Biofluid-Based Detection of the Migration Switch in Prostate Cancer to Predict Metastatic Disease
Abstract
Currently, the diagnosis and prognosis of prostate cancer depend primarily on tracking changes in circulating prostate specific antigen, monitoring for symptoms and intermittent needle biopsy if deemed necessary. Many of the newly diagnosed prostate cancer patients are at low risk of clinical progression. The lack of reliable tests and limited confidence in current parameters to distinguish between aggressive and indolent disease results in substantial overtreatment of patients. It is apparent that metastatic disease, which is the primary cause of death among prostate cancer patients, may occur early and originate in localized disease that is not aggressive by our current standard. Consequently, there is an urgent need for molecular indicators to distinguish indolent from aggressive disease. With those indicators, current clinical care would be effective at providing therapeutic intervention. The presence or absence of metastases is the only individual prognostic factor in multivariate analysis of prostate cancer outcomes. While the 5-year survival for localized prostate cancer in North America is close to 100%, the survival rate drops to 31.9% for metastatic disease. The success of metastatic dissemination is determined by a tumor cell s ability to move to a distant site, arrest, enter the stroma surrounding the vasculature and grow in a new microenvironment. Nevertheless, without the initial movement/entry into the circulation, subsequent steps become inconsequential and distant metastases fail to form. The appearance of circulating tumor cells in patients with metastatic disease suggests that the initial movement is a critical component of the metastatic process. Consequently, detecting the movement status of prostate cancer cells can be an effective mechanism to predict patient outcome and subsequently direct clinical care. We have identified some major molecular regulators of tumor cell movement, and by tracking these molecular indicators in tumor and biofluids (i.e., blood and urine), we have demonstrated that the detection of this migratory switch can accurately predict progression to metastatic disease and correspond to patient outcome. Based on our preliminary work, we want to validate and develop a biofluid-based biomarker strategy that detects activation of movement of cancer cells to accurately identify patients with aggressive disease before the onset of clinical progression with sufficient time remaining for therapeutic interventions. We will evaluate and validate our biomarker strategy using biofluids and surgical and surgical biopsy tissue from patients in three cohorts from Canada and the United States with a total population of 1500. Internal and external validation of the biomarker will be conducted at the University of Alberta in collaboration with Vanderbilt, Toronto, and Montreal clinicians and scientists. The ability to correctly distinguish indolent from metastatic disease will have significant impact on improving patient care and outcome without the inclusion of new therapies. Identifying aggressive disease in patients prior to clinical manifestation will allow for significant improvement in patient quality of life. Being able to accurately define disease as indolent and monitor the disease longitudinally will allow patients to avoid the morbidity of definitive treatment (e.g., surgery or radiation). The economic impact of managing prostate cancer is greatly reduced as an accurate prediction of disease progression significantly reduces the cost of clinical intervention. My overarching career goal is to have a positive impact on improving prostate cancer patient care by developing more accurate and personalized diagnostic/prognostic tools for early detection. The research plan proposed in this application will bring me closer to my career goal as it focuses on using a biofluid-based molecular indicator test to stratify prostate cancer patients into indolent and metastatic grou
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510416
Entities
People
- Lian Willetts
Organizations
- United States Army
- University of Alberta