Pioglitazone-Metformin Combination Treatment for High Risk Oral Preneoplasia

项目摘要/摘要 在治愈率停滞不前的情况下，对改善口腔和所有其他类型的策略的需求严重不足。 空气消化系统癌症的存活率。目前还没有强有力的化学预防药物或其他治疗方法来治疗高血压症 尽管进行了40年的临床试验研究，但仍存在口腔癌前病变或现场致癌的风险。高 口腔癌前病变(如白斑)是化学预防的标准靶点。 干预措施。第二类抗糖尿病药物，包括吡格列酮和二甲双胍，是很有希望的癌症药物 我们在NCI赞助的临床试验中使用的口腔癌预防药物。他们 在人体试验中有足够的安全性和中等的疗效，然而，单独使用可能还不够 推进大规模临床试验。这些代理具有不同的作用机制，每个 攻击口腔癌变中的不同事件。在这个项目中，我们建议进行12周的IIa阶段 联用吡格列酮-二甲双胍(15 mg-500 mg)治疗口腔癌患者的临床试验。 我们已经在明尼阿波利斯/明尼苏达州圣保罗组建了一个诊所联盟，为这项试验提供有效的收益。 我们将基于两种机制检查样本中的药效学终点 药物以及它们在治疗前后如何影响T细胞亚群。此外，我们还将分析 用RNA-Seq法检测治疗前后白斑标本及癌旁正常粘膜标本， 这将揭示药物的影响以及任何推定的“偏离目标”的影响。在完成时 通过这个项目，我们将更好地了解吡格列酮和二甲双胍对口腔的影响 致癌，以及早期临床试验，可以扩大到更大规模的随机试验 口腔癌或其他与烟草相关的癌症预防策略试验 恶性肿瘤。

Project Summary/Abstract With stagnant cure rates, there is a severe unmet need for strategies to improve oral and all other types of aerodigestive cancer survival. There are no robust chemoprevention drugs or other treatments for high risk oral precancerous conditions or field carcinogenesis despite 40 years of clinical trial research. High risk oral precancerous conditions (such as leukoplakia) represent a standard target for chemoprevention interventions. Type II anti-diabetic agents, including pioglitazone and metformin, are promising cancer prevention drugs for oral cavity preneoplasia that we have used in NCI sponsored clinical trials. They have adequate safety and moderate efficacy in human trials, however, individually are likely not sufficient to advance to large scale clinical trials. These agents have differing mechanisms of action which each attack different events in oral carcinogenesis. In this project, we propose to conduct a phase IIa 12 week clinical trial with combination BID pioglitazone-metformin (15mg-500mg) in oral preneoplasia patients. We have assembled a consortium of clinics in Minneapolis/St. Paul MN for efficient accrual to this trial. We will examine pharmacodynamic endpoints in specimens based on both the mechanisms of the agents and how they may affect T cell subsets before and after treatment. Further, we will also analyze leukoplakia specimens and adjacent normal mucosa specimens by RNA-Seq before and after treatment, which will shed light on effects of the drugs as well as any putative “off target” effects. At the completion of this project, we will have a better understanding of pioglitazone and metformin effects on oral carcinogenesis, as well as, an early stage clinical trial which could be expanded to larger randomized trials with a promising cancer prevention strategy for oral preneoplasia or other tobacco-associated malignancies.