Elucidating the Mechanisms Underlying Breast Cancer Cell Survival During Tumor Dormancy
Abstract
Research Proposal: Breast cancer is the most common cancer and the leading cause of cancer-related death in women worldwide. Primary breast cancer is highly treatable, with nearly 90% of patients surviving at least 5 years after initial diagnosis. In contrast, recurrent breast cancers can be treated, but are rarely cured. At present, there is no test that can accurately identify which patients will recur; as such, all breast cancer survivors are formally at risk for recurrence and many survivors harbor residual tumor cells (RTCs) within their bodies. In up to 30% of patients, residual tumor cells “re-awaken” following extended periods of dormancy and resume growth resulting in the emergence of recurrent cancers, typically at distant metastatic sites, such as in the bones, lung, or liver. Consistent with this, breast cancer patients who have detectable RTCs in their bone marrow are at a markedly increased risk of tumor recurrence. Although RTCs constitute the cellular reservoir from which recurrent tumors arise, at present there are no treatments that specifically target them, in part because we do not understand the cellular processes responsible for keeping these cells alive. Accordingly, the goal of our proposed research is to identify the biological properties of RTCs in order to identify those genes and pathways that are indispensable for their survival. To achieve this, we will utilize mouse models that recapitulate key aspects of breast cancer progression as it occurs in patients to directly test the impact on disease recurrence of modulating the signaling pathways required for RTC survival that we have begun to identify. The results from these studies have the potential to revolutionize current clinical management of breast cancer following initial therapy by providing new targets for intervention, thereby significantly improving patient outcomes. Career Goals: My long-term career goal is to pursue an academic career investigating the mechanisms underlying breast cancer progression and metastasis. In order to maximally leverage knowledge gained in the laboratory to improve breast cancer patient survival, I joined the laboratory of Dr. Lewis Chodosh for my postdoctoral research. Dr. Chodosh is the founder and co-director of the 2-PREVENT Translational Center of Excellence (TCE) at the University of Pennsylvania (UPenn) that seeks to translate knowledge gained from laboratory studies to prevent breast cancer recurrence in patients. Through my affiliation with this TCE, I will gain a broad understanding of the clinical aspects of breast cancer research, including analysis of results from two unique proof-of-principle clinical trials targeting patient RTCs that are currently ongoing, and how to conduct research that is truly impactful for breast cancer patients. The innovative research proposed here, combined with the resources and breast cancer expertise available to me at the UPenn, will provide me with a solid foundation in all aspects of breast cancer research, including the use of sophisticated mouse models and cutting-edge molecular biology techniques. Additionally, my routine participation and presentation in seminars and meetings within UPenn and at national conferences will help me gain valuable feedback and initiate collaborations with other researchers tackling the insidious challenge of recurrent disease. In aggregate, my postdoctoral studies will provide me with comprehensive training in breast cancer research and invaluable experience as I transition to developing and leading a robust, independent breast cancer research program. Applicability and Impact of Research: This research proposal addresses the overarching challenge of understanding why breast cancer cells lie dormant for years and then re-emerge, and how to prevent recurrence. Our studies will: (1) identify mechanisms underlying RTC survival following first-line therapy to treat primary disease, and (2) utilize this knowledge
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010013
Entities
People
- Amulya Sreekumar
Organizations
- United States Army
- University of Pennsylvania