Molecular Therapeutics of Kidney Cancer: VHL Gene and Fumarate Hydratase Gene

肾癌的分子治疗：VHL基因和富马酸水合酶基因

• 批准号: 7733437
• 负责人: William Marston Linehan
• 金额: $ 142.57万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733437
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; Affect; American; Binding; Cancer Etiology; Cancer Model; Carmustine/Dacarbazine/Hydroxyurea; Cell Line; Citric Acid Cycle; Clear Cell; Clinical; Clinical Trials; Complex; Condition; Conventional (Clear Cell) Renal Cell Carcinoma; Cutaneous; Development; Disease; Enzymes; Family; Foundations; Fumarate Hydratase; Fumarates; Geldanamycin Analogue; Genes; Genetic Transcription; Goals; Growth; Heat-Shock Proteins 90; Hereditary Neoplastic Syndromes; Hereditary Renal Cell Carcinoma; Histology; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Inherited; Kidney Neoplasms; Lead; Leiomyomatosis; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of kidney; Mediating; Molecular; Mutate; Mutation; New Agents; Numbers; Oncogenes; Papillary; Pathway interactions; Patients; Platelet-Derived Growth Factor; Process; Procollagen-Proline Dioxygenase; Proteins; Renal Cell Carcinoma; Renal carcinoma; Risk; Role; Scientist; Staining method; Stains; System; Therapeutic; Transforming Growth Factor alpha; Tumor Tissue; Ubiquitin; Urologic Oncology; Uterine Fibroids; VHL gene; VHL protein; Vascular Endothelial Growth Factors; Von Hippel-Lindau Syndrome; Work; beta catenin; cancer type; elongin C; in vitro Model; in vivo; novel; prevent; receptor; therapeutic target; transcription factor; tumor

Molecular Therapeutics of Kidney Cancer-VHL Gene and Fumarate Hydratase Gene Understanding the genes that cause kidney cancer provides the opportunity to develop approaches for molecular therapeutics for this disease. We have identified 3 genes that cause cancer of the kidney: the VHL gene (clear cell renal cell carcinoma); the c-Met gene (papillary type 1 renal carcinoma); and the BHD gene (chromophobe renal carcinoma). Targeting the VHL Clear Cell Kidney Cancer Gene Pathway Urologic Oncology Branch scientists are studying intensively how damage (mutation) to the VHL gene leads to the manifestations in VHL and sporadic renal carcinoma patients. Recently, it is has been shown that the VHL protein forms a complex with other proteins, including elongin C and B and the CUL-2 protein, and this complex targets the alpha subunit of hypoxia inducible factors (HIF1alpha and HIF2alpha) for ubiquitin-mediated degradation. This is a hypoxia-mediated process normally, i.e., under hypoxic conditions HIF is not degraded by the VHL complex. HIF is a transcription factor that regulates the transcription of a number of downstream genes important for cancer, such as VEGF, Glut 1, TGFalpha and PDGF. When the VHL gene is mutated, in the germline of VHL patients or in tumor tissue from patients with clear cell renal carcinoma, the HIFs cannot be degraded and the result is the over-transcription of VEGF, Glut1, TGFalpha and PDGF. One approach to evaluating the role of agents targeting the VHL pathway in VHL and clear cell renal carcinoma is to determine the activity of agents which block the VEGF and TGFalpha/EGFr pathways in-vitro and in-vivo. Another approach for molecular therapeutics of clear cell RCC is by use of agents such as geldanamycin analogues, which disrupt the binding of HIF to HSP-90. In-vitro studies have shown that the 17AAG geldanamycin analogues can degrade HIF even in VHL -/- cell lines. In-vitro and in-vivo studies are underway in kidney cancer models that we have developed from human material to evaluate the role of agents which block this cancer gene pathway as a potential approach for the treatment of clear cell kidney cancer. Clinical trials evaluating the role of geldanamycin analogues as well as agents which target the VEGF/EGFr receptors and other parts of the VHL pathway are currently in progress. Targeting the Fumarate Hydratase Gene: Type 2 Papillary Kidney Cancer The Krebs cycle enzyme, fumarate hydratase (FH), is the gene for Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC). HLRCC patients are at risk for the development of cutaneous and uterine leiomyomas as well as a very aggressive form of type 2 papillary kidney cancer. We have found mutations of the FH gene in the germline of 95% of our HLRCC families and loss of heterozygosity of the FH gene in HLRCC-associated kidney cancer. In order to understand how mutation of a Krebs cycle enzyme could cause kidney cancer we stained HLRCC-associated kidney tumors for the presence of hypoxia induced factor 1alpha (HIF1alpha) and hypoxia induced factor 2alpha (HIF2alpha). We found both HIF1alpha and HIF2alpha to be elevated in the HLRCC kidney tumors. We are developing novel in-vitro models from human tumors and evaluating growth in in-vitro and in-vivo systems. In in-vitro models we found that when fumarate hydratase was inactivated (with SiRNA), fumarate increased and the increase in fumarate inhibited prolyl hydroxylase. The inhibition of prolyl hydroxylase prevented normoxic VHL-mediated HIF degradation, providing a VHL-independent mechanism for dysregulation of HIF degradation in HLRCC kidney cancer. These studies provided the rationale for the development of a targeted therapeutic approach for the treatment of HLRCC-associated kidney cancer. In-vitro and in-vivo studies are underway to evaluate the role of agents which block this cancer gene pathway as a potential approach for the treatment of HLRCC-associated as well as sporadic type 2 papillary kidney cancer.

