HIF-alpha-independent Druggable Targets in Renal Cell Carcinoma

 描述（由申请人提供）： 肾皮质癌被称为肾细胞癌（RCC），占所有原发性肾肿瘤的约80-85%。透明细胞变异占所有RCC的85%，预计2014年美国将导致约64，000例新发病例和约14，000例死亡。透明细胞肾细胞癌是一种随年龄增长的疾病，在男性中更常见，因此代表了我们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。尽管一些新的治疗方法，包括小分子酪氨酸激酶抑制剂和雷帕霉素类似物，已获得监管机构的批准，但它们对生存的总体影响是适度的，转移性透明细胞RCC患者的中位生存期仅为~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，该基因最好的特征是其作为E3泛素连接酶的底物识别单位，靶向低氧诱导因子α（HIFα）进行蛋白酶介导的降解。重要的是，超过90%的透明细胞RCC散发病例表现出VHL失活。尽管VHL基因的蛋白产物pVHL表达的恢复与HIFα表达的抑制一样抑制肿瘤发生，但基因替代疗法和转录因子如HIFα的小分子抑制剂的开发对于临床转化并不容易可行。我们所提出的研究的总体目标是验证VHL损失作为透明细胞RCC的可行治疗靶点的HIF-1 α非依赖性作用。具体而言，我们建议生成临床前数据，以确定MAP激酶（称为转化生长因子β激活激酶（TAK 1），其在pVHL缺乏时被过度激活）是药物开发和转化为临床的合适靶标。我们已经确定TAK 1驱动c-Jun N-末端激酶（JNK）和核因子κ B（NF-κ B B）途径的活化，这两种途径都是促肿瘤发生的并且在pVHL缺陷的RCC中组成性活化。因此，我们的假设是TAK 1抑制代表了一个潜在的治疗靶点，其通过下游NF-κ B B和JNK途径的激活介导肾肿瘤的发生。基于这一背景和我们的初步研究，其中许多已发表，我们提出了三个目标：目标1。建立TAK 1抑制剂在体外和体内预防和延缓pVHL缺陷型RCC的生长。 目标二。阐明pVHL缺陷细胞中NF-κ B B和JNK通路同时组成性激活的潜在分子机制。 基于初步的研究，我们假设，pVHL缺陷型RCC获得的分子适应是关键的持续，组成性JNK激活的特征pVHL缺陷型细胞。 目标3。确定透明细胞RCC患者标本中存在组成性TAK 1和并发的NF-κ B B和JNK活化。作为分子靶标临床前验证过程的关键组成部分，确认患者标本中的相关通路确实以与我们的临床前模型一致的方式被激活至关重要。 成功执行所提出的目标将为TAK 1的验证奠定基础，TAK 1是一种由于VHL损失而过度活化的“可药物化”激酶，作为临床开发的分子靶标。以这种方式，我们的长期目标是将我们的发现转化为晚期透明细胞RCC的管理，这是我们退伍军人中相对常见的恶性肿瘤。

 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.