Dynamic Response of Disseminated Tumor Cells and Circulating Tumor Markers to Targeted Adjuvant Therapy
Abstract
Challenge: This proposal addresses the overarching challenge of determining how breast cancer cells survive in a dormant state for years and then re-emerge as recurrent cancers, and how to prevent this from occurring. Rationale: Patients diagnosed with breast cancer that has not spread beyond the breast and lymph nodes receive surgery and often other treatments, including chemotherapy, radiation, and/or anti-estrogen therapy, with the goal of cure. However, some patients will experience a recurrence despite their initial treatment, sometimes years or even decades later. Disseminated tumor cells (DTCs) are cancer cells that can be found in the bone marrow of some breast cancer patients after treatment and are associated with a substantially increased risk of recurrence. Although depleting the reservoir of DTCs that survive therapy would be a novel and promising way to prevent breast cancer recurrence and its associated mortality, no treatments have been developed that are specifically designed to kill these cells. This has largely been due to our lack of understanding of how residual cancer cells remain dormant, evade standard treatments, and ultimately reawaken and resume growth, as well as a lack of tools to find these cells and measure whether therapies designed to kill them are effective. This proposal will address this critical unmet need by identifying, characterizing, and elucidating the relationship between residual cancer cells in the bone marrow and bloodstream, which will enable the development of real-time markers for risk of recurrence and response to therapies that target this critical population of cells. Objective: For the more than 10 million breast cancer survivors worldwide -- all of whom are formally at risk for recurrence -- there is a pressing, unmet need to: (1) understand the mechanisms by which breast cancers recur; (2) develop methods to detect DTCs before they manifest as overt, incurable recurrent cancers; and (3) find ways to deplete or eradicate the reservoir of dormant residual cancer cells, and thereby cure the population of patients who will otherwise ultimately relapse and die of their disease. The overarching premise on which this proposal is based is that breast cancer mortality can be reduced by developing effective strategies for preventing breast cancer recurrence by identifying unique vulnerabilities of dormant tumor cells, developing markers to track them, and using that information to eliminate these cells. This proposal will break new ground by bridging fundamental discovery research in genetically engineered mouse models regarding the properties of dormant breast cancer cells that enable them to survive and persist in a dormant state, with novel translational studies of residual breast cancer cells in patients undergoing treatment with therapies targeted against DTCs. Together, information from the proposed studies will further the goal of identifying and targeting the unique vulnerabilities of dormant tumor cells, thereby preventing tumor recurrence, metastasis and mortality from this disease. This knowledge will enable development of more effective therapeutic approaches that could dramatically alter treatment options available to millions of breast cancer survivors. Aims: The aims of this proposal are to: (1) define the temporal and molecular changes in residual cancer cells in the bone marrow and blood during tumor dormancy and recurrence in mice; (2) determine the response of residual cancer cells in the bone marrow and bloodstream of mice to therapies that specifically target the vulnerabilities of residual cancer cells; and (3) determine the response of residual cancer cells in the bone marrow and bloodstream of breast cancer patients treated with these same therapies. Applicability and Timeline: The information gleaned from these studies will initially be most applicable to patients at high risk of recurrence, either due to lymph node-positive or t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710595
Entities
People
- Angela De Michele
Organizations
- United States Army
- University of Pennsylvania