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

项目摘要 尽管在治疗方面取得了进展，如靶向和免疫治疗，但肺癌仍然是一个致命的威胁。 恶性肿瘤，5年生存率低于25%。大约三分之二的NSCLC诊断是在前 吸烟者，与不吸烟者相比，患这种疾病的风险高出6倍。不幸的是， 鉴定降低戒烟者癌症风险的化学预防剂的尝试已经 不成功。目前在美国，大约60%的戒烟者超重或肥胖。我们有 观察到，对于肺癌，常见的糖尿病药物二甲双胍的众所周知的抗癌作用是 仅限于超重或肥胖的患者。在这一新发现之后的调查中，我们 发现在人类和小鼠中，肥胖与肺部肿瘤免疫系统的变化有关。 微环境，促进疾病进展，这些变化很容易逆转， 二甲双胍。这些变化中最突出的是二甲双胍对免疫抑制剂激活的影响。 调节性T细胞（TCRs），其已知是癌发生中的重要免疫事件。我们 假设二甲双胍的肥胖特异性免疫调节作用也发生在肥胖/超重 吸烟者患肺癌的风险很高。如果是真的，这一概念将为二甲双胍的治疗奠定基础。 在高风险人群中减少肺癌发展的化学预防潜力 治疗癌症为了检验二甲双胍的预防潜力，我们将进行一项小型II期试验， 高危肥胖/超重受试者，以确定长达数月的口服二甲双胍治疗可减少标志物 免疫抑制性THBE在肺中的表达，并增强局部肺和全身标记物 免疫监视活性（特异性目标1）。为了确定肥胖特异性 为了研究二甲双胍的免疫调节作用，我们将研究这种药物对肥胖和非肥胖小鼠的影响， 两种不同但互补的小鼠肺癌模型（特异性目标2）。

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).