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，长期结果不佳。即使采用最佳的多药化疗，总生存率仍约为 50%，对于出现转移性疾病的患者，总生存率下降至 25%，对于复发患者，总生存率则骤降至 10%。因此，迫切需要更好地了解这种疾病的生物学特性并开发新疗法。尤文肉瘤的发病机制是由 EWS/Ets 融合癌蛋白驱动的。 EWS/Ets 癌蛋白（其中 EWS/Fli1 最为常见）是异常转录因子，是尤文肉瘤肿瘤发生所必需的。尽管 EWS/Ets 融合癌蛋白代表了尤文肉瘤的合理治疗靶点，但事实证明这种靶向非常困难。针对 EWS/Ets 致癌作用的关键下游介质是一种重要的替代策略。我们发现了一种表观遗传调节因子 H3K9me1/2 组蛋白去甲基化酶 KDM3A，它在 EWS/Fli1 下游的尤文肉瘤中过度表达，并促进肿瘤发生和转移。通过转录组分析和功能分析，我们还确定了尤文肉瘤中 KDM3A 作用的候选介质。 KDM3A 是一种属于 Jumonji 结构域组蛋白去甲基化酶 (JHDM) 家族的酶，最近开发了一种具有体内功效的小分子抑制剂，并在体外显示出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种具有治疗靶向潜力的 KDM3A 作用候选介质。该提案的目的是更好地了解 KDM3A 在尤文肉瘤中的精确作用和作用机制，以确定抑制其促肿瘤和促转移功能的最佳策略，并测试 JHDM 药物抑制这些作用的功效，作为开发尤文肉瘤新疗法的长期计划的一部分。