Mechanisms of Mammary Tumor Recurrence
Abstract
Challenge: This proposal addresses the overarching challenge of determining how breast cancer cells escape therapy, 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 of their cancer from residual tumor cells that can persist in small numbers in some breast cancer patients following treatment. The presence of residual cancer cells in patients is associated with a substantially increased risk of recurrence. Moreover, the fact that breast cancers can recur decades after treatment of the original cancer suggests that these cells may survive and persist in a dormant state. Although depleting the reservoir of residual tumor cells that survive therapy would be a novel and promising way to prevent breast cancer recurrence, 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 evade standard treatments, survive in a dormant state, and ultimately reawaken and resume growth. This proposal will address this critical unmet need. Objective: For the more than 12 million breast cancer survivors worldwide – all of whom are formally at risk for recurrence – there is a pressing, unmet need to understand the mechanisms by which breast cancers recur and find ways to deplete or eradicate the reservoir of dormant residual cancer cells before they manifest as overt, incurable recurrent cancer. 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 residual tumor cells and using that information to eliminate these cells. Our preliminary studies have identified a protein, EHF, as a potential suppressor of tumor recurrence in women with breast cancer, as well as a cellular state (referred to “cellular senescence”) in which dormant residual cancer cells can reside. This proposal is focused on evaluating the therapeutic potential of targeting the EHF pathway and – as a corollary – the state of cellular senescence as a means to eradicate dormant residual tumor cells and thereby prevent cancer recurrence and mortality. Aims: This proposal will break new ground by combining fundamental discovery research in genetically engineered mouse models regarding the properties of residual breast cancer cells that enable them to survive and persist in a dormant state, with novel translational studies that leverage this information to eradicate these cells. The first aim of this proposal will determine whether loss of the EHF protein triggers breast cancer recurrence and whether preventing EHF loss will prevent recurrence. The second aim of this proposal will determine whether EHF loss in mouse tumors renders tumor cells resistant to chemotherapy, and whether loss of EHF in breast cancers in women can identify those patients who are less likely to respond to chemotherapy. The third aim of this proposal is exploratory and will determine whether drugs that can kill senescent cells, called “senolytics” are able to kill dormant residual tumor cells and thereby prevent breast cancers from recurring. In aggregate, these studies have the potential to provide new therapeutic approaches to eliminating the reservoir of cancer cells that gives rise to recurrent tumors, and to help identify patients who are less likely to respond to chemotherapy. Applicability and Timeline: The information gleaned from these studies investigating the EHF pathway and cellular senescence as therapeutic targets in patients will be applicable to any brea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110528
Entities
People
- Lewis A Chodosh
Organizations
- United States Army
- University of Pennsylvania