Enabling Discovery and Targeting of Macrophage-Mediated Therapeutic Resistance in Prostate Cancer Through Microscale Engineering of the Tumor Microenvironment
Abstract
Scientific Objective and Rationale: Prostate cancer is a lethal disease that, despite recent therapeutic advances, remains the second leading cause of cancer-related death in men. Death from prostate cancer is primarily due to the spread of cancerous cells to other sites in the body, such as the bones, lungs, and liver, through a process known as metastasis. Chemotherapy and hormone therapy are the two most effective treatments for men with metastatic prostate cancer. These therapies can cause tumors to shrink, improve symptoms from the disease, and help men live longer. Unfortunately, these therapies are not effective in everybody, and even when they do work, cancers inevitably find a way to grow, even with treatment. This therapeutic resistance represents one of the biggest challenges we face in treating prostate cancer. While there are a number of pathways within cancerous cells that can lead to therapeutic resistance, researchers have found that non-cancerous cells in these tumor lesions also play critical roles in the development of resistant disease. These non-cancerous cells include immune cells, blood vessels, and support cells (known as stroma) that are collectively known as the tumor microenvironment (TME). Within a tumor, cancer cells “co-opt” these normal cells and use them to support cancer progression and therapeutic resistance. In prostate cancer, one type of cell that appears to be particularly important in this process is an immune cell known as a tumor-associated macrophage (TAM). These cells promote resistance to a number of therapies, including chemotherapy and hormone therapy. However, we do not yet understand how TAMs are able to do this or how to disrupt this interaction. The goals of this project are to (1) identify the molecular pathways used by TAMs to promote therapeutic resistance and (2) develop therapies to block these pathways. To achieve these goals, we have developed new microfluidic technologies that allow us to use patient samples to recreate and tease apart their tumor microenvironment within the laboratory. We use this technology to help us better understand how cells are communicating within each patient’s tumor and which pathways lead to the development of therapeutic resistance. We can then test different therapies within these microfluidic technologies to identify those that can inhibit this process. Through the incredible generosity of our patients, we have tested their samples and already identified two promising targets that help tumor cells survive chemotherapy. In addition, we seek to use these models of patient tumors to inform us about which of these therapies may be most effective in each patient. Applicability: The men at highest risk of developing therapeutic resistance and dying from prostate cancer are those with metastatic prostate cancer and men with prostate cancer that appears confined to the prostate, but there is a high chance that it has already spread (high-risk disease). If successful, this project will help these men through the development of therapies that limit or prevent the development of resistance to chemotherapy and hormone therapy. In addition to directly helping these patients, this study will contribute to the field of prostate cancer research by providing an enhanced understanding of how interactions between tumor cells and cells in the TME lead to cancer progression and therapeutic resistance. Since we are able to work directly with patient cells within our microscale devices and perform many tests on each sample, we anticipate that the research from this project will translate into new clinical trials for men with advanced prostate cancer in 2-3 years. Career Goals: My overarching career goal is to develop new treatment strategies for men with prostate cancer as a physician-scientist in an independent laboratory. Together, this project and the accompanying mentorship plan will provide me with dedicated clinical trai
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810273
Entities
People
- David Kosoff
Organizations
- United States Army
- University of Wisconsin–Madison