Functional and Molecular Diversity in the Tumor Microenvironment Underlies Therapeutic Response and Resistance
Abstract
Scientific Objective and Rationale: Prostate cancer is the second leading cause of cancer death in the United States. Changes in PSA (prostate specific antigen) screening are leading to an increasing number of men being diagnosed with locally advanced or metastatic disease that cannot be surgically removed. New clinical studies found that combining chemotherapy and hormone therapy at the time of initial diagnosis dramatically improves survival for men with this stage of prostate cancer. A clinical trial at the University of Wisconsin is asking if these men would benefit from having the prostate removed after completion of chemohormonal therapy. However, we do not understand how resistance to chemohormonal therapy develops or if it impacts what other treatment options could be used in the future. We have assembled a comprehensive and experienced group of investigators to study these critical issues for men with prostate cancer. This team is led by a medical oncologist, urologist, and biomedical engineer. Our team is also comprised of a nuclear medicine physician, radiologist, pathologist, and bioinformatics specialist. This multidisciplinary team is uniquely situated to integrate the complementary technologies in our labs that we think can be leveraged to identify men that are likely to develop this resistance, as well as understand the reasons why resistance has developed. This will move us closer to the goal of achieving more precision in treating patients. To achieve these goals, we will utilize advanced PET/MRI (positron emission tomography/magnetic resonance imaging) imaging to better identify sites of disease and how they respond to chemohormonal therapy. We will use these images to guide dissection of the prostate for the cancer lesions that respond and progress on chemohormonal therapy. We anticipate these will be very small cancer lesions, thus we will employ three new microscale technologies to extract these rare cells for analysis of mutations in the androgen receptor and DNA repair genes. We will also extract the support cells in the prostate that can help cancers survive chemohormonal therapy. Known as stromal cells, they can send signals to prostate cancer during treatment that keep prostate cancer cells alive. By testing both the tumor and stromal cells simultaneously, from the same patient, we can evaluate many different potential mechanisms of resistance. We will further study the immune cells in these lesions to ask if chemohormonal therapy affects how the immune system can also be recruited to target prostate cancer. This will be the first study to comprehensively evaluate multiple mechanisms of resistance simultaneously, from precious patient samples, after chemohormonal therapy. Applicability: The outcome of this research has the potential to help all patients who suffer from prostate cancer, and especially those with newly diagnosed prostate cancer. This work could lead to the development of integrated imaging, biopsy, and blood tests to comprehensively interrogate prostate cancer in a way that has never been achieved. By the end of the 3-year grant period, we will have identified how resistance develops to chemohormonal therapy by simultaneously evaluating multiple potential mechanisms of resistance. We will be able to take the most important tests into larger clinical trials and advance them into routine clinical care. Advancing the Field of Prostate Cancer: If successful, the ultimate outcome of this work would advance the field by providing a suite of new imaging and molecular tests for physicians and their patients to predict and monitor responses to chemohormonal therapy. Identifying patients that are likely to develop resistance to these drugs would enable physicians to utilize alternative treatment strategies that may have a greater anti-cancer effect. It would also enable these men to avoid the toxicities of aggressive treatment, such as chemohormonal therapy, that
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610511
Entities
People
- Joshua M. Lang
Organizations
- United States Army
- University of Wisconsin–Madison