The Impact of Obesity on Radiotherapy Anti-Tumor Effects
肥胖对放射治疗抗肿瘤效果的影响
基本信息
- 批准号:10367904
- 负责人:
- 金额:$ 53.25万
- 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:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive TransferAffectApoptoticBCL2 geneBiologicalCancer ModelCancer PatientCell ProliferationClinicalClinical DataClinical ResearchDataDoseEffectivenessFunctional disorderGenesHormonal ChangeHormonesImmuneImmune System DiseasesImmune responseImmune systemImplantIn VitroInflammationKnowledgeLeadLeptinLinkMalignant NeoplasmsMediatingMetabolicModelingMusObese MiceObesityOutcomePatientsPhenotypePreventable cancer causeProductionPublishingRadiation PhysicsRadiation therapyRecurrenceRegulationResistanceSignal TransductionSmokingT-LymphocyteTestingThinnessToxic effectTumor BiologyTumor ImmunityUnited StatesUp-Regulationadipokinesantitumor effectbasecancer cellcancer recurrencecancer survivalcancer therapydiet-induced obesityexhaustionimmunosuppressedimprovedimproved outcomein vivomouse modelobese patientspandemic diseasepersonalized medicinepre-clinicalpreclinical studyradiation deliveryradiation resistanceradiation responseresponsesurvivintreatment strategytumortumor growthtumor metabolismtumor microenvironment
项目摘要
Abstract
Obesity has reached pandemic levels in the United States and will soon surpass smoking as the number one
cause of preventable cancer. Understanding how to best treat obese cancer patients is a critical unmet need.
Preclinical data from our lab show increased resistance to radiotherapy (RT) in obese mouse cancer models.
Clinical data demonstrates that obese cancer patients are more resistant to radiotherapy and have higher rates
of recurrence. Very few mechanistic studies have addressed these findings and understanding the mechanisms
governing radiotherapy resistance in obesity is a gap in knowledge. Our prior studies demonstrate that obesity,
likely via leptin, a hormone elevated in obesity, can alter the proliferation / survival of cancers and also change
the immune response to cancer, leading to changes in the efficacy of cancer therapies. Obesity suppresses
adaptive T cell anti-tumor immunity and the immune system strongly contributes to the anti-tumor effects of RT,
providing a potential mechanism linking obesity and RT resistance. Obesity related adipokines can induce anti-
apoptotic factors and RT resistance. Based on these observations we hypothesize that obesity induces
resistance to RT directly by increasing anti-apoptotic factors in cancer cells and indirectly by inducing
suppression of adaptive anti-tumor immunity in the tumor microenvironment (TME). We also hypothesize
that leptin signaling may mediate the RT resistance observed in obesity. This proposal seeks to test these
hypotheses and further delineate mechanistic links between obesity and RT resistance using three specific aims.
We will use lean and diet induced obesity (DIO) mouse models, immunosuppressed mice (Rag2 -/-), as well as
mice that lack functional leptin signaling (db/db) or lack endogenous leptin (ob/ob) to evaluate how obesity and
leptin signaling within cancer cells and within the tumor microenvironment influence resistance to radiotherapy.
In specific aim 1 we will examine the effects of obesity on the efficacy of RT and also examine the direct effects
on the tumor as well as the indirect effects via T cell dysfunction or other immune mechanisms. In specific aim
2 we will investigate leptin signaling as an underlying mechanism whereby obesity induces resistance to RT both
through direct effects on cancer cell proliferation / survival and also through indirect effects on the TME. In
specific aim 3 we will test an exploratory hypothesis that ablative RT is able to improve RT efficacy in obesity by
overcoming the mechanisms of obesity induced direct (but not immune related indirect) RT resistance.
Understanding how obesity impacts RT response and developing strategies to address these issues will
improve outcomes in obese patients treated with RT. Thus, these studies can have a major clinical impact
and represent a step towards personalized medicine by tailoring RT treatment strategies to a patient's metabolic
parameters.
摘要
肥胖症在美国已经达到了流行病的程度,很快就会超过吸烟成为头号杀手
可预防的癌症的原因。了解如何最好地治疗肥胖癌症患者是一个关键的未满足的需求。
我们实验室的临床前数据显示,肥胖小鼠癌症模型对放疗(RT)的抵抗力增加。
临床数据表明,肥胖的癌症患者对放射治疗更有抵抗力,
的复发。很少有机制研究已经解决了这些发现和理解的机制
在肥胖症中控制放射治疗抵抗是一个知识空白。我们之前的研究表明肥胖,
可能通过瘦素,一种在肥胖症中升高的激素,可以改变癌症的增殖/存活,
对癌症的免疫反应,导致癌症治疗效果的变化。肥胖抑制
适应性T细胞抗肿瘤免疫和免疫系统对RT的抗肿瘤作用有很大贡献,
提供了一种将肥胖和RT抗性联系起来的潜在机制。肥胖相关脂肪因子可诱导抗-
凋亡因子和RT抗性。基于这些观察,我们假设肥胖诱导
直接通过增加癌细胞中的抗凋亡因子和间接通过诱导
抑制肿瘤微环境(TME)中的适应性抗肿瘤免疫。我们还假设
瘦素信号可能介导肥胖中观察到的RT抗性。这项建议旨在测试这些
假设和进一步描绘肥胖和RT抵抗之间的机械联系,使用三个具体的目标。
我们将使用瘦型和饮食诱导的肥胖(DIO)小鼠模型、免疫抑制小鼠(Rag 2-/-),以及
缺乏功能性瘦素信号传导(db/db)或缺乏内源性瘦素(ob/ob)的小鼠,以评估肥胖和
癌细胞内和肿瘤微环境内的瘦素信号传导影响对放射疗法的抗性。
在具体目标1中,我们将检查肥胖对RT疗效的影响,并检查直接影响
以及通过T细胞功能障碍或其他免疫机制的间接作用。具体目标
我们将研究瘦素信号传导作为肥胖诱导RT抵抗的潜在机制,
通过对癌细胞增殖/存活的直接影响以及通过对TME的间接影响。在
具体目标3:我们将检验一个探索性假设,即消融性RT能够通过以下方式改善肥胖患者的RT疗效:
克服肥胖诱导的直接(而非免疫相关的间接)RT抗性的机制。
了解肥胖如何影响RT反应,并制定解决这些问题的策略,
因此,这些研究可能具有重大临床影响
并通过根据患者的代谢情况定制RT治疗策略,
参数
项目成果
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Arta Monir Monjazeb其他文献
Arta Monir Monjazeb的其他文献
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{{ truncateString('Arta Monir Monjazeb', 18)}}的其他基金
The Impact of Obesity on Radiotherapy Anti-Tumor Effects
肥胖对放射治疗抗肿瘤效果的影响
- 批准号:
10578820 - 财政年份:2022
- 资助金额:
$ 53.25万 - 项目类别:
The Impact of Obesity on Radiotherapy Anti-Tumor Effects
肥胖对放射治疗抗肿瘤效果的影响
- 批准号:
10738022 - 财政年份:2022
- 资助金额:
$ 53.25万 - 项目类别:
The impact of obesity on radiotherapy anti-tumor effects
肥胖对放疗抗肿瘤效果的影响
- 批准号:
10599593 - 财政年份:2022
- 资助金额:
$ 53.25万 - 项目类别:
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