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

项目总结 尽管在治疗方面取得了进展，如靶向治疗和免疫治疗，但肺癌仍然是致命的 五年存活率低于25%的恶性肿瘤。大约三分之二的非小细胞肺癌诊断是在以前的 吸烟者，他们患这种疾病的风险是不吸烟者的6倍。不幸的是， 人们一直在努力寻找能够降低戒烟者患癌症风险的化学预防药物 不成功。目前在美国，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抗癌效果是众所周知的 仅限于超重或肥胖的患者。在这一新发现之后的调查中，我们有 研究发现，在人类和小鼠中，肥胖都与肺部肿瘤免疫功能的变化有关 促进疾病进展的微环境，这些变化很容易被 二甲双胍。这些变化中最突出的是二甲双胍对免疫抑制激活的影响 调节性T细胞(Tregs)，它被认为是癌症发生过程中的重要免疫学事件。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/超重患者中 前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 在大部分高危人群中减少肺癌发展的化学预防潜力 治疗癌症。为了研究二甲双胍的这种预防作用，我们将进行一项小型的II期试验，试验对象为- 高危肥胖/超重受试者确定长达数月的口服二甲双胍治疗会减少标志物 肺内免疫抑制树突起和增强局部肺和全身标志物的研究 免疫监视活动(特定目标1)。找出肥胖症特有的机制 二甲双胍的免疫调节作用，我们将研究该药对肥胖和非肥胖小鼠的影响。 两种截然不同但互为补充的小鼠肺癌模型(特定目标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).