenges: “develop treatments that improve outcomes for men with lethal prostate cancer,” and “define the biology of lethal prostate cancer to reduce death.” The anticipated outcomes will lay the foundation for future clinical trials combining lipogenesis inhibitors and chemotherapeutics for the treatment of advanced prostate cancer. Ultimately, all the men with hormone-sensitive or -resistant metastatic prostate cancer might see a huge clinical benefit from new and novel combinatorial therapeutic strategies made possible by this work.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010185
Entities
People
- Mingwei Chen
Organizations
- Duke University
- United States Army