Targeting Senescence to Mitigate Chemotherapy-induced Functional Decline

靶向衰老以减轻化疗引起的功能衰退

基本信息

  • 批准号:
    10638071
  • 负责人:
  • 金额:
    $ 70.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2028-08-31
  • 项目状态:
    未结题

项目摘要

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.
项目概要/摘要 乳腺癌治疗的进步显着提高了生存率。然而,治愈或控制 乳腺癌并不一定伴随着健康的完全恢复。我们已经证明,随着乳腺癌 幸存者随着年龄的增长,与年龄匹配的人相比,他们会经历化疗引起的功能衰退加速 未接受化疗的幸存者和未患癌症的女性。化疗引起的功能衰退 导致生活质量差、丧失独立性和过早死亡。拟议的研究建立在我们的基础上 临床工作表明,细胞衰老是与化疗诱导的功能性功能障碍相关的一个核心过程。 衰退。细胞衰老是以细胞周期停滞为特征的基本衰老过程。衰老细胞 在衰老组织中积累并分泌促炎因子,导致与年龄相关的功能衰退。我们 观察到,在乳腺癌幸存者中,化疗会导致高水平的持续存在 循环衰老细胞,并且衰老细胞负担高的幸存者更有可能经历 化疗引起的疲劳、神经病变和功能衰退。这些数据为目标定位提供了依据 减少衰老细胞以减轻化疗引起的功能衰退。在非癌症人群中, 可以通过运动或senolytics(消除衰老细胞的药物)来减少衰老细胞。最近的 临床前研究还表明,senolytics 与运动相结合可以更大程度地减少衰老 细胞与单独干预相比。然而,运动和抗衰老药物可以减少衰老 细胞并最终改善乳腺癌幸存者的身体机能尚未经过测试。我们假设 通过运动和衰老药物针对乳腺癌幸存者的衰老细胞将产生独立和 改善身体机能并减少生物衰老标志的附加效应。为了检验这个假设,我们 提出一项多中心随机安慰剂对照试验来测试运动和抗衰老疗法的功效 (单独或组合)身体功能和生物衰老标志。我们将随机进行化疗- 使用 6 分钟步行评估治疗后功能减退的绝经后乳腺癌幸存者 距离 [6MWD],到 4 个臂中的 1 个:运动 + senolytic;独自锻炼;单独使用抗衰老剂;或控制。初级 终点是 6MWD 从基线到治疗结束的变化(目标 1)。次要终点包括 临床和生物衰老标志物(目标 2)。我们还将评估这两种干预措施的安全性和依从性。 总之,随着乳腺癌幸存者人数急剧增加(预计到 2040 年将超过 600 万), 减轻化疗引起的功能衰退是一个紧迫的公共卫生问题,也是 NIH 的首要任务。 该试验的成功完成将确定两种靶向治疗减轻化疗的功效- 诱发功能衰退。鉴于衰老是许多中晚年慢性疾病的基础,因此一种安全的治疗方法 改善身体机能的治疗将产生远远超出肿瘤学范围的重大积极影响。

项目成果

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Mina S Sedrak其他文献

Mina S Sedrak的其他文献

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{{ truncateString('Mina S Sedrak', 18)}}的其他基金

Targeting Senescence to Improve Frailty in Older Cancer Survivors
瞄准衰老以改善老年癌症幸存者的虚弱状况
  • 批准号:
    10866293
  • 财政年份:
    2023
  • 资助金额:
    $ 70.06万
  • 项目类别:
Targeting Senescence to Improve Frailty in Older Cancer Survivors
瞄准衰老以改善老年癌症幸存者的虚弱状况
  • 批准号:
    10514069
  • 财政年份:
    2022
  • 资助金额:
    $ 70.06万
  • 项目类别:
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:
    10880127
  • 财政年份:
    2022
  • 资助金额:
    $ 70.06万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 70.06万
  • 项目类别:
Improving Clinical Trial Participation of Older Adults with Cancer
提高老年癌症患者的临床试验参与度
  • 批准号:
    9812036
  • 财政年份:
    2019
  • 资助金额:
    $ 70.06万
  • 项目类别:
Improving Clinical Trial Participation of Older Adults with Cancer
提高老年癌症患者的临床试验参与度
  • 批准号:
    9982167
  • 财政年份:
    2019
  • 资助金额:
    $ 70.06万
  • 项目类别:

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