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: 10266042
• 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/10266042
• 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 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; patient derived xenograft model; 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%， 影响年轻和年长的男女退伍军人的寿命。目前的手术治疗选择， 米托坦和化疗是不够的。ACC肿瘤发生的潜在机制很差， 明白患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，在临床试验中还没有成功靶向ACC的途径。缺乏进展 该领域一直归因于缺乏ACC的细胞和动物模型。直到最近，只有一个ACC肿瘤， 细胞系和无动物模型可用。我们通过开发 4种新的人ACC细胞系和第一种患者来源的异种移植物（PDX）动物模型（N=5）， 使用这些临床前模型来测试新疗法的生物信息学鉴定的靶点。我们 总体目标是了解人类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。我们分析了多个可用的基因组数据库， 这些候选基因表达失调，并指出ACC肿瘤具有一致的细胞凋亡失调， 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已被鉴定为有丝分裂蛋白的主要调节剂，并且对于有丝分裂的发生至关重要。 胞质分裂其下游效应子是细胞特异性的。虽然在大多数正常人中很低或检测不到， 在多种组织中，它在包括乳腺癌、结肠癌、肺癌、前列腺癌和淋巴瘤在内的多种癌症中过表达。我们 初步数据显示，PBK控制ACC中的致瘤表型， 在我们的临床前研究中，shPBK或PBK抑制剂HITOPK 032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肿瘤作用的机制。 致瘤作用。此外，我们建议测试PI 3 K靶向与米托坦组合的效果。 这是FDA唯一批准的治疗肾上腺癌的药物。这些研究将验证一个假设， 细胞周期的特定成分与Mitotane（一种已知的ER应激诱导剂）结合， 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， 促进对肾上腺癌肿瘤发生的不同机制的理解，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患者在诊所。我们的研究将填补一个 内分泌肿瘤发生领域未得到满足的需求困扰着所有年龄的退伍军人，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深入了解， 有丝分裂激酶驱动程序每天都在影响退伍军人。