A Phase II Randomized Placebo Controlled Trial of Epigallocatechin-3-Gallate (EGCG) on Physical Frailty and Tumor Necrosis Factor-alpha and Associated Immune Markers in Older Cancer Survivors

对于年龄较大(65岁以上)的癌症幸存者，尤其是黑人幸存者来说，虚弱是一个重大问题。老年癌症 与没有癌症病史的人相比，幸存者身体虚弱的风险高出46%。更老的 与年长的白人幸存者相比，黑人癌症幸存者虚弱的风险高出18%。没有标准 治疗老年癌症幸存者身体虚弱的方法已经存在。肿瘤坏死因子-α及其相关因子α 免疫标记物与老年癌症幸存者的身体虚弱有关。黑人个人已经提升了 肿瘤坏死因子-α和相关的免疫标记物，由于心理社会应激源与他们的种族小型化状态有关。 表没食子儿茶素没食子酸酯(EGCG)是一种有效的抗炎营养制剂，可降低肿瘤坏死因子-α及其相关的 免疫标记物和功能衰退的风险。EGCG是一种很有前途的干预措施，可以减少老年人的身体虚弱 年长的癌症幸存者。这一提议建立在我之前的工作基础上，该工作证明了癌症与 治疗、身体虚弱、脱氧核糖核酸、肿瘤坏死因子-α及相关免疫标志物。我的工作还表明， EGCG干预(含800 mg EGCG+250 mg VitC的胶囊)对老年癌症幸存者是安全和可行的。 这份提案提出了一项为期五年的免费研究和职业发展计划。对于这项提议，我将 对118例(58例黑人)老年癌症进行II期多中心双臂安慰剂对照随机临床试验 幸存者(65岁以上)，已完成癌症治疗(≤12个月)，至少处于虚弱前期(油炸虚弱 评分≥2)，并随机接受EGCG干预或安慰剂治疗12周。拟议研究的目的 1)评估EGCG干预对身体虚弱的初步疗效；2)评估 EGCG干预对肿瘤坏死因子-α及相关免疫标志物影响的初步研究 肿瘤坏死因子-α及其相关免疫标志物和DNA抗体与基线和干预后体格检查的关系 4)探讨EGCG干预对体质虚弱及肿瘤坏死因子-α及相关免疫功能的影响 老年黑人癌症幸存者与白人癌症幸存者的标志物。我还将完成以下新的培训目标：1) 培养设计、实施、分析和领导多中心随机临床试验的专业知识，重点是 营养食品作为对老年癌症幸存者虚弱的干预；2)接受表观遗传学培训 脆弱的生物标记物；3)获得改善临床试验参与者多样性的战略方面的专业知识，具有 重点关注老年黑人癌症幸存者。我的导师委员会包括国内和国际专家。 在营养和行为干预、老年肿瘤学、转化科学、生物统计学和多样性方面， 公平和包容。在Michelle Janelsins博士和Luke Peppone博士(主要导师)的指导下， Supriya Mohile(共同导师)，Charles Kamen博士、Paula Vertino博士、Michael Sohn博士和Canin女士(顾问)i 将获得我目前所不具备的基本技能。培训和研究计划将使我能够 实现我的长期目标，成为一名R01资助的老年肿瘤学翻译科学家 世卫组织开发和测试公平和机械驱动的癌症控制干预措施。

Frailty is a significant problem for older (age 65+) cancer survivors, particularly Black survivors. Older cancer survivors are at 46% greater risk of being physically frail compared to those without a history of cancer. Older Black cancer survivors are at 18% greater risk of being frail compared to older white survivors. No standard treatments for physical frailty in older cancer survivors exist. Tumor necrosis factor-α (TNF-α) and related immune markers are associated with physical frailty in older cancer survivors. Black individuals have elevated TNF-α and related immune markers due to the psychosocial stressors tied to their racially minoritized status. Epigallocatechin-3-gallate (EGCG) is a potent anti-inflammatory nutraceutical that reduces TNF-α and related immune markers and risk of functional decline. EGCG is a promising intervention to reduce physical frailty in older cancer survivors. This proposal builds upon my previous work demonstrating a relationship between cancer treatments, physical frailty, DNAmage, and TNF-α and related immune markers. My work also shows that an EGCG intervention (capsules with 800mg EGCG + 250mg VitC) is safe and feasible in older cancer survivors. This proposal presents a five-year complimentary research and career development plan. For this proposal I will conduct a Phase II, multicenter, 2-arm placebo controlled randomized clinical trial in 118 (58 Black) older cancer survivors (aged 65+), who have completed cancer treatment (≤12 months) and are at least pre-frail (Fried Frailty Score ≥2) and randomized to the EGCG intervention or placebo for 12 weeks. The aims of the proposed study are: 1) To evaluate the preliminary efficacy of the EGCG intervention on physical frailty; 2) To evaluate the preliminary efficacy of the EGCG intervention on TNF-α and related immune markers; 3) To explore if baseline TNF-α and related immune markers and DNAmage are associated with baseline and post-intervention physical frailty; and 4) To explore the efficacy of the EGCG intervention on physical frailty and TNF-α and related immune markers in older Black vs. white cancer survivors. I will also complete the following new training goals: 1) To develop expertise to design, conduct, analyze and lead multicenter randomized clinical trials focused on nutraceuticals as interventions for frailty in older cancer survivors; 2) To obtain training in epigenetics as a biomarker of frailty; 3) To gain expertise in strategies to improve the diversity of clinical trial participants, with an emphasis on older Black cancer survivors. My mentorship committee includes national and international experts in nutraceutical and behavioral interventions, geriatric oncology, translational science, biostatistics, and diversity, equity, and inclusion. Under the guidance of Drs. Michelle Janelsins and Luke Peppone (primary mentors), Dr. Supriya Mohile (co-mentor), and Drs. Charles Kamen, Paula Vertino, Michael Sohn and Ms. Canin (advisors) I will obtain essential skills that I currently do not possess. The training and research plan will position me to achieve my long-term goal to become an independently R01-funded translational scientist in geriatric oncology who develops and tests equitable and mechanistically driven, cancer control interventions.