Metabolic implications of radiation response in oligometastatic prostate cancer.
放射反应对寡转移性前列腺癌的代谢影响。
基本信息
- 批准号:10515453
- 负责人:
- 金额:$ 29.37万
- 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:2022-08-04 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AffectBiologyCaloric RestrictionCancer ControlCancer EtiologyCancer PatientClinicalClinical TrialsCoupledDNA Sequence AlterationDataDiet ModificationDiseaseDown-RegulationDrug usageEnvironmentEragrostisEvaluationFutureGenomicsGrowthHormonesInterventionLaboratoriesLeadMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of prostateMetabolicMetabolic PathwayMetabolic syndromeMetabolismMetastatic toMolecular Diagnostic TestingMolecular ProfilingMusNeoplasm MetastasisNutritionalNutritional RequirementsObesityOncogenesOutcomePathway AnalysisPathway interactionsPatient-Focused OutcomesPatientsPositron-Emission TomographyPre-Clinical ModelProstatectomyProstatic NeoplasmsRaceRadiationRadiation OncologyRadiation therapyRegulatory T-LymphocyteRoleSerumTherapeuticTherapeutic UsesTimeTumor ImmunityVisionc-myc Genescancer cellcancer survivalcancer therapychemotherapydisorder controleffector T cellfirst-in-humanglucogenesisimaging modalityimmune functionimprovedimproved outcomelipid biosynthesismetabolic profilemetabolomicsmolecular drug targetneoplastic cellpatient populationpatient subsetspersonalized approachprecision medicineprecision nutritionpreventprostate cancer cellprostate cancer modelradiation responseresponsesocial health determinantssocial influencestressorsystemic inflammatory responsetargeted treatmenttreatment optimizationtrial designtumortumor metabolismtumor microenvironmenttumor progression
项目摘要
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.
癌细胞代谢的改变被认为是恶性转化的标志,并且已被认为是恶性转化的标志。
由于其在锚定转移灶的命运中的作用,被证明对转移扩散负有部分责任。
肿瘤微环境。因此,了解与肿瘤和患者相关的放射反应
代谢将是确定需要代谢干预的患者子集的关键
优化患有寡转移疾病的前列腺癌患者的预后。人们发现
前列腺癌的基因组驱动因素可以导致肿瘤及其肿瘤的代谢重编程
微环境创造具有特定营养需求的生态位,丰富关键的促生存
途径。例如,当激活脂肪生成代谢时,c-myc 驱动的肿瘤生长得最好,而 akt
激活的肿瘤通过激活经典的糖酵解开关而蓬勃发展。了解如何专门重新编程
肿瘤优先使用的代谢途径来创造有利的生长环境,可以
减少前列腺癌肿瘤进展、转移并增加对放射治疗的敏感性。
初步数据表明,利用饮食改变来改变肿瘤及其代谢的能力
减少肿瘤进展和转移的环境。加上辐射,我们的数据表明
热量限制通过增加效应 T 细胞和减少 T 调节性来增强抗肿瘤免疫力
细胞。首次在前列腺癌切除术前使用热量限制的人体试点临床试验
患者通过代谢组学评估发现 c-myc 和 akt 下调证实了这一点
脂肪生成和糖生成减少。血清谱的通路分析表明热量
限制最显着的效果是上调抗肿瘤免疫力。既然已经确定了
myc 驱动的癌症改变了 Treg 反应,而 akt 驱动的肿瘤改变了 Teff 谱,我们
假设精准营养可用于重新编程由
驱动癌基因通过以下方式改善放射反应和寡转移性前列腺癌结果
影响患者抗肿瘤免疫力的积极变化。为了研究这个问题,我们首先要确定
巩固性 SABR 对脂肪生成寡转移性前列腺癌的放射反应与
糖原代谢谱。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的重编程对辐射诱导的抗肿瘤免疫的影响
以及对转移潜力的影响。最后,我们将确定社会决定因素的影响
健康状况(包括种族)对接受寡转移性疾病的前列腺癌患者的放射反应的影响
有辐射。我们多样化的患者群体将有助于理解患者的贡献
辐射结果的压力源。该提案的结果将允许未来使用精度进行试验设计
代谢影响患者并改善放射治疗结果的方法。
项目成果
期刊论文数量(0)
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Nicole L Simone其他文献
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{{ truncateString('Nicole L Simone', 18)}}的其他基金
Metabolic implications of radiation response in oligometastatic prostate cancer.
放射反应对寡转移性前列腺癌的代谢影响。
- 批准号:
10676868 - 财政年份:2022
- 资助金额:
$ 29.37万 - 项目类别:
(11) Diet Modification to Augment Radiation for Breast Cancer Brain Metastases
(11) 调整饮食以增强乳腺癌脑转移的放射治疗
- 批准号:
10439798 - 财政年份:2018
- 资助金额:
$ 29.37万 - 项目类别:
(11) Diet Modification to Augment Radiation for Breast Cancer Brain Metastases
(11) 调整饮食以增强乳腺癌脑转移的放射治疗
- 批准号:
10206051 - 财政年份:2018
- 资助金额:
$ 29.37万 - 项目类别:
Diet Modification to Augment Radiation for Breast Cancer Brain Metastases
调整饮食以增强乳腺癌脑转移的放射治疗
- 批准号:
10260963 - 财政年份:2018
- 资助金额:
$ 29.37万 - 项目类别:
Mechanism of lung cancer resistance to tyrosine kinase inhibitor and radiation treatments
肺癌对酪氨酸激酶抑制剂和放射治疗的耐药机制
- 批准号:
10470829 - 财政年份:2018
- 资助金额:
$ 29.37万 - 项目类别:
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