Role of protein kinase ADCK5 in ovarian cancer

项目总结： 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，85%以上的患者 被诊断出患有对现有化疗药物具有抗药性的转移性疾病。因此，5年期 这些患者的存活率非常低(&lt；30%)。这一令人失望的临床现实强调了 迫切需要解决我们在了解导致卵巢癌的因素方面存在的知识差距 进展，并确定新的治疗靶点，将有助于克服现有战略的局限性。我们的 令人信服的初步数据表明，非典型的丝氨酸-苏氨酸蛋白激酶，AARF结构域包含 激酶5(ADCK5)在卵巢癌的进展和药物反应中起关键作用。基因组基因座 携带ADCK5的8q24.3在卵巢癌中频繁扩增，在约37%的卵巢癌中过表达 卵巢癌的百分比。临床数据显示ADCK5过表达显著降低了小鼠的存活率 卵巢癌患者中存在P53突变肿瘤。重要的是，在96%以上的高分化型肺癌中观察到了p53突变。 恶性浆液性卵巢癌。相比之下，ADCK5的过度表达对慢性阻塞性肺疾病患者没有任何影响。 野生型(WT)p53肿瘤。一致地，ADCK5的过表达促进了增殖、迁移、侵袭和 表达突变型P53而不表达WT-P53的卵巢癌细胞对细胞外基质蛋白的黏附 表达细胞系。有趣的是，ADCK5在突变型P53中过表达，而在表达WT-P53的细胞系中不过表达 导致对卡铂和阿霉素等化疗药物的耐药性增加。尽管 这些令人兴奋的数据，到目前为止还没有报道研究ADCK5的S在卵巢癌中的作用或它作为一种 治疗靶点。在这项提案中，我们将解决这一关键的知识差距。在目标1中，我们将确定 ADCK5‘S在卵巢癌进展和转移中的作用患者来源和工程化的卵巢癌细胞 LINES和临床相关的活体模型将被用来表征肿瘤之间的功能相互作用 卵巢癌中P53-Status和ADCK5的表达转录组和蛋白质组学方法将被用于 确定ADCK5介导的卵巢癌进展的生物学过程和分子途径 以及抗药性。目的2确定ADCK5‘S作为突变型P53表达的治疗靶点 使用临床相关的体外和体内卵巢肿瘤模型。因此，这些研究将为 ADCK5，一种在卵巢癌中很不为人所知但很重要的蛋白激酶。鉴于ADCK5过度表达 在几种人类恶性肿瘤中(肺、胰腺、肝脏、膀胱等)并观察到P53突变在 在所有人类癌症中，这项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.