HIF-alpha-independent Druggable Targets in Renal Cell Carcinoma

肾细胞癌中不依赖 HIF-α 的药物靶点

• 批准号: 9487898
• 负责人: MATTHEW B RETTIG
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9487898
• 关键词: Age; Apoptotic; Area; Biochemical; Biological Assay; CCI-779; Cancer Etiology; Cells; Cessation of life; Characteristics; Clear Cell; Clear cell renal cell carcinoma; Clinic; Clinical; Clinical Data; Clinical Management; Complement Factor B; Data; Disease; Down-Regulation; Drug Targeting; Elderly; Fibrinogen; Freezing; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Goals; Growth; Hypoxia Inducible Factor; Image Analysis; Immunohistochemistry; Impairment; In Vitro; Inflammatory Response; Inherited; Kidney; Kidney Neoplasms; MAP Kinase Kinase Kinase; MAP3K7 gene; MAPK8 gene; Malignant Neoplasms; Mediating; Molecular; Molecular Target; Morbidity - disease rate; N-terminal; NF-kappa B; Outcome; Pathway interactions; Patients; Pharmacology; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Pre-Clinical Model; Primary Neoplasm; Process; Proteins; Publishing; Renal Cell Carcinoma; Renal carcinoma; Research; Role; Sampling; Signal Transduction; Signaling Protein; Source; Specimen; System; Testing; Therapeutic; Tissue Microarray; Transforming Growth Factors; Translating; Translations; Tumor Suppressor Genes; Tyrosine Kinase Inhibitor; Validation; Variant; Veterans; attributable mortality; base; clinical development; clinical translation; drug development; druggable target; gene replacement; gene replacement therapy; gene therapy; in vivo; inhibitor/antagonist; kidney cell; kidney cortex; male; men; mortality; multicatalytic endopeptidase complex; neoplastic cell; novel; pre-clinical; prevent; programs; protein expression; public health relevance; response; restoration; sample collection; small hairpin RNA; small molecule; small molecule inhibitor; success; therapeutic target; therapy development; transcription factor; tumor; tumor initiation; tumorigenesis; tumorigenic; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Cancers of the renal cortex are known as renal cell carcinomas (RCC) and represent ~80-85% of all primary renal neoplasms. The clear cell variant comprises up to 85% of all RCCs, which are expected to result in ~64,000 new cases and ~14,000 deaths in the U.S. in 2014. Clear cell RCC is a disease that increases with age and is more common in men, and as such represents a common source of cancer-related morbidity and mortality amongst our Veterans. The disease is lethal at the advanced, metastatic stage. Although several novel treatments, including small molecule tyrosine kinase inhibitors and rapamycin analogs, have received regulatory approval, their overall impact on survival is modest, and median survival for patients with metastatic clear cell RCC remains at only ~24 months. The molecular hallmark of hereditary and sporadic clear cell RCC is the biallelic inactivation of the vonHippel-Lindau (VHL) tumor suppressor gene, which is most well characterized for its role as the substrate recognition unit of an E3 ubiquitin ligase that targets hypoxia-inducible factor alpha (HIFα) for proteasomemediated degradation. Importantly, upwards of 90% of sporadic cases of clear cell RCC manifest VHL inactivation. Although restoration of the expression pVHL, the protein product of the VHL gene, suppresses tumorigenesis as does inhibition of HIFα expression, gene replacement therapy and the development of small molecule inhibitors of transcription factors such as HIFα s not readily feasible for clinical translation. The overarching goal of our proposed research is to validate HIF-independent effects of VHL loss as viable therapeutic targets for clear cell RCC. Specifically, we propose to generate the pre-clinical data to establish that a MAP kinase kinase kinase known as transforming growth factor β activated kinase (TAK1), which is hyperactivated in response to pVHL deficiency, is a suitable target for drug development and translation into the clinic. We have already established that TAK1 drives the activation of the c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-B) pathways, both of which are pro-tumorigenic and constitutively activated in pVHL-deficient RCCs. Thus, our hypothesis is that TAK1 inhibition represents a potential therapeutic target that mediates renal oncogenesis through downstream activation of the NF-B and JNK pathways. Based on this background and our preliminary studies, many of which have been published, we have proposed three aims: Aim 1. To establish that TAK1 inhibition prevents and retards the growth of pVHL-deficient RCCs in vitro and in vivo. Aim 2. To elucidate the underlying molecular mechanisms that are permissive for concurrent, constitutive activation of the NF-B and JNK pathways in pVHL-deficient cells. Based on preliminary studies, we postulate that molecular adaptations acquired by pVHL-deficient RCCs are critical to the ongoing, constitutive JNK activation that characterizes pVHL-deficient cells. Aim 3. To establish that constitutive TAK1 and concurrent NF-B and JNK activation occur in clear cell RCC patient specimens. As a critical component to the process of pre-clinical validation of a molecular target, it is vital to confirm that the relevant pathways ar indeed activated in patient specimens in a fashion that is consistent with our pre-clinical models. Successful execution of the proposed aims will lay the groundwork for the validation of TAK1, a "druggable" kinase that is hyperactivated as a consequence of VHL loss, as a molecular target for clinical development. In this fashion, our long-term goal is to translate our findings to the management of advanced clear cell RCC, a relatively common malignancy amongst our Veterans.