肾癌的分子治疗-VHL基因和富马酸水合酶基因 了解导致肾癌的基因提供了发展的机会 这种疾病的分子治疗方法。我们已经确定了三个基因， 肾癌：VHL基因（肾透明细胞癌）; c-Met基因 （乳头状1型肾癌）;和BHD基因（嫌色肾癌）。靶向 VHL透明细胞肾癌基因通路泌尿肿瘤学分支的科学家们正在研究 深入研究VHL基因的损伤（突变）如何导致VHL的表现， 散发性肾癌患者。最近，已经表明VHL蛋白形成一种 与其他蛋白质的复合物，包括延伸蛋白C和B以及CUL-2蛋白，并且该复合物 靶向缺氧诱导因子的α亚单位（HIF 1 α和HIF 2 α）， HIF 2 α）用于泛素介导的降解。这是一个缺氧介导的过程 通常，即，在低氧条件下，HIF不被VHL复合物降解。HIF是一种 调节许多下游基因转录的转录因子 对癌症很重要的因子，如VEGF、Glut 1、TGF α和PDGF。当VHL基因 在VHL患者的生殖系中或在来自透明细胞癌患者的肿瘤组织中， 在肾癌中，HIF不能被降解，结果是VEGF的过度转录， Glut 1、TGF α和PDGF。评估靶向药物作用的一种方法是， VHL和肾透明细胞癌中VHL通路的研究是为了确定 在体外和体内阻断VEGF和TGF α/EGFr通路。的另一种方法 透明细胞RCC的分子治疗是通过使用诸如格尔德霉素类似物的试剂， 其破坏HIF与HSP-90的结合。体外研究表明，17 AAG 格尔德霉素类似物甚至可以在VHL -/-细胞系中降解HIF。体外和体内 我们正在对肾癌模型进行研究，这些模型是从人体材料中开发出来的， 评估阻断这种癌症基因通路的药物的作用，作为一种潜在的方法， 肾透明细胞癌的治疗评价格尔德霉素作用的临床试验 类似物以及靶向VEGF/EGFr受体和VHL的其它部分的药剂 目前正在进行中。靶向富马酸水合酶基因：2型乳头状瘤 Krebs循环酶，富马酸水合酶（FH），是遗传性肾癌的基因。 肾细胞癌（HLRCC）。HLRCC患者有发生以下疾病的风险 皮肤和子宫平滑肌瘤，以及一个非常积极的形式2型乳头状肾 癌我们在95%的HLRCC家系中发现了FH基因的突变 和FH基因杂合性丢失的HLRCC相关的肾癌。为了 了解克雷布斯循环酶的突变如何导致肾癌， 缺氧诱导因子1 α在HLRCC相关性肾肿瘤中的表达 缺氧诱导因子1 α（HIF 1 alpha）和缺氧诱导因子2 α（HIF 2 alpha）。我们发现 HIF 1 α和HIF 2 α在HLRCC肾肿瘤中均升高。我们 正在开发新的人类肿瘤体外模型，并评估体外生长， 体内系统。在体外模型中，我们发现当富马酸水合酶失活时， (with SiRNA），富马酸盐增加，富马酸盐的增加抑制脯氨酰羟化酶。 脯氨酰羟化酶的抑制阻止了常氧VHL介导的HIF降解， 为HLRCC肾中HIF降解的失调提供了VHL非依赖性机制 癌这些研究为开发靶向治疗药物提供了理论基础。 治疗HLRCC相关肾癌的方法。体外和体内研究是 目前正在评估阻断这种癌症基因通路的药物的作用， 治疗HLRCC相关和散发性2型乳头状肾的方法 癌