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:
- 金额:$ 6.6万
- 依托单位:
- 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:
- 关键词:AccelerationAddressAdverse effectsAgeAge YearsAgingBiological MarkersBreast Cancer survivorCD3 AntigensCDKN2A geneCancer PatientCancer SurvivorCardiovascular systemCell AgingCell secretionCellsCessation of lifeChronic DiseaseClinicalClinical TrialsCompensationDataDevelopmentDiabetes MellitusDouble-Blind MethodEatingElderlyExposure toFatty acid glycerol estersFibrosisFoodFrail ElderlyFruitFunctional disorderGait speedGrowthGrowth FactorHalf-LifeHand StrengthHumanImmune System DiseasesImpairmentInflammationInflammatoryInterleukin-6InterventionLinkLongevityMalignant NeoplasmsMeasuresMulti-Institutional Clinical TrialMulticenter TrialsMusMusculoskeletal SystemNeurologicOlder PopulationOncologyOralPatientsPersonsPhenotypePhysical FunctionPhysical PerformancePhysiologicalPlacebosPopulationPreventionProcessPulmonary FibrosisQuality of lifeRandomizedReducing AgentsSF-36SafetySerumStrawberriesSurvivorsSystemT-LymphocyteTestingTissuesTreatment-Related CancerUrineWomanWorkadherence rateage relatedcancer riskcancer therapychemokinechemotherapychildhood cancer survivorclinical practicecytokinedietary supplementsdisabilityexperiencefisetinfrailtyfunctional declinefunctional disabilityfunctional improvementhuman tissueimprovedindexinginstrumental activity of daily livingmiddle agemouse modelnecrotic tissueolder patientperipheral bloodpharmacologicphenotypic biomarkerpre-clinicalpreventprimary endpointrandomized placebo controlled trialsecondary endpointsenescenceside effecttherapy designyoung 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.
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.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
$ 6.6万 - 项目类别:
Targeting Senescence to Mitigate Chemotherapy-induced Functional Decline
靶向衰老以减轻化疗引起的功能衰退
- 批准号:
10638071 - 财政年份:2023
- 资助金额:
$ 6.6万 - 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:
$ 6.6万 - 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:
$ 6.6万 - 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:
$ 6.6万 - 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:
$ 6.6万 - 项目类别:
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