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)是男性和女性最常见的10种恶性肿瘤之一。它也是一种 在退伍军人中普遍存在的恶性肿瘤。退伍军人事务部癌症登记中心近期分析 (VACCR)数据显示，肾癌是退伍军人中第四常见的癌症 人口。绝大多数关于肾细胞癌生物学的研究都集中在原发肿瘤上，包括最近 大规模测序数据集。仅限于肾脏疾病的患者预后良好。在……里面 相反，转移的发展是发生在屈从于此的患者身上的精液事件。 疾病。虽然有几种被批准的治疗晚期肾癌的方法，但现实是，在 转移瘤的全身治疗是循序渐进的。这一事实要求有必要 新的治疗方法。这项建议的目标是确定主要的更改，特别是 并利用这一信息来改善受这种疾病影响的患者的预后。 对正常肾、原发肾细胞癌和转移性肾细胞癌样本的转录分析表明， 过氧化物酶体增殖物激活受体γ共激活因子1α(Pgc1)的表达是一种 转移相关改变。这种转录因子在线粒体和脂肪中具有既定的作用。 酸代谢以及其他代谢途径。以前对癌症的研究表明了相互矛盾的 这一因素在癌症中的作用。初步研究表明，前列腺素C_1在肾脏中的表达恢复 癌细胞在体外抑制侵袭表型，在体内抑制转移。除了失去这一因素外， 转移组织中几种胶原基因的表达增加是值得注意的。初步数据显示 胶原蛋白促进了肾癌细胞的侵袭行为。根据这些初步数据，中央银行 这一设想的假设是，pgc1通过协调其表观遗传和代谢来抑制转移。 抑制前侵入性信号的程序。基于强劲的初步数据，核心假设将是 通过追求以下具体目标进行测试：1)确定Pgc1的表观遗传学基础 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，以及3)确定胶原蛋白促进侵袭行为的机制。这项提案已经 翻译意义，因为从每个目标收集的信息可以为新的治疗方法铺平道路 晚期肾癌患者的治疗策略。归根结底，收集到的知识有改进的潜力 晚期肾细胞癌退伍军人的治疗效果，这是一个挑战当代的未得到满足的需求 这种疾病的管理。