Mechanisms of T-cell leukemogenesis induced by NOTCH1

描述(申请人提供)：伽马分泌酶抑制剂(GSI)阻断早老素-伽马分泌酶复合体，抑制与阿尔茨海默病发病机制有关的淀粉样蛋白A多肽的产生和Notch受体的激活。最近在超过50%的T淋巴细胞白血病(T-ALL)病例中发现了NOTCH1受体基因的激活突变，这促使了一项临床试验的启动，以测试用小分子GSI阻断NOTCH1信号转导在本病中的有效性。然而，基于GSI的治疗方法的临床发展一直受到这些药物诱导人类T-ALL细胞凋亡的有限能力的限制，以及由于肠道中Notch信号的抑制而产生的严重的胃肠道毒性。在过去的两年里，我们的团队结合了芯片上的分析和微阵列基因表达谱来阐明T-ALL中由致癌的NOTCH1信号控制的转录调控网络结构。这项研究揭示了NOTCH1激活的致癌程序的基本方面。在这项竞争性修订申请中，我们将把我们的项目范围扩大到阐明肠上皮细胞中由Noch信号控制的基因和通路。这些研究将提供有价值的信息，通过全身抑制GSI对Noch信号的抑制来调节胃肠道毒性的发生机制。 与公共健康相关：伽马分泌酶抑制剂(GSI)可以阻断早老素-伽马分泌酶复合体，是治疗人类癌症的有前途的药物。然而，由于肠道中Notch信号的抑制，基于GSI的治疗的临床发展一直阻碍着严重的胃肠道毒性的发展。这一竞争性修订申请解决了通过GSI全身抑制Notch信号而导致胃肠道毒性发展的机制。

DESCRIPTION (provided by applicant): Gamma-secretase inhibitors (GSIs), which block the presenilin-gamma secretase complex, inhibit the production of amyloidogenic A peptides involved in the pathogenesis of Alzheimer's disease and the activation of NOTCH receptors. Recent identification of activating mutations in the NOTCH1 receptor gene in over 50% of cases of T-cell lymphoblastic leukemia (T-ALL) prompted the initiation of a clinical trial to test the effectiveness of blocking NOTCH1 signaling with a small molecule GSI in this disease. However, the clinical development of GSI-based therapies has been hampered by the limited ability of these drugs to induce apoptosis in human T-ALL and by the development of severe gastrointestinal toxicity due to inhibition of NOTCH signaling in the gut. Over the last two years our group has used a combination of ChIP-on-chip analysis and microarray gene expression profiling to elucidate the structure of the transcriptional regulatory network controlled by oncogenic NOTCH1 signaling in T-ALL. This research has revealed fundamental aspects of the oncogenic program activated by NOTCH1. In this Competitive Revision Application we will expand the scope of our project to the elucidation of genes and pathways controlled by NOTCH signaling in intestinal epithelial cells. These studies will provide valuable information regarding the mechanisms mediating the development of gastrointestinal toxicity upon systemic inhibition of NOTCH signaling with GSIs. PUBLIC HEALTH RELEVANCE: Gamma-secretase inhibitors (GSIs), which block the presenilin-gamma secretase complex, are promising drugs for the treatment of human cancer. However, the clinical development of GSI-based therapies has been hampered the development of severe gastrointestinal toxicity due to inhibition of NOTCH signaling in the gut. This Competitive Revision Application address the mechanisms mediating the development of gastrointestinal toxicity upon systemic inhibition of NOTCH signaling with GSIs.