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。