Enhancing the Efficacy of AR Antagonist Therapy with TNF-Alpha Blockade in Metastatic Prostate Cancer
Abstract
Hormone therapy is the backbone of treatment for men with prostate cancer. Hormone therapy works by shutting down the production of testosterone and preventing its binding to the androgen receptor in prostate cancer cells. Prostate cancer cells die when the androgen receptor is prevented from functioning. But these effects don’t last. Eventually, the cancer cells persist and multiply even in the presence of hormone therapy. Understanding what factors influence resistance is critical to counteracting it and preventing progression to a lethal disease. The immune system is well-recognized to influence the development and growth of cancer. The immune system consists of a variety of different types of cells that communicate via cell-to-cell interaction and by sending signals to each other in the blood. Chemical messengers, or cytokines, travel throughout the body and deliver signals to cells. Some of these cytokines directly interact with the androgen receptor in prostate cancer cells and may be responsible for inducing resistance to hormone therapy. Understanding if inhibiting or blocking certain cytokines might prevent resistance to hormone therapy in men with prostate cancer is not well understood. We have recently shown that an inflammatory cytokine, named tumor necrosis factor-?? (TNF-??) may stimulate the androgen receptor in prostate cancer cells prompting the cells to grow even in the presence of hormone therapy. When TNF is present, the androgen receptor keeps working to stimulate prostate cancer cell growth even when it is being blocked. When TNF is blocked, the hormone therapy is rescued and is freed to block the androgen receptor again and delay cancer cell growth. We will be testing this notion in a clinical trial using the combination of a TNF blocking drug and an androgen receptor blocking drug in men with lethal prostate cancer. In this proposal, we will take a closer look at the molecular and immune features that make men more likely to respond to this treatment regimen. We hypothesize that blocking TNF will cause hormone therapy to work more effectively, thereby improving outcomes for patients. We will study the relationship between the blood levels of TNF, the androgen receptor activity in tumor tissue, and treatment response in men treated with this combination enrolled on our clinical trial. We want to understand if blocking TNF alpha rescues the ability of hormone therapy to work again within the tumor cells. We will also study social factors, such as patient-reported stress levels and the presence of external stressors, that might make TNF higher in certain subgroups of patients. This will allow us to determine whether having higher stress levels and living in an environment with increased social vulnerabilities may contribute to having higher TNF levels that then ultimately influence treatment response or resistance. The final goal of this research is to identify a multi-pronged approach in treating men with prostate cancer that includes targeting the immune system, prostate cancer cells, and identifying social factors that we may be able to provide additional resources to improve outcomes for patients. Prostate cancer is a devastating disease and there is a great need for better therapies. The work proposed here will provide important information how the immune system induces resistance in prostate cancer cells and how blocking the TNF signal might rescue the ability of hormone therapy to work better and longer. We will use these insights to explore vulnerabilities in invasive cancer cells to intercept their lethal trajectory. This could ultimately lead to a novel class of therapies to treat aggressive prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310383
Entities
People
- Jessica E Hawley
Organizations
- United States Army
- University of Washington