Targeting Senescence to Improve Frailty in Older Cancer Survivors

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PROJECT SUMMARY/ABSTRACT Cancer treatment accelerates aging. In people over 65, accelerated aging may have far greater consequences than in younger adults. One of the most important consequences of accelerated aging is frailty. Frailty is linked to loss of independence, falls, and death. Older cancer survivors develop frailty 2- to 4-fold more frequently and at an earlier age than age-matched controls. Mechanisms underlying frailty are just starting to be understood. One key aging mechanism driving frailty is cellular senescence – a state of terminal growth arrest. Senescence is the result of both natural aging and cancer treatment; radiation and chemotherapy both generate senescent cells (Sncs). In pilot biomarker studies, I observed that older survivors treated with chemotherapy (vs. no chemotherapy) have increased T-cell expression of P16INK4a (p16). p16 is an established marker of Sncs. I also observed that the percentage of T-cells expressing p16 correlates with clinical frailty. My findings are consistent with published studies linking p16 and frailty in childhood cancer survivors. Together, these data provide the premise for testing clinical interventions to target and eliminate Sncs in older survivors. Recently, drugs have been discovered that selectively eliminate Sncs – senolytics. One such senolytic is fisetin, a natural product flavonoid found in strawberries and other fruits. Because the amount of fisetin varies considerably in food, it is not possible to achieve sufficient levels for eliminating Sncs in a natural diet; however, fisetin is available as a dietary supplement. In preclinical models, fisetin reduces Sncs, inflammation, and frailty. As such, fisetin is now in >10 efficacy trials to alleviate age-related conditions in frail older adults and, so far, has had a favorable safety profile. No trial to date has tested fisetin in frail older cancer survivors. Here, I propose a randomized placebo- controlled trial with multi-modality biomarkers to test the preliminary efficacy, safety, and tolerability of fisetin to improve frailty and reduce Snc burden in frail older cancer survivors. Guided by a firm mechanistic rationale and preliminary data, my overall hypothesis is that fisetin is efficacious (improves frailty), safe, and tolerable in frail older survivors. To test my hypothesis, I will randomize cancer survivors age >65 with diminished gait speed (<0.8 m/s) to a 60-day course of fisetin vs. placebo. The primary endpoint is change in gait speed from day 1 to day 60. Secondary endpoints include changes in p16, inflammatory biomarkers, and frailty measures (Fried’s criteria, frailty index, grip strength). I also will assess safety and tolerability of fisetin and explore longer- term sustainability of efficacy, as measured by gait speed at 150 days. Promising results from this study will provide preliminary evidence for a large multi-center clinical trial (R01) to establish the efficacy of fisetin in older survivors. Additionally, by completing this study, I will fill a gap in my prior training in cancer clinical trials with training in geroscience research. This study will form the basis of my independent research program to develop geroprotective interventions to ensure that older cancer survivors live healthy lives well after cancer treatment.