Renal Cancer Metastasis: Molecular Mechanisms to Therapy

肾癌转移：治疗的分子机制

• 批准号: 9890780
• 负责人: SUNIL SUDARSHAN
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890780
• 关键词: 3' Untranslated Regions; 3-phosphoglycerate; Affect; Anabolism; Behavior; Binding; Biochemical; Biology; CRISPR/Cas technology; Carbon; Clinic; Collagen; Collagen Gene; Common Neoplasm; Conflict (Psychology); Coupled; Data; Data Set; Development; Disease; Disease Management; Disease Progression; Epigenetic Process; Event; Exposure to; Face; Gene Expression Alteration; Genes; Glucose; Glycine; Glycolysis Pathway; Goals; In Vitro; Isotope Labeling; Kidney; Kidney Neoplasms; Knowledge; Large-Scale Sequencing; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metastasis Suppression; Metastatic Renal Cell Cancer; Methodology; MicroRNAs; Mitochondria; Modeling; Molecular; Neoplasm Metastasis; Outcome; PPAR gamma; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Phosphotransferases; Population; Primary Neoplasm; Production; Protein Tyrosine Kinase; Proteins; Proteomics; Receptor Protein-Tyrosine Kinases; Renal Cell Carcinoma; Renal carcinoma; Role; Sampling; Seminal; Serine; Signal Transduction; Small RNA; Source; Systemic Therapy; Testing; Therapeutic; Tissues; Treatment Efficacy; Tyrosine; Veterans; Woman; advanced disease; base; cancer cell; cell motility; data registry; epigenome; fatty acid metabolism; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; insight; knowledge base; loss of function; mRNA Expression; men; mitochondrial metabolism; neoplasm registry; next generation sequencing; novel; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; programs; response; restoration; transcription factor; transcriptome; transcriptomics; treatment strategy; tumor

Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men and women. It is also a malignancy that is prevalent in the Veteran population. A recent analysis of VA Central Cancer Registry (VACCR) data demonstrates that cancer of the kidney is the fourth most common cancer in the veteran population. The vast majority of studies on RCC biology have focused on primary tumors including recent large-scale sequencing data sets. Patients with disease confined to the kidney have excellent outcomes. In contrast, the development of metastasis is the seminal event that occurs in patients who succumb to this disease. While there are several approved therapies for advanced renal cancer, the reality is that progress in the treatment of metastasis with systemic therapies has been incremental. This fact mandates the need for new therapeutic approaches. The objective of this proposal is to identify the key alterations specifically in metastasis and to use this information to improve the outcomes of those affected with this disease. Transcriptomic analysis of normal kidney, primary RCC, and metastatic RCC samples demonstrates that loss of expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1) is a metastasis-associated alteration. This transcription factor has an established role in mitochondrial and fatty acid metabolism as well as other metabolic pathways. Prior studies in cancer have demonstrated conflicting roles for this factor in cancer. Preliminary studies demonstrate that restoration of PGC1 expression in kidney cancer cells suppresses invasive phenotypes in vitro and metastasis in vivo. In addition to loss of this factor, metastatic tissues are notable for increased expression of several collagen genes. Preliminary data indicates that collagens promote invasive behavior in RCC cells. Based on these preliminary data, the central hypothesis of this proposal is that PGC1 suppresses metastasis by coordinating its epigenetic and metabolic programs to inhibit pro-invasive signaling. The central hypothesis, based on strong preliminary data, will be tested through pursuit of the following specific aims: 1) determine the epigenetic basis by which PGC1 suppresses metastasis, 2) determine the role of metabolism in supporting collagen biosynthesis in renal cancer cells, and 3) determine the mechanisms by which collagen promotes invasive behavior. The proposal has translational significance as the information gathered from each aim could pave the way for new treatment strategies for patients with advanced RCC. Ultimately, the knowledge gathered has the potential to improve the efficacy of treatment for Veterans with advanced RCC, an unmet need challenging the contemporary management of this disease.

肾细胞癌（RCC）是男性和女性中最常见的10种恶性肿瘤之一。也是一 在退伍军人群体中普遍存在的恶性肿瘤。VA中央癌症登记处的最新分析 （VACCR）数据表明，肾癌是退伍军人中第四大常见癌症。 人口绝大多数关于RCC生物学的研究都集中在原发性肿瘤上，包括最近的研究。 大规模测序数据集。局限于肾脏的疾病患者预后良好。在 相比之下，转移的发展是发生在死于这种疾病的患者中的重要事件。 疾病虽然有几种获批的晚期肾癌治疗方法，但现实是， 用全身疗法治疗转移是逐渐增加的。这一事实要求必须 新的治疗方法。本提案的目的是确定主要改动，具体如下： 转移，并利用这些信息来改善受这种疾病影响的人的结果。 正常肾、原发性RCC和转移性RCC样品的转录组学分析表明， 过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC1 α）的表达是一个重要的因素。 转移相关的改变。这种转录因子在线粒体和脂肪细胞中具有确定的作用， 酸代谢以及其他代谢途径。先前的癌症研究表明， 在癌症中的作用。初步研究表明，恢复PGC1在肾脏中的表达， 癌细胞抑制体外侵袭表型和体内转移。除了这个因素的损失外， 转移性组织以几种胶原基因的表达增加而著称。初步数据表明 胶原促进肾细胞癌细胞的侵袭行为。根据这些初步数据，中央 该建议的假设是PGC1 β通过协调其表观遗传和代谢抑制转移 抑制促侵入信号的程序。基于强有力的初步数据，中心假设将是 通过追求以下特定目标进行测试：1）确定PGC1表达的表观遗传基础 抑制转移，2）确定代谢在支持肾癌胶原生物合成中的作用 细胞，和3）确定胶原蛋白促进侵入行为的机制。该提案 翻译的意义，因为从每个目标收集的信息可以为新的治疗铺平道路 晚期RCC患者的治疗策略。最终，收集的知识有可能改善 患有晚期RCC的退伍军人的治疗效果，这是一个挑战当代的未满足的需求 管理这种疾病。