Targeting Senescence to Mitigate Chemotherapy-induced Functional Decline

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PROJECT SUMMARY/ABSTRACT Advances in breast cancer treatment have resulted in significant survival gains. However, cure or control of breast cancer is not necessarily accompanied by full restoration of health. We have shown that as breast cancer survivors age, they experience accelerated chemotherapy-induced functional decline compared to age-matched survivors not treated with chemotherapy and women without cancer. Chemotherapy-induced functional decline results in poor quality of life, loss of independence, and premature death. The proposed study builds on our clinical work showing that cellular senescence is a central process linked to chemotherapy-induced functional decline. Cellular senescence is a fundamental aging process characterized by cell cycle arrest. Senescent cells accumulate in aging tissues and secrete proinflammatory factors that drive age-related functional decline. We have observed that, in breast cancer survivors, chemotherapy induces the persistent presence of high levels of circulating senescent cells, and that survivors with high senescent cell burden are more likely to experience chemotherapy-induced fatigue, neuropathy, and functional decline. These data provide rationale for targeting and reducing senescent cells to alleviate chemotherapy-induced functional decline. In non-cancer populations, senescent cells can be reduced through use of exercise or senolytics (drugs that ablate senescent cells). Recent preclinical studies also showed that senolytics combined with exercise yielded a greater reduction in senescent cells compared to either intervention alone. However, the ability of exercise and senolytics to reduce senescent cells and, ultimately, improve physical function in breast cancer survivors has not been tested. We hypothesize that targeting senescent cells via exercise and senolytics in breast cancer survivors will yield independent and additive effects to improve physical function and reduce markers of biological aging. To test this hypothesis, we propose a multicenter randomized placebo-controlled trial to test the efficacy of exercise and senolytic therapy (alone or combined) on physical function and markers of biological aging. We will randomize chemotherapy- treated postmenopausal breast cancer survivors with diminished function, assessed using the 6-minute walk distance [6MWD], to 1 of 4 arms: exercise + senolytic; exercise alone; senolytic alone; or control. The primary endpoint will be the change in 6MWD from baseline to end of treatment (Aim 1). Secondary endpoints include clinical and biological aging markers (Aim 2). We also will assess the safety and adherence of both interventions. In summary, as the number of breast cancer survivors rises dramatically (estimated to be >6 million by 2040), mitigating chemotherapy-induced functional decline is an urgent public health issue and a priority of the NIH. Successful completion of this trial will establish the efficacy of two targeted treatments to mitigate chemotherapy- induced functional decline. Given that senescence underlies many mid- and late-life chronic diseases, a safe treatment that improves physical function would have a major positive impact that extends far beyond oncology.