Functional Characterization and Modeling of Acquired Resistance to Immune Modulation in Lung Cancer
Abstract
Lung cancer is the leading cause of cancer death worldwide and is responsible for ~160,000 deaths per year in the United States. Despite these dismal statistics, in recent years there have been unprecedented advances in our understanding of the biology of lung cancer with new, effective, and less toxic treatment strategies becoming available for patients. Even these new treatments, however, are rarely curative and tumors eventually develop resistance to therapy. Knowledge of the mechanisms that underlie acquired resistance to cancer therapy is necessary to discover better and potentially even curative treatment regimens for patients. There is great excitement in the cancer research community for emerging drugs that “re-awaken” the immune system so that it can fight cancer cells. These immunotherapies are showing promise for the treatment of several cancers including lung cancer. Just in 2015, two immunotherapies, nivolumab and pembrolizumab, were approved for lung cancer treatment, and many other similar drugs are currently under investigation. Responses to these agents are durable compared to standard chemotherapy and yet they are rarely curative because acquired resistance eventually develops. To complicate matters, very little is known about the mechanisms that lead to acquired resistance to immunotherapies. As immunotherapies become mainstream for the treatment of lung cancer, understanding the mechanisms that allow tumors to escape treatment with these drugs is going to become increasingly important. However, the clinical experience with these agents is so new that availability of patient samples for analysis has been limited to date. I propose to capitalize on two major strengths of my laboratory to overcome these problems: (1) access to precious clinical samples from patients treated with immunotherapies and (2) expertise using mouse models of lung cancer to study drug resistance. Working together, my collaborators and I will use the unique samples from patients to discover mechanisms of acquired resistance to immunotherapy. We will also use our expertise with mouse models to study how resistance to these therapies emerges. Finally, we plan to evaluate potential therapeutic approaches to overcome acquired resistance. The proposal directly addresses one area of emphasis of the 2016 Lung Cancer Research Program: to understand susceptibility or resistance to treatment. This highly innovative, high-risk research in relevant lung cancer models and patient specimens will maximize our chances of finding valuable new targets and approaches that can be investigated in clinical trials, ultimately advancing care for patients with lung cancer and specifically those who have developed resistance to treatment with immune checkpoint inhibitors including military personnel, Veterans, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710351
Entities
People
- Katerina Politi
Organizations
- United States Army
- Yale University