Metabolic implications of radiation response in oligometastatic prostate cancer.
Metabolic implications of radiation response in oligometastatic prostate cancer.
批准号:
10676868
负责人:
Nicole L Simone
金额:
$27.44万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-08-04 至 2027-07-31
关键词:
AffectBiologyCaloric RestrictionCancer ControlCancer EtiologyCancer PatientClinicalClinical TrialsCoupledDNA Sequence AlterationDataDiagnosticDiet ModificationDiseaseDown-RegulationDrug usageEnvironmentEragrostisEvaluationFutureGenomicsGrowthHormonesInterventionLaboratoriesLeadMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of prostateMetabolicMetabolic PathwayMetabolic syndromeMetabolismMolecularMolecular ProfilingMusNeoplasm MetastasisNutritionalNutritional RequirementsObesityOncogenesOutcomePathway AnalysisPathway interactionsPatient-Focused OutcomesPatientsPositron-Emission TomographyPre-Clinical ModelProstatectomyProstatic NeoplasmsRaceRadiationRadiation OncologyRadiation therapyRegulatory T-LymphocyteRoleSerumTestingTherapeuticTherapeutic UsesTimeTumor ImmunityVisionc-myc Genescancer cellcancer survivalcancer therapychemotherapydisorder controleffector T cellfirst-in-humanglucogenesisimaging modalityimmune functionimprovedimproved outcomelipid biosynthesismetabolic profilemetabolomicsmolecular drug targetneoplastic cellpatient populationpatient subsetspersonalized approachprecision medicineprecision nutritionpreventprogramsprostate cancer cellprostate cancer modelradiation responseresponsesocial health determinantssocial influencestressorsystemic inflammatory responsetargeted treatmenttreatment optimizationtreatment responsetrial designtumortumor metabolismtumor microenvironmenttumor progression
中文摘要
癌细胞的代谢改变被认为是恶性转化的标志,并已被
被证明是转移扩散的部分原因,因为它在将转移锚定到
肿瘤微环境。因此,了解辐射反应与肿瘤和患者的关系
新陈代谢将是确定需要代谢干预的患者亚组的关键
优化前列腺癌少转移疾病患者的预后。现已发现,
前列腺癌的基因组驱动因素可导致肿瘤及其周围组织的代谢重新编程
微环境创造具有特定营养需求的利基环境,丰富关键的生存条件
小路。例如,当激活脂肪代谢时,c-myc驱动的肿瘤生长最好,而AKT
激活的肿瘤通过激活经典的糖酵解开关而茁壮成长。了解如何具体重新编程
肿瘤优先用于创造良好生长环境的代谢途径可能
减少前列腺癌肿瘤进展、转移,增加对放射治疗的敏感性。
初步数据表明,利用饮食变化来代谢改变肿瘤及其代谢的能力
减少肿瘤进展和转移的环境。再加上辐射,我们的数据显示
热量限制通过增加效应T细胞和减少T调节来增强抗肿瘤免疫
细胞。前列腺癌患者前列腺癌切除术前限制热量的首例人体临床试验
患者通过c-myc和AKT的下调证实了这一点,代谢组评估揭示了这一点
脂肪生成和糖类生成减少。血清图谱通径分析表明,卡路里
限制措施最显着的效果是在上调抗肿瘤免疫方面。因为已经确定了
MYC驱动的癌症改变了Treg反应,AKT驱动的肿瘤改变了Tef谱,我们
假设精确营养可以被用来重新编程由
驱动癌基因通过以下方式改善放射反应和少转移前列腺癌预后
影响患者抗肿瘤免疫的积极变化。为了研究这一点,我们首先要确定
增强型SABR对低转移性前列腺癌的放射反应
生糖代谢谱。接下来,我们将使用临床前模型来确定代谢的影响
前列腺癌细胞和肿瘤微环境重编程对辐射诱导的抗肿瘤免疫的影响
以及对转移潜能的影响。最后,我们将确定社会决定因素对
包括种族在内的健康对前列腺癌少转移患者治疗后的辐射反应的影响
伴随着辐射。我们多样化的患者群体将使我们能够了解患者的贡献
影响辐射结果的压力源。该提案的结果将允许未来的试验设计使用精确度
通过辐射对患者进行代谢影响并改善预后的方法。
英文摘要
Altered metabolism in cancer cells is recognized as a hallmark of malignant transformation and has been
shown to be in part responsible for metastatic spread due to its role in the fate of anchoring metastases to the
tumor microenvironment. Therefore, understanding radiation response as it relates to the tumor and patient
metabolism will be key in determining the subset of patients who will require metabolic interventions to
optimize outcomes for prostate cancer patients with oligometastatic disease. It has been discovered that
genomic drivers of prostate cancer can cause metabolic reprogramming of both the tumor and its
microenvironment to create niches with specific nutrient requirements that enrich for key pro-survival
pathways. For example, that c-myc driven tumors thrive best when activating lipogenic metabolism while akt
activated tumors thrive by activating the classic glycolytic switch. Understanding how to specifically reprogram
the metabolic pathways that the tumor is preferentially using to create a favorable growth environment, could
decrease prostate cancer tumor progression, metastases and increase sensitivity to radiation therapy.
