Mechanism of tumor promotion by the H3K9 histone demethylase KDM3A in Ewing Sarcoma.

尤文肉瘤中 H3K9 组蛋白去甲基化酶 KDM3A 促进肿瘤的机制。

• 批准号: 9015798
• 负责人: PAUL JEDLICKA
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015798
• 关键词: Adverse effects; Affect; Animal Model; Anoikis; Biological Assay; Biology; Bone Tissue; Cell Line; Cell Surface Proteins; Cell Survival; Cells; Child; Childhood; Clinical; Combination Drug Therapy; Data; Dependence; Development; Disease; Disease Outcome; Drops; Enzymes; Epigenetic Process; Ewings sarcoma; Family; Genes; Goals; Growth; Health; Histones; In Vitro; Laboratories; MCAM gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediator of activation protein; MicroRNAs; Neoplasm Metastasis; Oncogenes; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Population; Publications; Recurrence; Regulation; Research; Resistance; Role; Sampling; Survival Rate; Tail; Testing; Therapeutic; Tumor Promotion; Veins; Work; Xenograft Model; Xenograft procedure; cell growth; cell motility; chemotherapy; cost; demethylation; efficacy testing; histone demethylase; improved; in vivo; inhibitor/antagonist; insight; knock-down; migration; novel; novel therapeutics; overexpression; overexpression analysis; pre-clinical; small molecule inhibitor; soft tissue; targeted treatment; therapeutic target; transcription factor; transcriptome; tumor; tumor growth; tumorigenesis; tumorigenic; young adult

 DESCRIPTION (provided by applicant): Ewing Sarcoma, a cancer of bone and soft tissue in children and young adults, is an aggressive malignancy with a poor long-term outcome. Even with optimal multi-agent chemotherapy, overall survival remains around 50%, drops to 25% for patients presenting with metastatic disease, and plummets to 10% for patients with recurrence. Thus, there is a tremendous need for better understanding of the biology of this disease, and the development of new therapies. The pathogenesis of Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins. EWS/Ets oncoproteins, of which EWS/Fli1 is the most common, are aberrant transcription factors, which are necessary for Ewing Sarcoma oncogenesis. Although EWS/Ets fusion oncoproteins represent logical therapeutic targets in Ewing Sarcoma, such targeting has proven very difficult. Targeting of key downstream mediators of EWS/Ets oncogenic action is an important alternative strategy. We have identified an epigenetic regulator, the H3K9me1/2 histone demethylase KDM3A, which is overexpressed in Ewing Sarcoma downstream of EWS/Fli1, and promotes tumorigenesis and metastasis. Using transcriptome profiling and functional analysis, we have also identified candidate mediators of KDM3A action in Ewing Sarcoma. KDM3A is an enzyme belonging to the Jumonji-domain histone demethylase (JHDM) family, for which a small molecule inhibitor with in vivo efficacy has recently been developed, and shown by us to have activity against Ewing Sarcoma cells in vitro. Furthermore, our preliminary data identify at least one candidate mediator of KDM3A action with therapeutic targeting potential. The goal of this proposal is to gain better understanding of the precise roles and mechanism of action of KDM3A in Ewing Sarcoma, in order to determine the optimal strategies for inhibiting its pro-tumorigenic and pro-metastatic functions, and to test the efficacy of JHDM pharmacologic inhibition against these effects, as part of a long-term plan to develop new treatments for Ewing Sarcoma.

 描述（由申请人提供）：尤文肉瘤是一种儿童和年轻人的骨和软组织癌症，是一种侵袭性恶性肿瘤，长期预后不良。即使采用最佳的多药化疗，总生存率仍保持在50%左右，对于转移性疾病患者，总生存率降至25%，对于复发患者，总生存率降至10%。因此，非常需要更好地了解这种疾病的生物学，并开发新的治疗方法。尤文肉瘤的发病机制由EWS/Ets融合癌蛋白驱动。EWS/Ets癌蛋白是尤文肉瘤（Ewing Sarcoma）肿瘤发生所必需的异常转录因子，其中EWS/Fli 1最为常见。虽然EWS/Ets融合癌蛋白代表尤文肉瘤的合理治疗靶点，但这种靶向已经被证明是非常困难的。靶向EWS/Ets致癌作用的关键下游介质是一种重要的替代策略。我们已经确定了一种表观遗传调节因子，H3 K9 me 1/2组蛋白去甲基化酶KDM 3A，它在EWS/Fli 1下游的尤文肉瘤中过表达，并促进肿瘤发生和转移。使用转录组分析和功能分析，我们还确定了候选介质的KDM 3A行动在尤文肉瘤。KDM 3A是属于Jumonji结构域组蛋白去甲基化酶（JHDM）家族的酶，最近已经开发出具有体内功效的小分子抑制剂，并且我们显示其在体外具有针对尤文肉瘤细胞的活性。此外，我们的初步数据确定了至少一个候选介体的KDM 3A行动与治疗靶向潜力。该提案的目的是更好地了解KDM 3A在尤文肉瘤中的确切作用和作用机制，以确定抑制其促肿瘤发生和促转移功能的最佳策略，并测试JHDM药理学抑制对这些作用的疗效，作为开发尤文肉瘤新治疗方法的长期计划的一部分。