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：
10737808
负责人：
Joseph Barbi
金额：
$ 6.79万
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/10737808
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 Color 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 Institution Investigation KRASG12D 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 Predisposition Preventive Preventive therapy Randomized Recording of previous events Records Regulatory T-Lymphocyte Research Personnel Risk Reduction Sampling Serum Site Squamous cell carcinoma Survival Rate T-Cell Activation Testing Therapeutic Tissues Tobacco-Associated Carcinogen anti-cancer antitumor effect 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).

项目摘要尽管治疗方面取得了进步，例如靶向和免疫疗法，但肺癌仍然是致命的五年生存率低于25％的恶性肿瘤。大约三分之二的NSCLC诊断是以前的与非吸烟者相比，吸烟者的风险高6倍。很遗憾，试图鉴定降低前吸烟者癌症风险的化学预防剂已是不成功。目前，在美国，大约60％的前吸烟者要么超重或肥胖。我们有观察到，对于肺癌，普通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。在这一小说发现之后的调查中，我们有发现在人类和小鼠中，肥胖都与肺部肿瘤免疫的变化有关促进疾病进展的微环境，并且这些变化容易逆转二甲双胍。这些变化中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），这是癌变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/超重前吸烟者患肺癌的风险很高。如果是真的，这个概念将为二甲双胍建立基础减轻肺癌发展的化学预防潜力，大部分人口中有很高的风险为癌症。为了检查二甲双胍的预防潜力，我们将进行一项小型II期试验高风险的肥胖/超重受试者确定长达数月的口服二甲双胍治疗会减少标记肺中的免疫抑制tregs并增强标记局部肺和全身性免疫监护活性（特定目标1）。确定特定于肥胖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个不同但互补的小鼠肺癌模型（特定目标2）。