Targeting Kinases in Novel Preclinical Models of Adrenocortical Carcinoma

肾上腺皮质癌(ACC)是一种致命的恶性肿瘤，5年存活率为35%。 无论是年轻的还是年长的男性和女性退伍军人都遭受着生命的折磨。目前的手术治疗方案， 米托坦和化疗是不够的。ACC肿瘤发生的机制尚不清楚 明白了。有遗传综合征的患者患ACC的风险增加；然而，大多数病例 是零星的。到目前为止，还没有一条通路在临床试验中成功地在ACC中靶向。在……方面缺乏进展 这一领域归因于缺乏ACC的细胞和动物模型。直到最近，只有一种ACC肿瘤 细胞系，没有可用的动物模型。我们已经通过发展 4个新的人类ACC细胞系和第一个患者来源的异种移植(PDX)动物模型(N=5) 使用这些临床前模型来测试生物信息识别的新疗法的靶点。我们的 首要目标是了解人类ACC的不同分子发病机制并确定新的靶点 在我们的新细胞和动物模型中进行测试。我们分析了多个公开可用的基因组数据库 候选基因是失调的，并注意到ACC肿瘤藏有一致的细胞失调 周期控制和DNA损伤途径的组成。我们鉴定出pBK(PDZ结合激酶)是最高的 不受监管的候选人。PBK已被确定为有丝分裂蛋白的主要调节者，并对 胞质分裂。它的下游效应器是细胞特有的。尽管在大多数正常人身上检测不到或很低 在组织中，它在多种癌症中过度表达，包括乳腺癌、结肠癌、肺癌、前列腺癌和淋巴瘤。我们的 初步数据显示，PBK控制了ACC的致瘤表型，并以PBK为靶点 在我们的临床前研究中，shPBK或PBK抑制剂HITOPK032减少了细胞增殖和肿瘤生长 模特们。本应用将剖析PBK抑制或靶向发挥其抗肿瘤作用的机制 致癌作用。此外，我们建议测试PBK靶向与米托坦联合应用的效果 治疗，FDA唯一批准的治疗肾上腺癌的药物。这些研究将检验这样一种假设，即破坏 与米托坦(一种已知的内质网应激诱导剂)联合使用，将增强细胞特定成分的周期 抗肿瘤反应。我们的新型ACC细胞系和PDX模型提供了一个独特的机会 加深对肾上腺癌不同发生机制的认识，以及对肾上腺癌的检测 第一次相关的ACC目标，将允许翻译到我们的临床患者。我们的研究将填补一个 内分泌肿瘤发生领域的未得到满足的需求，困扰着各个年龄段的退伍军人，并揭示了 这种研究很少的癌症的生物学。此外，这些数据将提供对其他癌症的洞察 有丝分裂激酶驱动因素每天都会影响退伍军人。

Adrenocortical carcinoma (ACC) is a deadly malignancy with survival <35% at 5 years and occurs across the lifespan afflicting both young and older male and female veterans. Current treatment options of surgery, mitotane and chemotherapy are inadequate. The mechanisms underlying ACC tumorigenesis are poorly understood. Patients with genetic syndromes have an increased risk of ACC; however, the majority of cases are sporadic. To date, no pathway has been successfully targeted in ACC in clinical trials. Lack of progress in the field has been attributable to the lack of cell and animal models of ACC. Until recently, only one ACC tumor cell line and no animal models were available. We have approached this unmet need by the development of 4 new human ACC cell lines and the first patient derived xenograft (PDX) animal models (N=5) with a strategy to use these pre-clinical models to test bioinformatically identified targets for novel therapeutics. Our overarching goal is to understand the diverse molecular pathogenesis of human ACC and identify novel targets to test in our new cell and animal models. We analyzed multiple publically available genomic databases for candidate genes that are dysregulated and noted that ACC tumors harbored a consistent dysregulation of cell cycle control and DNA damage pathway constituents. We identified PBK (PDZ binding kinase) as the highest dysregulated candidate. PBK has been identified as a master regulator of mitotic proteins and is critical for cytokinesis. Its downstream effectors are cell specific. Although low or undetectable in most normal human tissues, it is overexpressed in diverse cancers including breast, colon, lung, prostate and lymphomas. Our preliminary data show that PBK controls the tumorigenic phenotype in ACC and that targeting PBK with either shPBK or the PBK inhibitor, HITOPK032, reduced cell proliferation and tumorigenic growth in our pre-clinical models. This application will dissect the mechanisms by which PBK inhibition or targeting exert their anti- tumorigenic effects. In addition, we propose to test the effects of PBK targeting in combination with Mitotane therapy, the only FDA approved drug for adrenal cancer. These studies will test the hypothesis that disruption of specific components of cell the cycle in conjunction with Mitotane, a known ER stress inducer, will enhance the anti-tumorigenic responses. Our novel ACC cell lines and PDX models provide a unique opportunity to advance the understanding of the diverse mechanisms of adrenal cancer tumorigenesis as well as test for the first time relevant ACC targets that will allow translation to our patients in the clinic. Our studies will fill an unmet need in the area of endocrine tumorigenesis that afflicts veterans of all ages and shed light into the biology of this poorly studied cancer. In addition, the data will provide insight into other cancers with these mitotic kinase drivers which affect veterans every day.