Genomic analysis of prostate tumor heterogeneity in metastasis

前列腺肿瘤转移异质性的基因组分析

• 批准号: 10314076
• 负责人: CARLOS Sanchez MORENO
• 金额: $ 17.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-08 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314076
• 关键词: Amino Acids; Biochemical; Biological Markers; Biology; Breast Cancer Patient; Caliber; Clinical Trials; DNA; Detection; Disease; Dissection; Enrollment; FDA approved; Funding; Gene Expression; Gene Expression Profile; Genomics; Harvest; Heterogeneity; Histology; Image; Indolent; Knowledge; Lead; Lesion; Localized Disease; Malignant neoplasm of prostate; Metastatic Neoplasm to Lymph Nodes; Metastatic Prostate Cancer; Neoplasm Metastasis; Nonmetastatic; Pathway interactions; Patient-Focused Outcomes; Patients; Positive Lymph Node; Positron-Emission Tomography; Primary Neoplasm; Prostatic Neoplasms; RNA; Radical Prostatectomy; Recurrence; Resources; Sample Size; Sampling; Signal Transduction Pathway; Somatic Mutation; Specimen; Testing; Tissue Sample; Tissues; United States National Institutes of Health; advanced disease; amino acid metabolism; base; driver mutation; exome sequencing; high risk; improved; innovation; insight; lymph nodes; metastatic process; mortality; neoplastic cell; new therapeutic target; novel strategies; prostate cancer cell; prostate cancer risk; radiotracer; response; transcriptome sequencing; tumor; tumor heterogeneity; uptake

Summary: Prostate cancer is a highly heterogeneous disease, and mortality from prostate cancer is due to metastases, and thus, understanding the mechanisms of metastasis is essential for improving patient outcomes. In this proposal, we plan to leverage the resources of an ongoing NIH-funded clinical trial of patients with high-risk prostate cancer who have had extensive dissection of surrounding lymph nodes and imaging with the FDA-approved radiotracer [18F]-fluciclovine, a biomarker of amino acid transport, which is upregulated in prostate cancer cells. We hypothesize that genomic analysis of multiple foci within the primary tumor, and lymph nodes positive and negative for [18F]-fluciclovine uptake and metastatic disease, will provide new insights into the mechanisms of the earliest steps in metastasis and help identify key driver mutations and signal transduction pathways. We plan to test this hypothesis via the following specific aims: Aim 1) perform whole exome sequencing of multiple primary foci and corresponding lymph nodes to identify somatic mutations associated with LN mets; Aim 2) perform RNAseq analysis of multiple primary foci and corresponding lymph nodes to identify gene expression changes associated with LN metastasis; Aim 3) determine RNA and DNA signatures associated with the presence and degree of uptake of fluciclovine in LN mets. This proposal is innovative in that we will be using multiple samples from the same patients to interrogate the heterogeneity of primary prostate tumors and the genomic and gene expression changes that drive the initial step of metastasis as they migrate to the lymph nodes. In addition, we will generate new understandings of the changes that are associated with uptake of the radiotracer [18F]-fluciclovine, which reflects upregulated amino acid metabolism in tumor cells. Discoveries from this project could lead to new approaches for treatment of advanced disease by identifying the genomic changes essential to the first steps of metastasis and defining the biology of lethal prostate cancer. New drug targets that are critical for metastasis may be identified from the knowledge gained through this study.

摘要：前列腺癌是一种高度异构疾病，前列腺癌的死亡率是由于 转移，因此了解转移的机制对于改善患者至关重要 结果。在此提案中，我们计划利用正在进行的NIH资助的患者的资源 与周围淋巴结和成像的高风险前列腺癌已广泛解剖 与FDA批准的radiotracer [18F] -Fluciclovine（氨基酸转运的生物标志物）一起上调 在前列腺癌细胞中。我们假设对原发性肿瘤中多个局部局部局部的基因组分析，以及 淋巴结阳性和阴性[18F] - 氟丙洛文氏菌的摄取和转移性疾病将提供新的 洞悉转移中最早步骤的机制，并有助于确定关键的驱动突变和 信号转导途径。我们计划通过以下特定目的检验这一假设：目标1）执行 多个主要焦点和相应淋巴结的整个外显子组测序以识别体细胞突变 与LN Mets相关； AIM 2）对多个原发灶和相应淋巴进行RNASEQ分析 鉴定与LN转移相关的基因表达变化的节点；目标3）确定RNA和DNA 与LN Mets中氟维氏菌吸收的存在和程度相关的特征。该提议是 创新的是，我们将使用来自同一患者的多个样本来询问异质性 原发性前列腺肿瘤以及基因组和基因表达变化，驱动转移的初始步骤 当它们迁移到淋巴结时。此外，我们将对更改的新理解产生新的理解 与摄取radiotracer [18F] - 荧光素有关，它反映了上调的氨基酸代谢 肿瘤细胞。该项目的发现可能会导致通过 确定转移的第一步必不可少的基因组变化并定义致命的生物学 前列腺癌。可以从获得的知识中确定对转移至关重要的新药物靶标 通过这项研究。