Mechanisms of Immune Checkpoint Resistance Mediated by LKB1 Tumor Suppressor in Lung Cancer
Abstract
What scientific objectives and rationales does this study address? Recent advances in lung cancer have shown that treatment strategies that activate the body’s immune system to recognize and attack lung cancer cells can be effective for many patients. However, mutations in a particular gene called LKB1 cause resistance to this immune-based approach, and patients with this type of lung cancer are much less likely to have a good response to these treatments; their cancer continues to progress more rapidly, and they have shorter survival than similarly treated patients whose cancer does not have this mutation. We hope that, if our research uncovers the reasons that LKB1 mutations cause resistance to immune-based treatments, we can identify better treatments to overcome this resistance. How does this work inform the DOD LCRP areas of emphasis? This work addresses several Areas of Emphasis for the DOD Lung Cancer Research Program. It will address the use of LKB1 mutations as a marker of patients who may do worse with immune-based treatments; it will help to understand the mechanisms of resistance to immune based treatment; and understanding these mechanisms may lead to new and innovative strategies for the treatment of patients with this type of lung cancer. What type of patients may benefit from this work? Our work may lead to better treatments for patients with lung cancer with mutations in LKB1; about one in five patients with lung cancer will have this type of mutation, or about 45,000 affected patients in the United States every year. What are the potential clinical applications, benefits, and risks? The potential benefits of our work will be the identification of new drugs or treatment strategies that could be combined with existing immune-based treatments to improve how well they work for patients with LKB1-mutant lung cancer. If a promising drug candidate is identified in this work, then the next steps might include studies in animals to evaluate safety and effectiveness when combined with immune-based treatments, and then clinical trials in lung cancer patients, first to evaluate safety and then to evaluate effectiveness. What is the projected time it may take to achieve a clinically relevant outcome? Within 1 year, we will have completed the experiments proposed in this study that aim to identify promising drug candidates. Depending on what type of candidates result from this work, an additional 1 to 2 years of work might be required to validate these findings before they could begin to be studied in patients in the setting of a clinical trial. What are the likely contributions of this study to advancing the field of lung cancer research? This work will improve our understanding of how lung cancers with LKB1 mutations have different biology that allows them to evade the immune system and be resistant to immune-based treatments. Understanding these mechanisms will be crucial for developing new treatment strategies to overcome it and will also inform our understanding of immune therapy resistance that occurs in other circumstances. How is the project relevant to military Service members, Veterans, and their families? Better treatments are needed to improve the lives and outcomes of all patients with advanced lung cancer. Lung cancer is of particular importance among U.S. Veteran populations because smoking is more common in Veterans in comparison to the general civilian population. LKB1 mutations occur most commonly among heavy smokers, and research devoted to the study of these types of cancers is likely to be particularly beneficial to the military Veteran population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910408
Entities
People
- Jacob Kaufman
Organizations
- Duke University
- United States Army