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）： 肾皮质的癌症被称为肾细胞癌（RCC），占所有原发性肾脏肿瘤的约80-85％。清晰的细胞变体占所有RCC的85％，预计在2014年在美国导致约64,000例新病例，约有14,000例死亡。清晰的细胞RCC是一种随着年龄的增长而增加的疾病，在男性中更为普遍，因此代表了我们的兽医中与癌症相关的发病率和死亡的常见来源。该疾病在晚期转移阶段致命。尽管几种新型治疗方法，包括小分子酪氨酸激酶抑制剂和雷帕霉素类似物，已经获得了监管批准，但它们对生存的总体影响是适度的，对于转移性透明细胞RCC患者的中位存活率仅为24个月。遗传性和零星透明细胞RCC的分子标志是Vonhippel-lindau（VHL）肿瘤抑制基因的生物平行性失活，该基因的作用最有特征，其作用是靶向低氧诱导的E3泛素连接酶的底物识别单元，该单位靶向低氧诱导型Alpha（HifAr-arpha）（hifar-arpha）。重要的是，透明细胞RCC的零星病例中有90％以上表现为VHL失活。尽管VHL基因的蛋白质产物的表达PVHL恢复抑制了肿瘤发生，就像对HIFα表达，基因替代疗法的抑制作用一样，以及转录因子的小分子抑制剂的发展，例如HIFαS，例如HIFαS，对于临床翻译而言，HIFαS的抑制剂也不容易受到可比性。我们提出的研究的总体目标是验证VHL损失作为透明细胞RCC的可行治疗靶标的HIF独立的影响。具体而言，我们建议生成临床前数据，以确定被称为转化生长因子β活化激酶（TAK1）的MAP激酶激酶激酶（TAK1）响应于PVHL缺乏，是药物发育和转化为临床的合适靶标。我们已经确定，TAK1驱动C-JUN N末端激酶（JNK）和核因子Kappa B（NF-B）途径的激活，这两种途径都是促肿瘤的，并且在PVHL缺乏的RCC中均可激活。这是我们的假设是，TAK1抑制是一个潜在的治疗靶标，该靶标通过NF-B和JNK途径的下游激活来介导肾脏肿瘤发生。基于这种背景和我们的初步研究，其中许多已经发表了，我们提出了三个目的：目标1。确定TAK1抑制作用可阻止并阻止缺乏PVHL缺陷的RCC在体外和体内的增长。目的2。阐明允许同时发生的基本分子机制，在PVHL缺陷型细胞中的NF-B和JNK途径的本构激活。基于初步研究，我们假设PVHL缺陷型RCC获得的分子适应性对于持续的，构成的JNK激活至关重要，该JNK激活表征了PVHL缺陷型细胞。目的3。确定本构型TAK1和并发NF-B和JNK激活发生在清晰的细胞RCC患者样本中。作为分子靶临界前验证过程的关键组成部分，至关重要的是，确认相关的途径AR确实以与我们的临床前模型一致的方式在患者标本中被激活。 拟议的目标的成功执行将为验证TAK1奠定基础，TAK1是一种“可吸毒”激酶，由于VHL丢失而被过度激活，这是临床发育的分子靶标。以这种方式，我们的长期目标是将我们的发现转化为先进的Clear Cell RCC的管理，这是我们退伍军人中相对常见的恶性肿瘤。