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: 10425219
• 负责人: PARINDA A. MEHTA
• 金额: $ 43.38万
• 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/10425219
• 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.

项目摘要/摘要 目前治疗儿童Fanconi贫血(FA)和鳞状细胞癌(SCC)(常见)的方法 老年和/或移植后(HCT)患者)包括放射和化疗，这与 严重的发病率和死亡率。因此，显然需要一种新的方法，使其具有越来越少的 严重的副作用。动物和人类的研究表明，活性氧物种(ROS)在 这些儿童鳞状细胞癌的发病机制。我们的长期目标是阻止鳞状细胞癌在后 伴有FA的HCT患者。我们的总体目标是在第二阶段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。我们的中心假设是 使用ROS清除剂槲皮素治疗将调节患者全身和唾液/粘膜的ROS水平 与FA，这反过来将改善SCC的发展。在非FA设置中，Quercetin显示为防止或 调节小鼠鳞状细胞癌形成。我们自己的初步数据显示，槲皮素可以逆转ROS的不良影响 作用于FA SCC肿瘤细胞，并以剂量依赖的方式杀死它们。牙周炎儿童的口腔刷牙样本 FA显示口服治疗后微核(DNA损伤/肿瘤形成的标志)减少 栎素。这些数据有力地表明，栎素将有益于减少正在进行的DNA损伤和 预防FA儿童的鳞癌。我们的多学科团队做好了充分的准备，将有机会获得足够的 病人数量。槲皮素是一种天然的抗氧化剂，耐受性良好，能够达到 在我们最近的第一阶段先导性研究中，FA患者具有生物学相关性。在此第二阶段研究中，我们将测试 以上假设有以下具体目的：1.测定槲皮素的降颊效果 微核(DNA损伤和基因组不稳定引起的鳞癌易感性的替代标记) HCT后FA患者。38名HCT术后FA患者将接受口服槲皮素治疗，共24个月 并进行口腔微核系列检测。2.测量栎素治疗对患者的影响 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 容量，通过呼出的呼吸冷凝液(EBC)测量的生物标志物-抗氧化剂、醛等，口服 微生物群，和皮肤弹性。槲皮素对小鼠口腔微核和血液中微核含量的影响 唾液ROS可作为预防鳞癌的替代标志物。此外，对改善唾液的作用 总抗氧化能力、口腔微生物群和皮肤弹性将被量化。预期结果包括 证明长期服用栎素可降低口腔微核(DNA的替代标记物 HCT后FA患者的损害和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，避免 放疗和化疗的必要性。这项拟议的研究具有创新性，因为它将微核作为 一个新的治疗靶点，在一种可行的方法预防鳞状细胞癌与独特的干预口服槲皮素。