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

基本信息

批准号：
10297482
负责人：
Joseph Barbi
金额：
$ 63.05万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
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/10297482
关键词：
Abate Adenocarcinoma Age Antidiabetic Drugs Biological Response Modifiers Biopsy Blood Body mass index Bronchoalveolar Lavage Cancer Etiology Cancer Model Cells Chemoprevention Chemopreventive Agent Clinical Data Clinical Research Clinical Trials Collaborations Cytometry Development Diabetes Mellitus Disease Disease Progression Division of Cancer Prevention Environment Enzyme-Linked Immunosorbent Assay Evaluable Disease Event Flow Cytometry Gene Expression High-Risk Cancer Human Immune Immune response Immunologic Surveillance Immunologics Immunosuppression Immunotherapy Individual Investigation Light Link Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Measurement Metformin Modeling Molecular Mus Mutation Non obese Non-Small-Cell Lung Carcinoma Obesity Oral Outcome Overweight Pathway interactions Patients Pharmaceutical Preparations Phase Play Population Populations at Risk Preventive Preventive therapy Randomized Recording of previous events Records Reducing Agents Regulatory T-Lymphocyte Research Personnel Sampling Serum Site Squamous cell carcinoma Suggestion Survival Rate Testing Therapeutic Tissues Tobacco-Associated Carcinogen anti-cancer antitumor effect base cancer diagnosis cancer prevention cancer risk carcinogenesis cigarette smoking cytokine disorder risk experimental study former smoker high body mass index high dimensionality high risk human subject immunoregulation improved lung cancer prevention mortality mouse model non-diabetic non-smoker novel obese patients obese person phase II trial prevent primary endpoint programmed cell death protein 1 programs protocol development randomized trial targeted treatment tobacco smokers transcriptome transcriptome sequencing transcriptomics tumor tumor-immune system interactions waist circumference

项目摘要

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).

项目概要尽管靶向治疗和免疫治疗等治疗方法取得了进步，但肺癌仍然是一种致命的癌症五年生存率低于 25% 的恶性肿瘤。大约三分之二的 NSCLC 诊断是在以前诊断的吸烟者患此病的风险是不吸烟者的 6 倍。很遗憾，人们一直在尝试寻找可以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，大约 60% 的戒烟者体重超重或肥胖。我们有观察到，对于肺癌，常见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，我们发现发现在人类和小鼠中，肥胖与肺肿瘤免疫的变化有关促进疾病进展的微环境，并且这些变化很容易被逆转二甲双胍。这些变化中最突出的是二甲双胍对免疫抑制激活的影响调节性 T 细胞 (Treg)，已知是致癌过程中的重要免疫事件。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/超重人群中戒烟者患肺癌的风险很高。如果属实，这个概念将为二甲双胍奠定基础化学预防潜力可减少大部分高危人群的肺癌发展对于癌症。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，试验对象为：高风险肥胖/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肺部免疫抑制性 Tregs 的表达并增强局部肺部和全身标记物免疫监视活动（具体目标 1）。确定肥胖特异性背后的机制二甲双胍的免疫调节作用，我们将研究该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（具体目标 2）。