Metformin for chemoprevention of lung cancer in obese subjects at high risk

二甲双胍用于高危肥胖受试者的肺癌化学预防

• 批准号: 10599530
• 负责人: Joseph Barbi
• 金额: $ 6.92万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599530
• 关键词: Abate; Antidiabetic Drugs; Cancer Model; Chemoprevention; Chemopreventive Agent; Clinical Trials; Development; Diabetes Mellitus; Diagnosis; Disease Progression; Event; High-Risk Cancer; Human; Immune; Immunologic Surveillance; Immunologics; Immunotherapy; Investigation; Link; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Metformin; Mus; Non obese; Non-Small-Cell Lung Carcinoma; Obesity; Oral; Outcome; Overweight; Patients; Pharmaceutical Preparations; Population; Preventive; Preventive therapy; Reducing Agents; Regulatory T-Lymphocyte; anti-cancer; cancer prevention; cancer risk; carcinogenesis; disorder risk; experimental study; former smoker; high risk; immunoregulation; improved; non-smoker; novel; obese person; phase II trial; targeted treatment; tobacco smokers; tumor-immune system interactions

PROJECT SUMMARY Despite advances in treatment, such as targeted and immune therapies, lung cancer remains a deadly malignancy with five-year survival below 25%. About two-thirds of NSCLC diagnoses are made in former tobacco smokers, who are at 6-fold higher risk for the disease compared to non-smokers. Unfortunately, attempts to identify chemopreventive agents that reduce the risk of cancer in ex-smokers have been unsuccessful. Currently in the US, about 60% of ex-smokers are either overweight or obese. We have observed that for lung cancer, the well-known anti-cancer effect of the common diabetes drug metformin is restricted to patients who are overweight or obese. In investigations that followed this novel finding, we have found that in both humans and mice, obesity is associated with changes in the lung tumor immune microenvironment that promote disease progression, and that these changes are susceptible to reversal by metformin. Prominent among these changes is the impact of metformin on activation of immunosuppressive regulatory T cells (Tregs), which is known to be an important immunological event in carcinogenesis. We hypothesize that the obesity-specific immunomodulatory action of metformin also occurs in obese/overweight ex-smokers at high risk of lung cancer. If true, this concept will establish a basis for metformin's chemopreventive potential to abate lung cancer development in a major fraction of the population at high risk for the cancer. To examine this preventive potential of metformin, we will conduct a small phase II trial with at- high-risk obese/overweight subjects to establish that months-long oral metformin treatment diminishes markers of immunosuppressive Tregs in lungs and enhances markers local pulmonary and systemic immunosurveillance activity (Specific Aim 1). To identify mechanisms that underlie the obesity-specific immunomodulatory effects of metformin, we will study the impact of this drug in obese and non-obese mice of two distinct but complementary mouse lung cancer models (Specific Aim 2).

项目总结