Therapeutic targeting of demethylation-deubiquitination axis in acute leukemia

项目摘要/摘要 急性淋巴细胞性白血病(ALL)是一种侵袭性血癌，具有高治愈率和高未满足的需求。 高强度的放化疗是以高毒副作用和继发性风险为代价的。 恶性肿瘤。尽管如此，高达25%的儿童ALL患者在一线化疗后失败或复发，而有效 复发率令人沮丧(约20%)。全基因组测序能力为我们揭示了 致癌过程，但识别“干净”的靶点仍然难以捉摸(容易下药的蛋白质，失调的 癌症，但不是在健康细胞中)。 我们假设致癌转化是由癌基因相关染色质的异常活性驱动的。 (表观遗传学)修饰伴侣。这些变化创造了恶性状态所特有的染色质环境。 我们的初步数据，包括发表在临床癌症研究上的数据，提供了强有力的证据 总共有两个染色质致癌伙伴，JMJD3，一个由NOTCH1等癌基因选择的表观遗传参与者， 和去泛素酶USP7，代表了T-ALL的新治疗靶点。USP7似乎可以控制肿瘤 生长和JMJD3和NOTCH1的稳定至少是一个潜在的机制。JMJD3各自的抑制作用 而使用小分子的USP7似乎在体外显著抑制白血病细胞的生长。 我们建议进一步研究JMJD3和USP7在相关的人和小鼠中的致癌作用 模型，癌症中USP7突变的模型和进行小分子抑制剂的临床前分析 这两个靶点(单独使用或组合使用)。其他机械学研究将包括蛋白质组学 筛选USP7相互作用蛋白和全球组蛋白变化。 我们将评估JMJD3和USP7(单独和联合)对人类的基因组和化学抑制研究 T-ALL系、原发患者样本和小鼠：人类异种移植疾病模型：1) 转录和表观遗传变化，2)细胞活性，3)动物存活。 在目前尚无针对T细胞ALL的靶向治疗方法的情况下，发现两种新的抑制物靶点 鸡尾酒可以为未来的药物开发提供一个有用的概念。我们的生物制药合作者已经 为JMJD3和USP7生成了化学缓蚀剂。我们预计我们的机械分析可以帮助 作为未来毒理学分析的坚实基础，以及进一步的化学优化。

PROJECT SUMMARY/ABSTRACT Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with high unmet needs, as high cure rates achieved with intensive chemoradiation come at the expense of high toxicity rates and risk of secondary malignancies. Still, up to 25% pediatric ALL patients fail or relapse post-frontline chemoradiation, while response rates for relapsed disease are dismal (~20%). Whole-genome sequencing capabilities have shed new light on oncogenic processes, but identifying “clean” targets remain elusive (easily druggable proteins, dysregulated in cancer but not in healthy cells). We hypothesize that oncogenic transformation is driven by aberrant activity of oncogene-associated chromatin (epigenetic) modifying partners. These changes create a chromatin environment unique to the malignant state. Our preliminary data, including the ones published in Clinical Cancer Research, provides strong evidence that two chromatin oncogenic partners in ALL, JMJD3, an epigenetic player coopted by oncogenes such as NOTCH1, and the deubiquitinase USP7, represent novel therapeutic targets in T-ALL. USP7 appears to control tumor growth and JMJD3 and NOTCH1 stabilization is at least one potential mechanism. Inhibition of each of JMJD3 and USP7 using small molecules appears to significantly inhibit growth of leukemia cells in vitro. We propose to further characterize the pro-oncogenic roles of JMJD3 and USP7 in relevant human and murine models, model USP7 mutations in cancer and conduct preclinical analyses of small molecule inhibitors against these two targets (used as single agents or in combinations). Other mechanistic studies will include a proteomic screen for USP7 interactors and global histone changes. We will evaluate study genomic and chemical inhibition of JMJD3 and USP7 (individual and combined), in human T-ALL lines, primary patient samples, and mouse:human xenograft disease models with respect to: 1) transcriptional and epigenetic changes, 2) cellular viability, and 3) animal survival. Absent any targeted therapies currently in use for T cell ALL, identification of two novel targets for inhibitor cocktails could provide a useful concept for future drug development. Our biopharma collaborators have already generated chemical inhibitors for both JMJD3 and USP7. We anticipate our mechanistic analyses could serve as solid foundation for future toxicology analyses, along with further chemical optimization.