Pioglitazone-Metformin Combination Treatment for High Risk Oral Preneoplasia

项目总结/摘要 随着治愈率的停滞，对改善口腔和所有其他类型的策略的需求严重未得到满足。 呼吸消化道癌症存活率的百分比。目前还没有强有力的化学预防药物或其他治疗高血压的方法。 尽管有40年的临床试验研究，高 口腔癌前病变（如白斑病）的风险代表了化学预防的标准目标 干预措施。II型抗糖尿病药物，包括吡格列酮和二甲双胍，是有希望的癌症 我们在NCI赞助的临床试验中使用的口腔癌前病变预防药物。他们 在人体试验中具有足够的安全性和适度的疗效，然而，单独使用可能不够 进行大规模的临床试验这些药物具有不同的作用机制， 攻击口腔癌发生的不同事件。在这个项目中，我们建议进行第二阶段12周 在口腔癌前病变患者中联合BID吡格列酮-二甲双胍（15 mg-500 mg）的临床试验。 我们在明尼阿波利斯/圣保罗MN组建了一个诊所联盟，以有效地增加本试验的费用。 我们将根据两种机制检查标本中的药效学终点， 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 通过RNA-Seq对治疗前后的白斑标本和邻近正常粘膜标本进行分析， 这将阐明药物的作用以及任何假定的“脱靶”作用。完成时 通过本项目，我们将更好地了解吡格列酮和二甲双胍对口服给药的影响。 致癌作用，以及早期临床试验，可以扩大到更大的随机 对口腔癌前病变或其他烟草相关疾病的有希望的癌症预防策略的试验 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.