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.

PROJECT NARRATIVE Older cancer survivors are at 46% greater risk of being physically frail compared to those without a history of cancer and older Black cancer survivors are at 18% greater risk of being frail compared to older white survivors. An Epigallocatechin-3-gallate (EGCG) intervention is a safe, feasible, and promising intervention to reduce physical frailty in older cancer survivors. The proposed study will evaluate the preliminary effect of the EGCG intervention on physical frailty and Tumor Necrosis Factor-alpha (TNF-α) and related immune markers, explore if baseline TNF-α and related immune markers and DNA methylation age are associated with physical frailty, and explore the effect of the EGCG intervention on physical frailty and TNF-α and related immune markers in older Black compared to white cancer survivors.