Role of protein kinase ADCK5 in ovarian cancer

项目摘要： 卵巢癌是最致命的妇科恶性肿瘤，也是癌症相关死亡的第五大原因 在美国的女性中。由于缺乏可靠的早期生物标志物，超过85%的患者 被诊断患有对现有化疗药物有抗性的转移性疾病。因此，五年 这些患者的存活率极低（<30%）。这种令人失望的临床现实强调了 迫切需要解决我们对卵巢癌驱动因素的理解中存在的知识差距 研究进展并确定新的治疗靶点，这将有助于克服现有策略的局限性。我们 令人信服的初步数据表明，非典型丝氨酸-苏氨酸蛋白激酶，AarF结构域含有 激酶5（ADCK 5）在卵巢癌进展和药物反应中起关键作用。基因组基因座 携带ADCK 5的8q24.3在卵巢癌中频繁扩增，ADCK 5在约37个卵巢癌中过表达。 %的卵巢癌。临床数据显示，ADCK 5过表达显著降低了患者的生存率。 卵巢癌患者p53突变肿瘤。重要的是，在超过96%的高血压患者中观察到p53突变。 卵巢恶性浆液性癌相比之下，ADCK 5过表达对患者没有任何影响。 野生型（WT）p53肿瘤。因此，ADCK 5过表达促进细胞增殖、迁移、侵袭， 表达突变型p53但不表达WT-p53的卵巢癌细胞系与细胞外基质蛋白的粘附 表达细胞系。有趣的是，ADCK 5在突变型p53，而不是WT-p53表达细胞系中过表达， 导致对化疗剂如卡铂和阿霉素的抗性增加。尽管 尽管有这些令人兴奋的数据，但迄今为止还没有报道研究ADCK 5在卵巢癌中的作用或其作为卵巢癌治疗剂的效用。 治疗靶点在本提案中，我们将解决这一关键的知识差距。在目标1中，我们将确定 ADCK 5在卵巢癌进展和转移中的作用患者来源的和工程化的卵巢癌细胞 线和临床相关的体内模型将用于表征肿瘤之间的功能相互作用， 卵巢癌中p53状态和ADCK 5的研究转录组学和蛋白质组学方法将被用于 确定驱动ADCK 5介导的卵巢癌进展的生物学过程和分子途径 和耐药性。目的2将确定ADCK 5作为突变型p53表达的治疗靶点的效用。 使用临床相关的体外和体内模型。因此，这些研究将为 ADCK 5，一种在卵巢癌中很大程度上未知但重要的蛋白激酶。由于ADCK 5在细胞中过度表达， 在几种人类恶性肿瘤（肺、胰腺、肝、膀胱等）中p53基因突变在 所有人类癌症的50%，拟议工作的影响将远远超出卵巢癌。

Project Summary: Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause for cancer-related deaths among women in the United States. Due to the absence of reliable early biomarkers, more than 85% patients are diagnosed with metastatic disease that are resistant to extant chemotherapeutics. Consequently, the 5-year survival rate for these patients is extremely poor (<30%). This disappointing clinical reality underscores the urgent need to address existing knowledge gaps in our understanding of factors that drives ovarian cancer progression and identify new therapeutic targets that will help overcome the limitations of extant strategies. Our compelling preliminary data suggests that the atypical serine-threonine protein kinase, AarF domain containing kinase 5 (ADCK5) plays a key role in ovarian cancer progression and drug response. The genomic locus harboring ADCK5, 8q24.3, is amplified frequently in ovarian cancer and ADCK5 is overexpressed in about 37 percent ovarian cancers. Clinical data reveal that ADCK5 overexpression significantly decreased survival in ovarian cancer patients with p53 mutant tumors. Importantly, p53 mutations are observed in over 96% of high- grade serous ovarian carcinomas. In contrast, ADCK5 overexpression did not have any impact on patients with wild type (WT) p53 tumors. Consistently, ADCK5 overexpression promoted proliferation, migration, invasion, and attachment to extracellular matrix proteins in mutant p53 expressing ovarian cancer cell lines but not WT-p53 expressing cell lines. Interestingly, ADCK5 overexpression in mutant p53, but not WT-p53, expressing cell lines resulted in increased resistance to the chemotherapeutic agents such as carboplatin and doxorubicin. Despite these exciting data, no report till date has investigated ADCK5’s role in ovarian cancer or its utility as a therapeutic target. In this proposal we will address this critical knowledge gap. In Aim 1, we will determine ADCK5’s role in ovarian cancer progression and metastasis. Patient-derived and engineered ovarian cancer cell lines and clinically relevant in vivo models will be used to characterize the functional interaction between tumor p53-status and ADCK5 in ovarian cancer. Transcriptomic and proteomic approaches will be employed to determine biological processes and molecular pathways that drive ADCK5 mediated ovarian cancer progression and drug resistance. Aim 2 will determine the ADCK5’s utility as a therapeutic target in mutant p53 expressing ovarian tumors using clinically relevant in vitro and in vivo models. These studies will therefore establish role for ADCK5, a largely unknown but important protein kinase, in ovarian cancer. Given that ADCK5 is overexpressed in several human malignancies (lung, pancreatic, liver, bladder etc.) and p53 mutations are observed in over 50% of all human cancers, the impact of the proposed work will extend well beyond ovarian cancer.