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: 10515453
• 负责人: Nicole L Simone
• 金额: $ 29.37万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10515453
• 关键词: Affect; Biology; Caloric Restriction; Cancer Control; Cancer Etiology; Cancer Patient; Clinical; Clinical Trials; Coupled; DNA Sequence Alteration; Data; Diet Modification; Disease; Down-Regulation; Drug usage; Environment; Eragrostis; Evaluation; Future; Genomics; Growth; Hormones; Intervention; Laboratories; Lead; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Metastatic to; Molecular Diagnostic Testing; Molecular Profiling; Mus; Neoplasm Metastasis; Nutritional; Nutritional Requirements; Obesity; Oncogenes; Outcome; Pathway Analysis; Pathway interactions; Patient-Focused Outcomes; Patients; Positron-Emission Tomography; Pre-Clinical Model; Prostatectomy; Prostatic Neoplasms; Race; Radiation; Radiation Oncology; Radiation therapy; Regulatory T-Lymphocyte; Role; Serum; Therapeutic; Therapeutic Uses; Time; Tumor Immunity; Vision; c-myc Genes; cancer cell; cancer survival; cancer therapy; chemotherapy; disorder control; effector T cell; first-in-human; glucogenesis; imaging modality; immune function; improved; improved outcome; lipid biosynthesis; metabolic profile; metabolomics; molecular drug target; neoplastic cell; patient population; patient subsets; personalized approach; precision medicine; precision nutrition; prevent; prostate cancer cell; prostate cancer model; radiation response; response; social health determinants; social influence; stressor; systemic inflammatory response; targeted treatment; treatment optimization; trial design; tumor; tumor metabolism; tumor microenvironment; tumor progression

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.

癌细胞中改变的代谢被认为是恶性转化的标志，并且已经被证实是恶性转化的标志。 由于其在将转移锚定到肿瘤细胞的命运中的作用， 肿瘤微环境因此，了解与肿瘤和患者相关的辐射反应， 代谢将是确定需要代谢干预的患者亚组的关键， 优化前列腺癌寡转移性疾病患者的结局。已经发现 前列腺癌的基因组驱动因素可以引起肿瘤及其代谢的重编程。 微环境，以创造具有特定营养需求的生态位， 途径。例如，c-myc驱动的肿瘤在激活脂肪代谢时生长最好，而akt 激活的肿瘤通过激活经典的糖酵解开关而茁壮成长。了解如何具体地重新编程 肿瘤优先使用的代谢途径可以创造有利的生长环境， 减少前列腺癌肿瘤进展、转移并增加对放射疗法的敏感性。 初步数据表明，使用饮食改变代谢改变肿瘤及其 环境，以减少肿瘤进展和转移。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调节细胞来增加抗肿瘤免疫力。 细胞前列腺癌根治术前限制热量摄入的首次人体临床试验 代谢组学评估显示，患者c-myc和akt下调证实了这一点， 减少脂肪生成和葡萄糖生成。血清谱的途径分析表明，热量 限制最显著的作用是上调抗肿瘤免疫。既然已经确定， myc驱动的癌症改变了Treg反应，akt驱动的肿瘤改变了Teff谱，我们 假设精确营养可用于重新编程由代谢引起的代谢改变， 驱动癌基因改善放射反应和寡转移性前列腺癌的结果， 影响患者抗肿瘤免疫力的积极变化。为了研究这个问题，我们将首先确定 巩固SABR对少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的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的影响， 健康，包括种族，对接受治疗的少转移性前列腺癌患者放射反应的影响 用辐射。我们多样化的患者人群将允许了解患者的贡献 辐射结果的压力源。该提案的结果将允许未来的试验设计使用精密度 方法来影响患者的代谢并改善放射治疗的结果。