Specific Inhibition of NOTCH2 Signaling in Bladder Cancer

膀胱癌中 NOTCH2 信号传导的特异性抑制

• 批准号: 427790756
• 负责人: Dr. Gerald Bastian Schulz
• 金额: --
• 依托单位: Prostate Centre
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/427790756?language=en
• 关键词: Specific; Inhibition; NOTCH2; Signaling; Bladder

The prognosis of patients with metastatic bladder cancer (BC) is poor. Individual targeted therapies seem to be a putative strategy in order to extend therapeutic options beyond systemic chemo- and immunotherapy. The group of Dr. Peter Black identified NOTCH2 (N2) as an oncogene in urothelial BC and both tumor growth and metastasis were suppressed using a specific N2-targeting antibody in an orthotopic xenograft mouse model. Furthermore, N2 RNA overexpression was correlated with poor survival in The Cancer Genome Atlas 2017 cohort in BC. Intriguingly, NOTCH1 (N1) signaling was demonstrated to play a tumor-suppressive role in BC. Two druggable sites on the N2 receptor were identified by Dr. Black’s group, which were both significantly dissimilar to the N1 molecular receptor configuration. Therefore, we intend to conduct a project aimed to identify and evaluate novel highly selective N2 inhibitors that do not interfere with other Notch receptors in BC.We will perform a structure-based virtual screening with ~10 million compounds from publicly available databases such as ZINC15 and ChEMBL, utilize computer-aided drug design programs and chemoinformatic techniques to identify the most promising small molecular compounds for selective N2 inhibition. In the next step, we will select compounds by in vitro screening of N2 inhibition using a Notch-specific responsive plasmid in a cell-based luciferase assay. Compound stability and metabolic degradation will be assessed in a microsomal instability assay. Antineoplastic effects of N2 inhibitors will be further analysed in BC cell lines, utilizing cell growth, cell-cycle progression, migration and invasion in vitro assays. Dosing parameters, degradation of compounds and toxicity as well as impact on tumor growth and metastasis will be assessed in an orthotopic BC xenograft mouse model in vivo.Importantly, there are no therapies targeting Notch signaling approved for patient care so far. A small molecule N2 specific inhibitor might bypass not only common side effects seen in unspecific pan-Notch inhibitors, but also disadvantages of monoclonal antibodies like antibody degradation and low tissue penetration. Taken together, our translational approach might lead to a highly specific small molecule N2 inhibitor with the capability to offer novel therapeutic options for patients with metastatic BC.

转移性膀胱癌患者预后较差。个体化靶向治疗似乎是一种推定的策略，目的是将治疗选择扩大到全身化疗和免疫治疗之外。Peter Black博士的团队发现NOTCH2(N2)是尿路上皮BC中的癌基因，在原位异种移植小鼠模型中，使用特定的n2靶向抗体抑制了肿瘤的生长和转移。此外，N2RNA的过度表达与不列颠哥伦比亚省癌症基因组图谱2017队列中的低生存率相关。有趣的是，NOTCH1(N1)信号被证明在BC中起到肿瘤抑制作用。布莱克博士的研究小组发现，N2受体上有两个可用药部位，这两个部位都与N1分子受体的构型显著不同。因此，我们打算开展一项旨在寻找和评估新型高选择性、不干扰BC中其他Notch受体的氮气抑制剂的项目。我们将从ZINC15和ChEMBL等公开数据库中对约1000万种化合物进行基于结构的虚拟筛选，利用计算机辅助药物设计程序和化学信息学技术来识别最有希望的选择性氮气抑制小分子化合物。在下一步中，我们将在基于细胞的荧光素酶实验中使用Notch特异的反应质粒通过体外筛选N2抑制来选择化合物。化合物的稳定性和代谢降解将在微粒体不稳定性分析中进行评估。将利用细胞生长、细胞周期进展、迁移和体外侵袭试验，进一步分析N2抑制剂在BC细胞系中的抗肿瘤作用。剂量参数、化合物的降解和毒性以及对肿瘤生长和转移的影响将在活体BC异种移植小鼠模型中进行评估。重要的是，到目前为止还没有针对Notch信号的治疗方法被批准用于患者护理。小分子氮气特异性抑制剂不仅可以避免非特异性PAN-Notch抑制剂的常见副作用，还可以避免单抗的缺点，如抗体降解和组织渗透率低。综上所述，我们的翻译方法可能会导致一种高度特异的小分子氮气抑制剂，能够为转移性结肠癌患者提供新的治疗选择。