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

• 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
• 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

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.

项目概要/摘要 乳腺癌幸存者在术后 3 至 12 个月内身体机能急剧急剧下降 癌症治疗。癌症治疗会损害心血管、神经和肌肉骨骼系统。通常情况下， 这些生理系统协同工作以实现身体功能，当一个系统受到损害时， 其他系统进行补偿。然而，当多个生理系统同时受到损害时， 患者出现身体机能障碍。乳腺癌幸存者经历身体机能 与年龄匹配的未患癌症的人相比，损伤发生的年龄较早，且发生频率高出 2 至 4 倍。在 65 岁以上的女性，功能衰退的后果可能比年轻人严重得多；功能衰退 对于老年人来说，这与丧失独立性、残疾和死亡有关。目前尚无批准的缓解疗法 治疗或预防功能衰退的地方。我们假设癌症治疗相关的功能衰退可以 通过针对基本的衰老过程（例如细胞衰老）来缓解。细胞衰老是 终末生长停滞状态。衰老是自然衰老和化疗的结果。衰老细胞 (Sncs) 分泌促炎因子（衰老相关分泌表型，SASP），导致组织 损伤和年龄相关的功能障碍。在小鼠模型中，Sncs/SASP 可以通过选择性地减少的药物来减少 消除 Sncs（senolytics）。 Senolytics 可缓解小鼠的虚弱，并在多个正在进行的人类研究中显示出希望 试验； senolytics 可减少人体脂肪组织中的 SNC 负担，减少老年糖尿病患者的炎症， 并减少肺纤维化患者的虚弱。然而，senolytics 减少 Sncs/SASP 的能力 最终，改善老年乳腺癌幸存者的身体机能尚未得到测试。我们的初步 数据提供证据表明，接受化疗（与未接受化疗）治疗的老年乳腺癌幸存者 更高的系统性 Snc 负担（循环 Sncs/SASP 标记）以及身体功能和系统性 Snc 负担是相连的。我们假设用 senolytics 靶向 Snc 将改善身体功能并减少 接受化疗的老年乳腺癌幸存者的全身性 Snc 负担。我们将在以下情况中检验这个假设： 在老年（年龄 >65 岁）乳房中进行 senolytic 疗法与安慰剂的双盲、随机安慰剂对照试验 化疗完成后 3 至 12 个月且步态速度减慢的癌症幸存者 (n=44)。 我们的具体目标是确定 senolytic 疗法（与安慰剂相比）对身体功能的影响（目标 1）和 系统性 Snc 负担（目标 2）。这项研究将为大型多中心试验提供初步证据，以建立 senolytics 对体弱的老年乳腺癌幸存者的功效。如果成功的话，这将满足一个重要的临床需求， 由于这些妇女目前没有治疗或预防化疗的药物选择- 诱发功能衰退。此外，由于衰老是许多中晚年慢性疾病的基础， 一种能够改善功能的安全的 senolytic 将会产生重大的积极影响，其影响将远远超出肿瘤学的范围。