Targeting Kinases in Novel Preclinical Models of Adrenocortical Carcinoma

肾上腺皮质癌新型临床前模型中的靶向激酶

• 批准号: 10001967
• 负责人: Margaret E Wierman
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001967
• 关键词: Adrenal Gland Cancer; Adrenocortical carcinoma; Affect; Age; Animal Model; Area; Beckwith-Wiedemann Syndrome; Bioinformatics; Biology; Breast; Candidate Disease Gene; Cell Cycle; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cell Survival; Cell model; Cells; Cellular Structures; Clinic; Clinical Trials; Colon; Cytokinesis; DNA Damage; DNA Repair; Data; Databases; Development; Disease; Effector Cell; Endocrine; FDA approved; Female; Genes; Genetic; Genomics; Goals; Growth; Hereditary Nonpolyposis Colorectal Neoplasms; Human; In Vitro; Investigation; Light; Longevity; Lung; Malignant Neoplasms; Mitotic; Modeling; Molecular; Molecular Profiling; Mutation; Nude Mice; Operative Surgical Procedures; Orphan; PDZ-binding kinase; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Pre-Clinical Model; Prostate Lymphoma; Proteins; Risk; Role; Syndrome; TP53 gene; Testing; Therapeutic Agents; Time; Translations; Tumor Cell Line; Tumorigenicity; Veterans; Xenograft Model; Xenograft procedure; beta catenin; chemotherapy; effectiveness testing; endoplasmic reticulum stress; experimental study; human tissue; in vivo; insight; kinase inhibitor; male; malignant phenotype; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; response; tumor; tumor growth; tumorigenesis; tumorigenic

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.

肾上腺皮质癌 (ACC) 是一种致命的恶性肿瘤，5 年生存率 <35%，发生在整个世界 寿命困扰着年轻和年长的男性和女性退伍军人。目前手术治疗选择， 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。患有遗传综合征的患者罹患 ACC 的风险增加；然而，大多数情况 是零星的。迄今为止，临床试验中还没有成功针对 ACC 的通路。缺乏进展 该领域一直缺乏ACC的细胞和动物模型。直到最近，只有一个 ACC 肿瘤 细胞系和没有可用的动物模型。我们通过开发解决了这一未满足的需求 4 个新的人类 ACC 细胞系和第一个采用策略的患者衍生异种移植 (PDX) 动物模型 (N=5) 使用这些临床前模型来测试生物信息学确定的新疗法的靶点。我们的 总体目标是了解人类 ACC 的多种分子发病机制并确定新靶标 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 失调的候选基因并指出 ACC 肿瘤具有一致的细胞失调 循环控制和 DNA 损伤途径成分。我们确定 PBK（PDZ 结合激酶）是最高的 失调的候选人。 PBK 已被确定为有丝分裂蛋白的主要调节因子，并且对于有丝分裂蛋白至关重要 胞质分裂。其下游效应器是细胞特异性的。尽管在大多数正常人中含量较低或无法检测到 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 初步数据表明，PBK 控制 ACC 中的致瘤表型，并且以 PBK 为靶点 shPBK 或 PBK 抑制剂 HITOPK032 在我们的临床前研究中减少了细胞增殖和致瘤生长 模型。本申请将剖析 PBK 抑制或靶向发挥其抗作用的机制 致瘤作用。此外，我们建议测试 PBK 靶向与 Mitotane 组合的效果 疗法，FDA 批准的唯一治疗肾上腺癌的药物。这些研究将检验以下假设：颠覆 细胞特定成分的循环与已知的 ER 应激诱导剂 Mitotane 结合使用，将增强 抗肿瘤发生反应。我们的新型 ACC 细胞系和 PDX 模型提供了独特的机会 促进对肾上腺癌肿瘤发生的多种机制的理解并测试 首次相关的 ACC 目标将允许翻译给我们诊所的患者。我们的研究将填补 内分泌肿瘤发生领域未满足的需求困扰着各个年龄段的退伍军人，并为我们揭示了 这种癌症的生物学研究很少。此外，这些数据还将提供对其他癌症的深入了解 有丝分裂激酶驱动因素每天影响着退伍军人。