 描述（由申请人提供）： 肾皮质癌被称为肾细胞癌 (RCC)，约占所有原发性肾肿瘤的 80-85%。透明细胞变体占所有 RCC 的 85%，预计 2014 年将在美国导致约 64,000 例新病例和约 14,000 例死亡。透明细胞 RCC 是一种随着年龄的增长而增加的疾病，在男性中更为常见，因此是退伍军人中癌症相关发病率和死亡率的常见来源。这种疾病在晚期转移阶段是致命的。尽管包括小分子酪氨酸激酶抑制剂和雷帕霉素类似物在内的几种新疗法已获得监管部门的批准，但它们对生存的总体影响不大，转移性透明细胞肾细胞癌患者的中位生存期仍仅为约 24 个月。 遗传性和散发性透明细胞肾细胞癌的分子标志是 vonHippel-Lindau (VHL) 肿瘤抑制基因的双等位基因失活，该基因最明确的特征是其作为 E3 泛素连接酶的底物识别单元的作用，该酶以缺氧诱导因子 α (HIFα) 为目标，进行蛋白酶体介导的降解。重要的是，超过 90% 的散发性透明细胞肾细胞癌病例表现出 VHL 失活。尽管恢复表达 pVHL（VHL 基因的蛋白质产物）与抑制 HIFα 表达一样可以抑制肿瘤发生，但基因替代疗法和转录因子（如 HIFα）小分子抑制剂的开发对于临床转化来说并不容易实现。我们提出的研究的总体目标是验证 VHL 丢失的独立于 HIFα 的影响作为透明细胞肾细胞癌的可行治疗靶点。具体来说，我们建议生成临床前数据，以确定一种称为转化生长因子 β 激活激酶 (TAK1) 的 MAP 激酶激酶（TAK1）是药物开发和转化为临床的合适靶标，该激酶因 pVHL 缺陷而过度激活。我们已经确定 TAK1 驱动 c-Jun N 末端激酶 (JNK) 和核因子 kappa B (NF-κB) 途径的激活，这两种途径均具有促肿瘤发生作用，并且在 pVHL 缺陷的 RCC 中持续激活。因此，我们的假设是 TAK1 抑制代表了一个潜在的治疗靶点，通过下游 NF-κB 和 JNK 通路的激活介导肾肿瘤发生。基于这一背景和我们已发表的初步研究，我们提出了三个目标： 目标 1. 确定 TAK1 抑制可在体外和体内预防和延缓 pVHL 缺陷型 RCC 的生长。 目标 2. 阐明 pVHL 缺陷细胞中 NF-B 和 JNK 通路同时、组成性激活的潜在分子机制。 根据初步研究，我们假设 pVHL 缺陷型 RCC 获得的分子适应对于持续的、组成性 JNK 激活至关重要，而 JNK 激活是 pVHL 缺陷型细胞的特征。 目标 3. 确定透明细胞 RCC 患者标本中存在组成型 TAK1 以及并发的 NF-κB 和 JNK 激活。作为分子靶点临床前验证过程的关键组成部分，确认相关通路确实以与我们的临床前模型一致的方式在患者样本中激活至关重要。 成功执行拟议目标将为验证 TAK1（一种“可成药”激酶，由于 VHL 丢失而过度激活）作为临床开发的分子靶点奠定基础。通过这种方式，我们的长期目标是将我们的发现转化为晚期透明细胞肾细胞癌的治疗，这是退伍军人中相对常见的恶性肿瘤。