Using Senolytics to Improve Physical Function in Older Breast Cancer Survivors

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PROJECT SUMMARY/ABSTRACT Breast cancer survivors experience steep and rapid declines in physical function within 3 to 12 months after cancer treatment. Cancer treatment impairs cardiovascular, neurologic, and musculoskeletal systems. Normally, these physiologic systems work in concert to enable physical function, and when one system is compromised, other systems compensate. However, when multiple physiologic systems are simultaneously compromised, patients develop impairments in physical function. Breast cancer survivors experience physical functional impairments at an earlier age and 2- to 4-fold more frequently than age-matched persons without cancer. In women over 65, functional decline may have far greater consequences than in younger adults; functional decline in older adults is linked to a loss of independence, disability, and death. No approved mitigating therapies are in place to treat or prevent functional decline. We hypothesize that cancer treatment-related functional decline can be alleviated by targeting fundamental aging processes, such as cellular senescence. Cellular senescence is a state of terminal growth arrest. Senescence results from both natural aging and chemotherapy. Senescent cells (Sncs) secrete proinflammatory factors (senescence-associated secretory phenotype, SASP) that cause tissue damage and age-related dysfunction. In mouse models, Sncs/SASP can be reduced by agents that selectively eliminate Sncs (senolytics). Senolytics alleviate frailty in mice and show promise in humans in multiple ongoing trials; senolytics reduce Snc burden in human fat tissue, decrease inflammation in older patients with diabetes, and reduce frailty in patients with pulmonary fibrosis. However, the ability of senolytics to reduce Sncs/SASP and, ultimately, improve physical function in older breast cancer survivors has not been tested. Our preliminary data provide evidence that older breast cancer survivors treated with chemotherapy (vs. no chemotherapy) have a higher systemic Snc burden (circulating Sncs/SASP markers) and that physical function and systemic Snc burden are linked. We hypothesize that targeting Sncs with senolytics will improve physical function and reduce systemic Snc burden in chemotherapy-treated older breast cancer survivors. We will test this hypothesis in a double-blind, randomized placebo-controlled trial of senolytic therapy vs. placebo in older (age >65) breast cancer survivors (n=44) who are 3 to 12 months post-chemotherapy completion and have diminished gait speed. Our specific aims are to determine the effects of senolytic therapy (vs. placebo) on physical function (Aim 1) and systemic Snc burden (Aim 2). This study will provide preliminary evidence for a large multi-center trial to establish the efficacy of senolytics in frail older breast cancer survivors. If successful, this would fill a crucial clinical need, as these women currently have no pharmacological options for the treatment or prevention of chemotherapy- induced functional decline. Moreover, since senescence underlies many of the mid and late-life chronic diseases, a safe senolytic that improves function would have a major positive impact that will extend far beyond oncology.