CCSG Pilot: COE: Understanding How to Implement Methionine Restriction to Improve Lung Cancer Treatments

SCIENTIFIC ABSTRACT Although immune-checkpoint inhibitors (ICIs) combined with chemotherapy are currently FDA-approved as first line treatment for almost all lung cancer patients, long-term efficacy of this treatment approach is limited. One modifiable factor for each patient is diet – specifically the amount and quality of nutrients they consume during treatment. Our recent studies found that in aggressive lung cancer models that are mutant for KRAS and STK11 (aka LKB1), dietary methionine restriction limits tumor growth in a prevention setting, and allows for improved carboplatin response in a treatment setting. However, there are conflicting data in the literature regarding whether methionine restriction would enhance or inhibit ICI responses. Furthermore, we do not currently understand the opinions of patients in our catchment area about dietary restrictions, nor do we understand if weight loss drugs, such as GLP1 receptor agonists, could allow for more effective methionine restriction. Therefore, the goals of the proposal are to validate the use of methionine restriction during chemo/ICI treatment as an effective treatment augmentation strategy, and to take steps towards understanding how to implement this strategy in the clinic. Our central hypothesis is that methionine restriction will potentiate lung cancer response to chemo/ICI and will be feasible to implement in our catchment population. To test this hypothesis, we propose two specific aims. In Aim 1, we will complete a 100-patient survey of lung cancer patients at the Markey Cancer Center to understand opinions and possible barriers to implementing a dietary intervention during chemo/immunotherapy treatment in the clinic. We will also utilize human samples, including plasma from patients on the GLP1 receptor agonists trizepatide, and data and tissue from lung cancer patients to understand if weight loss drugs lower methionine, and to correlation methionine biomarkers with immunotherapy responses. In Aim 2, we will treat immune-competent tumor-bearing mice on methionine restriction with carboplatin and the immunotherapy PD-1 antibody and follow tumor growth. We will characterize tumor phenotypes in responders and non-responders, and examine tumors that show resistance to this therapeutic drug combination. Completion of these aims will solidify the efficacy of a promising dietary intervention, and uncover mechanisms by which lung tumor phenotypes and microenvironments are changed by methionine restriction. This research is designed to fill gaps in knowledge about implementation and mechanisms of methionine restriction that will be essential data for our future R01 proposals.