IND: 113343 Quercetin Chemoprevention for Squamous Cell Carcinoma in Patients with Fanconi Anemia

IND：113343 槲皮素化学预防范可尼贫血患者的鳞状细胞癌

• 批准号: 10652481
• 负责人: PARINDA A. MEHTA
• 金额: $ 43.62万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10652481
• 关键词: IND; 113343; Quercetin; Chemoprevention; Squamous

Project Summary/Abstract Current therapies for children with Fanconi anemia (FA) and squamous cell carcinoma (SCC) (commonly seen in older and/or post-transplant (HCT) patients) include radiation and chemotherapy, which are associated with significant morbidity and mortality. Thus, there is clearly a need for a novel approach that has fewer and less severe side effects. Animal and humans studies indicate that reactive-oxygen species (ROS) play a key role in the pathogenesis of SCC in these children. Our long-term goal is to interdict the development of SCC in post- HCT patients with FA. Our overall objective, is to develop, at a phase 2 level, a novel approach to treatment of SCC in FA that is safer and more efficacious compared to existing approaches. It is our central hypothesis that treatment with the ROS scavenger quercetin will modulate systemic and salivary/mucosal ROS levels in patients with FA, which in turn will ameliorate development of SCC. In non-FA setting, Quercetin is shown to prevent or modulate SCC formation in mice. Our own preliminary data show that quercetin reverses the ill effects of ROS on FA SCC tumor cells and kills them in a dose dependent fashion. Buccal brushing samples from children with FA showed decreased number of micronuclei (marker of DNA damage/tumor formation) after treatment with oral Quercetin. These data strongly suggest that quercetin will be beneficial in decreasing ongoing DNA damage and preventing SCC in children with FA. Our multidisciplinary team is well prepared and will have access to sufficient number of patients. Quercetin is a naturally occurring anti-oxidant, and was well tolerated and able to achieve biologically relevant in patients with FA in our recent Phase 1 pilot study. In this Phase 2 study, we will test the above hypothesis with the following specific aims: 1.Determine the efficacy of Quercetin in reducing buccal micronuclei (a surrogate marker of DNA damage and susceptibility to SCC due to genomic instability) in post-HCT patients with FA. Thirty eight post-HCT FA patients will receive oral quercetin for a total of 24 months and be followed with assessment of serial buccal micronuclei. 2. Measure the impact of Quercetin therapy on additional potential surrogate markers Peripheral blood ROS and salivary ROS, Salivary total antioxidant capacity, Biomarkers measured via Exhaled Breath Condensate (EBC) - anti-oxidants, aldehydes etc., Oral microbiome, and Skin elasticity. The impact of quercetin on reduction of buccal micronuclei and blood as well as salivary ROS will serve as surrogate markers for prevention of SCC. Additionally, effect on improving salivary total antioxidant capacity, oral microbiome and skin elasticity will be quantified. Expected outcomes include the demonstration that long-term quercetin therapy decreases buccal micronuclei (a surrogate marker of DNA damage and susceptibility to squamous cell carcinoma due to genomic in-stability) in post-HCT patients with FA. Expected positive impact is that success will lead to a new first line therapy for post-HCT FA patients, obviating the need for radiation and chemotherapy. The proposed research is innovative, as it incorporates micronuclei as a novel therapeutic target, in a feasible approach for SCC prevention with a unique intervention of oral quercetin.

项目总结/摘要 目前治疗范可尼贫血（FA）和鳞状细胞癌（SCC）（常见于 在老年和/或移植后（HCT）患者中）包括放疗和化疗，这与 严重的发病率和死亡率。因此，显然需要一种新颖的方法， 严重的副作用动物和人类的研究表明，活性氧（ROS）在 这些儿童SCC的发病机制。我们的长期目标是在术后阻断SCC的发展， HCT伴FA患者。我们的总体目标是在2期水平上开发一种新的治疗方法， 与现有方法相比，FA中的SCC更安全、更有效。我们的核心假设是， 用ROS清除剂槲皮素治疗将调节患者的全身和唾液/粘膜ROS水平 这反过来又会改善SCC的发展。在非FA设置中，槲皮素被证明可以预防或 调节小鼠SCC形成。我们自己的初步数据表明，槲皮素逆转活性氧的不良影响 并以剂量依赖性方式杀死它们。儿童口腔刷牙样本 FA显示经口给药后微核（DNA损伤/肿瘤形成的标志物）数量减少 槲皮素这些数据强烈表明，槲皮素将有利于减少正在进行的DNA损伤， 预防FA患儿的SCC。我们的多学科团队已做好充分准备， 患者数量。槲皮素是一种天然存在的抗氧化剂，耐受性良好， 在我们最近的1期初步研究中，FA患者的生物学相关性。在这项2期研究中，我们将测试 以上假设具有以下具体目的：1.确定槲皮素在减少口腔粘膜中的 微核（由于基因组不稳定性导致的DNA损伤和SCC易感性的替代标志物）， HCT后FA患者。38名HCT后FA患者将接受口服槲皮素治疗，共24个月 并随后进行连续口腔微核评估。2.测量槲皮素治疗对 其他潜在的替代标志物外周血ROS和唾液ROS，唾液总抗氧化剂 通过呼出的呼吸冷凝物（EBC）测量的生物标志物-抗氧化剂，醛等，口服 微生物组和皮肤弹性。槲皮素对小鼠口腔微核率和血液微核率的影响 唾液ROS将作为预防SCC的替代标记物。此外，改善唾液分泌的效果 将量化总抗氧化能力、口腔微生物组和皮肤弹性。预期成果包括： 证明长期槲皮素治疗可减少口腔微核（DNA的替代标记物 损伤和由于基因组不稳定而对鳞状细胞癌的易感性）。 预期的积极影响是，成功将为HCT后FA患者带来新的一线治疗， 需要放疗和化疗。拟议的研究是创新的，因为它结合了微核， 一种新的治疗靶点，在一种可行的方法中，通过口服槲皮素的独特干预来预防SCC。