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Using Senolytics to Improve Physical Function in Older Breast Cancer Survivors

使用 Senolytics 改善老年乳腺癌幸存者的身体机能

基本信息

批准号：
10575707
负责人：
Mina S Sedrak
金额：
$ 6.6万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-22 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10575707
关键词：
Acceleration Address Adverse effects Age Age Years Aging Biological Markers Breast Cancer survivor CD3 Antigens CDKN2A gene Cancer Patient Cancer Survivor Cardiovascular system Cell Aging Cell secretion Cells Cessation of life Chronic Disease Clinical Clinical Trials Compensation Data Development Diabetes Mellitus Double-Blind Method Eating Elderly Exposure to Fatty acid glycerol esters Fibrosis Food Frail Elderly Fruit Functional disorder Gait speed Growth Growth Factor Half-Life Hand Strength Human Immune System Diseases Impairment Inflammation Inflammatory Interleukin-6 Intervention Link Longevity Malignant Neoplasms Measures Multi-Institutional Clinical Trial Multicenter Trials Mus Musculoskeletal System Neurologic Older Population Oncology Oral Patients Persons Phenotype Physical Function Physical Performance Physiological Placebos Population Prevention Process Pulmonary Fibrosis Quality of life Randomized Reducing Agents SF-36 Safety Serum Strawberries Survivors System T-Lymphocyte Testing Tissues Treatment-Related Cancer Urine Woman Work adherence rate age related cancer risk cancer therapy chemokine chemotherapy childhood cancer survivor clinical practice cytokine dietary supplements disability experience fisetin frailty functional decline functional disability functional improvement human tissue improved indexing instrumental activity of daily living middle age mouse model necrotic tissue older patient peripheral blood pharmacologic phenotypic biomarker pre-clinical prevent primary endpoint randomized placebo controlled trial secondary endpoint senescence side effect therapy design young adult

项目摘要

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.