Targeting Glutaminase Isoforms for Therapy-Resistant Prostate Cancer
Abstract
Although most prostate cancer (PCa) patients respond to hormonal therapy initially, the tumor eventually recurs as castration-resistant prostate cancer, which invariably leads to death. Years of studies focusing on androgen receptor (AR) signaling have not significantly improved the outcome of the disease. The main problem with hormonal therapy is that its effect is only temporary, and there are significant side effects, such as sexual dysfunction and disorders of the cardiovascular and metabolic systems. We think this is because AR is a physiologic protein required for the normal functions of many organs. In tumor cells, only some aspects of AR function are related to tumor growth, but our current approach inhibits everything AR does. The goal of our research is to find out exactly what aspects of hormonal therapy lead to tumor suppression so that we can target only those aspects, but do not touch others. We have discovered that an important function of AR in prostate cancer cells is that it promotes the expression of an enzyme glutaminase (GLS1), allowing cells to use glutamine, an amino acid, as a source of energy and building materials, supporting the uncontrolled growth of cancer cells. Hormonal therapy shuts down the whole process, achieving tumor inhibition. However, under the stressful hormonal therapy conditions, tumor cells evolve to express an isoform of GLS1 called GAC that is not controlled by AR and can be expressed despite hormonal therapy. What is worse, GAC has much stronger enzymatic activity, allowing more glutamine to be used by tumor cells, resulting in therapy resistance, disease progression, and the emergence of more aggressive tumors. We have proposed to study the process in greater detail to firmly establish that GLS1 function and glutamine utilization should be more specifically targeted rather than the more general targeting of AR. The new therapeutic approach will inhibit tumor cells more directly, achieving better therapeutic efficacy and causing fewer side effects. The study will focus on the function and molecular mechanisms, with the goal of translating these findings into useful treatment for patients who would not have any treatment options otherwise.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910411
Entities
People
- Jiaoti Huang
Organizations
- Duke University
- United States Army