Using Senolytics to Improve Physical Function in Older Breast Cancer Survivors

项目摘要/摘要 乳腺癌幸存者在术后3至12个月内身体机能急剧下降 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， 这些生理系统协同工作以实现物理功能，当一个系统受损时， 其他系统会进行补偿。然而，当多个生理系统同时受到损害时， 患者会出现身体功能障碍。乳腺癌幸存者体验身体功能 与年龄匹配的非癌症患者相比，年龄更早的患者出现损伤的几率高2至4倍。在……里面 65岁以上的女性，功能衰退的后果可能比年轻人严重得多； 在老年人中，与丧失独立性、残疾和死亡有关。目前还没有批准的缓解疗法 治疗或防止功能衰退的地方。我们假设癌症治疗相关的功能下降可以 通过针对基本的衰老过程，如细胞衰老来缓解。细胞衰老是一种 终末生长停滞状态。衰老是自然衰老和化疗共同作用的结果。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 消除SNCs(感觉剂)。感觉剂缓解小鼠的虚弱，并在人类身上显示出希望 试验：感觉剂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， 并降低肺纤维化患者的虚弱程度。然而，感觉剂降低SNCS/SASP的能力 而且，最终改善老年乳腺癌幸存者的身体功能还没有得到测试。我们的预赛 数据提供的证据表明，接受化疗(与不接受化疗)的老年乳腺癌幸存者 更高的全身SNC负荷(循环SNCs/SASP标志物)以及身体功能和全身SNC 负担是相互关联的。我们假设，使用感觉剂靶向SNCs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SNC负担。我们将在一个 老年(65岁)乳房过敏治疗与安慰剂对照的双盲随机安慰剂对照试验 癌症幸存者(n=44)，他们在化疗完成后3至12个月，步态速度减慢。 我们的具体目标是确定感觉神经溶解疗法(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)。这项研究将为建立一个大型多中心试验提供初步证据 老年乳腺癌患者中使用抗衰老药物的疗效。如果成功，这将满足一个关键的临床需求， 由于这些妇女目前没有治疗或预防化疗的药物选择- 诱发的功能衰退。此外，由于衰老是许多中老年慢性病的基础， 一种安全的改善功能的感觉剂将产生重大的积极影响，远远超出肿瘤学的范畴。

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.