Preliminary data demonstrates the ability to use dietary alterations to metabolically alter the tumor and its
environment to decrease tumor progression and metastases. Coupled with radiation, our data shows that
caloric restriction increases anti-tumor immunity by increasing effector T-cells and decreasing T-regulatory
cells. A first in-human pilot clinical trial using caloric restriction before prostatectomy for prostate cancer
patients has confirmed this with a downregulation of c-myc and akt with metabolomic evaluation revealing
decreased lipogenesis and glucogenesis. Pathway analysis of serum profiling demonstrates that caloric
restrictions most significant effect was in upregulating anti-tumor immunity. Since it has been established that
myc driven cancers have altered Treg response and akt driven tumors have altered Teff profiles, we
hypothesize that precision nutrition can be used to reprogram the metabolic alterations induced by the
driver oncogenes to improve radiation response and oligometastatic prostate cancer outcomes by
affecting a positive change in the patients’ anti-tumor immunity. To study this, we will first determine
radiation response of consolidative SABR on oligometastatic prostate cancers that have lipogenic versus
glucogenic metabolic profiles. Next, we will use preclinical models to determine effects of metabolic
reprogramming of prostate cancer cells and tumor microenvironment on radiation-induced anti-tumor immunity
and consequences on metastatic potential. Finally, we will determine the influence of social determinants of
health, including race, on radiation response in prostate cancer patients with oligometastatic disease treated
with radiation. Our diverse patient population will allow for the understanding on the contribution of patient
stressors on radiation outcomes. Results from this proposal will allow for future trial design using a precision
approach to metabolically impact patients and improve outcomes with radiation.
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会议论文
Metabolic implications of radiation response in oligometastatic prostate cancer.
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批准号:10515453
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项目类别:
-
资助金额:$29.37万
-
财政年份:2022
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负责人:Nicole L Simone
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依托单位:
(11) Diet Modification to Augment Radiation for Breast Cancer Brain Metastases
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批准号:10439798
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资助金额:$34.97万
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财政年份:2018
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负责人:Nicole L Simone
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依托单位:
(11) Diet Modification to Augment Radiation for Breast Cancer Brain Metastases
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批准号:10206051
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项目类别:
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资助金额:$35.69万
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财政年份:2018
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负责人:Nicole L Simone
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依托单位:
Diet Modification to Augment Radiation for Breast Cancer Brain Metastases
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批准号:10260963
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项目类别:
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资助金额:$23.4万
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财政年份:2018
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负责人:Nicole L Simone
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依托单位:
Mechanism of lung cancer resistance to tyrosine kinase inhibitor and radiation treatments
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批准号:10470829
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项目类别:
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资助金额:$60.45万
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财政年份:2018
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负责人:Nicole L Simone
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依托单位:
国内基金
海外基金
Journal of Integrative Plant Biology
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批准号:31024801
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项目类别:专项基金项目
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资助金额:24.0万元
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批准年份:2010
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负责人:贺萍
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依托单位: