Investigating the Cellular and Molecular Mechanisms of Disseminated Tumor Cell Dormancy in Brain
Abstract
Ninety percent of all cancer patients die as a result of the spread of their disease to other tissues. A subset of breast cancer patients exhibit an increased risk for the development of brain metastases. Unfortunately, patients diagnosed with brain metastasis have a very low 5-year survival rate along with significant reduction in quality of life. The standard of care for brain metastasis is whole brain radiation therapy or surgery, which can provide local control in some patients but does not change the overall prognosis of patients with brain metastasis. Currently, the field lacks effective treatments to either prevent development of brain metastasis or eliminate established metastases. Disseminated tumor cells (DTCs), which leave the primary tumor, stop proliferating, and survive within various tissues for years despite anti-cancer therapy, initiate metastatic relapse years or even decades after initial treatment. Thus, identifying therapies that can effectively eliminate DTCs or small micrometastases prior to their growth into lethal metastases is a major unmet need. Fortunately, the quiescent nature of breast cancer metastasis, up to 15 years or more after the initial diagnosis, provides the opportunity to target these DTCs or newly growing micrometastatic lesion at early stages. Understanding how DTCs survive within the brain, how they avoid the immune cell attack, and what signals awaken them is the first step toward design therapeutic approaches that target and eliminate DTCs. In this proposed project, I aim to (1) identify the first known regulators of breast tumor cell quiescent within the brain, (2) establish the direct contribution of inflammatory immune response to quiescent DTC activation, and (3) unveil how DTCs evade microglia/macrophage-mediated immune attack in brain. The only way we can create a breast cancer-free existence is through meticulous research into the biological mechanisms that control metastatic recurrence. This project will significantly contribute toward the foundation of work necessary to achieve this goal. With the knowledge gain from this project, we will be able to understand the molecular mechanisms how the DTCs manage to survive and thrive in brain. Properly treating DTCs or small micrometastases could lead to the prevention of deadly brain metastasis. This project has significant potential to decrease mortality resulting from breast cancer brain metastasis within the next decade. Ultimately, we anticipate that uncovering microenvironmental factors and cues comprising the dormant niche will inform novel therapeutic strategies to target quiescent DTCs. On the other hand, immunotherapy represents one potentially viable option to selectively kill quiescent DTCs or growing micrometastases for the purpose of metastasis prevention in the brain. We will determine the role of macrophage phagocytosis in preventing micrometastatic outgrowth into lethal macrometastases and why they stop working in the case brain metastasis re-emergence. We will identify novel innate immunity-based targets that eliminate dormant DTCs or growing micrometastases to prevent lethal recurrence in the brain. Addressing and treating the root cause of metastatic relapse -- which we can only do through understanding DTC biology -- is integral for improving patient quality of life, as well as decreasing mortality. Further, since the biology we propose to uncover relates to physiologic regulation of DTC behavior, including the alteration of perivascular niche that sustain their quiescence and the innate immune surveillance that keep them under check. We anticipate that potential therapeutic strategies to re-enforce the growth inhibitory niche or provoke innate immune response to target DTCs will result in less toxicity aimed at preventing metastatic relapse. This will particularly benefit the HER2-positive and triple-negative breast cancer patients who have a high chance of developing brain metasta
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810028
Entities
People
- Jinxiang Dai
Organizations
- Fred Hutchinson Cancer Center
- United States Army