Regulation of Lung Cancer Dormancy and Recurrence by Stress-Activated Neutrophils
Abstract
Local recurrence and distant metastases are the biggest clinical challenges in lung cancer. For patients with early stages of lung cancer surgical resection is the best treatment option. However, despite complete tumor resection, more than 30% of patients undergo local or distant recurrence with limited benefit of further treatment and relatively short survival. The reason for the recurrence remained unclear. It is widely accepted that small numbers of tumor cells persist in a non-proliferating (dormant) state after early dissemination from primary tumor until cells reenter the cell cycle, thus originating metastases. Cancer cell dormancy can be the initial response to radiation and chemotherapy. Although signaling in dormant tumor cells is relatively well understood, much less is known about the mechanisms that made tumor cells leave dormant state and form local recurrence or distant metastases. The elucidation of the mechanisms by which tumor cells are reawakened from dormancy is crucial to achieve eradication of lung cancer. The main objective of this study is to identify the mechanism of recurrence of lung cancer and to determine therapeutic targeting strategy to control this process. We propose that reactivation of dormant tumor cells in lung cancer could be caused by prolonged stress with release of neuroendocrine adrenergic hormones. These hormones induce activation of neutrophils, resulting in their sequestration in lungs with release of S100A9/A8 proteins. We propose that these proteins promote lipid peroxidation. Local release of oxidized lipids directly drives reactivation of dormant tumor cells. Targeting of S100A9/A8 and use of ß2-adrenergic receptor blockade can substantially reduce tumor recurrence. Proposed research addresses the following two Lung Cancer Research Program Areas of Emphasis: “Understand the molecular mechanisms of initiation and progression to clinically significant lung cancer,” and “Identify innovative strategies for prevention and treatment of lung cancer.” This project will establish the role of stress and neutrophils in reactivation of tumor dormant cells and lung cancer recurrence and identify the mechanism of this process. We will test, for the first time, the possibility of reducing lung cancer recurrence by blocking specific mechanisms regulating this process. We expect to offer novel mechanism of therapeutic regulation of lung cancer recurrence. If successful, it may have major impact for patients with non-small cell lung cancer. Treatment can be applicable for patients after complete tumor resection with expected substantial risk of recurrence. Since tested compounds have been used in clinical trials for other indications, this approach can be rapidly (within 3 years) translated to clinical trials. Lung cancer is the second most common cancer in Veterans. It represents critical medical challenge for Veterans in their families. This proposal seeks to address the major problem—lung cancer recurrence after successful initial treatment and its therapeutic correction—and may potentially have a substantial impact on Veterans and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910571
Entities
People
- Dmitry I. Gabrilovich
Organizations
- United States Army
- Wistar Institute