Pioglitazone-Metformin Combination Treatment for High Risk Oral Preneoplasia

吡格列酮-二甲双胍联合治疗高危口腔癌前病变

• 批准号: 10390245
• 负责人: Frank G. Ondrey
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390245
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Aftercare; Animal Model; Antidiabetic Drugs; Apoptosis; Biguanides; CASP3 gene; CD8B1 gene; Cancer Patient; Carcinoma; Cell Line; Chemoprevention; Chemopreventive Agent; Clinic; Clinical; Clinical Chemoprevention; Clinical Trials; Data; Development; Dose; Drug Combinations; Epigallocatechin Gallate; Event; FRAP1 gene; Foxes; Funding; Gene Expression; Head and Neck Cancer; Healthcare; Histologic; Human; Individual; Inflammation; Inflammatory; Intervention; Lesion; Leukoplakia; Light; Link; Malignant Neoplasms; Metformin; Mucous Membrane; Nuclear; Oral; Oral Leukoplakia; Oral cavity; PPAR gamma; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Physiological; Pioglitazone; Population; Precancerous Conditions; Prevention strategy; Prevention trial; Prostaglandin-Endoperoxide Synthase; Recurrence; Research; Risk; S-Phase Fraction; Safety; Series; Signal Transduction; Specimen; Stains; T-Lymphocyte Subsets; Testing; Thiazolidinediones; Tobacco; Tobacco-Associated Carcinogen; Toxic effect; Tretinoin; Work; antagonist; anti-cancer; base; cancer prevention; cancer survival; carcinogenesis; cohort; experience; high risk; improved; malignant mouth neoplasm; non-diabetic; oral cancer prevention; oral carcinogenesis; oral premalignancy; pharmacodynamic biomarker; premalignant; prevent; programmed cell death ligand 1; programmed cell death protein 1; randomized trial; response; stemness; transcriptome sequencing

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.

项目概要/摘要 由于治愈率停滞不前，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 没有有效的化学预防药物或其他治疗方法来治疗高呼吸消化癌症。 尽管经过 40 年的临床试验研究，仍存在口腔癌前病变或现场致癌的风险 高。 口腔癌前病变风险（如白斑）是化学预防的标准目标 II 型抗糖尿病药物，包括吡格列酮和二甲双胍，是有前途的癌症药物。 我们已在 NCI 赞助的临床试验中使用了口腔癌前病变的预防药物。 在人体试验中具有足够的安全性和中等功效，但是，单独来看可能还不够 为了推进大规模临床试验，这些药物具有不同的作用机制。 在这个项目中，我们建议进行为期 12 周的 IIa 期研究。 在口腔癌前期患者中联合 BID 吡格列酮-二甲双胍（15mg-500mg）进行的临床试验。 我们在明尼苏达州明尼阿波利斯/圣保罗组建了一个诊所联盟，以有效地开展这项试验。 我们将根据两种机制检查样本中的药效学终点 此外，我们还将分析这些药物在治疗前后如何影响 T 细胞亚群。 对治疗前后的白斑标本和邻近正常粘膜标本进行RNA-Seq分析， 这将揭示药物的作用以及完成时任何假定的“脱靶”作用。 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 致癌作用，以及早期临床试验，可以扩展到更大的随机试验 针对口腔癌前期或其他与烟草相关的癌症预防策略的试验 恶性肿瘤。