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赖氨酸特异性去甲基化酶1作为一种生物标志物及其抑制剂在临床试验中的结果:肿瘤治疗机遇

LSD1 as a Biomarker and the Outcome of Its Inhibitors in the Clinical Trial: The Therapy Opportunity in Tumor.

作者信息

Agboyibor Clement, Dong Jianshu, Effah Clement Yaw, Drokow Emmanuel Kwateng, Pervaiz Waqar, Liu Hong-Min

机构信息

School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.

Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou 450001, China.

出版信息

J Oncol. 2021 Mar 25;2021:5512524. doi: 10.1155/2021/5512524. eCollection 2021.

Abstract

Tumors are the foremost cause of death worldwide. As a result of that, there has been a significant enhancement in the investigation, treatment methods, and good maintenance practices on cancer. However, the sensitivity and specificity of a lot of tumor biomarkers are not adequate. Hence, it is of inordinate significance to ascertain novel biomarkers to forecast the prognosis and therapy targets for tumors. This review characterized LSD1 as a biomarker in different tumors. LSD1 inhibitors in clinical trials were also discussed. The recent pattern advocates that LSD1 is engaged at sauce chromatin zones linking with complexes of multi-protein having an exact DNA-binding transcription factor, establishing LSD1 as a favorable epigenetic target, and also gives a large selection of therapeutic targets to treat different tumors. This review sturdily backing the oncogenic probable of LSD1 in different tumors indicated that LSD1 levels can be used to monitor and identify different tumors and can be a useful biomarker of progression and fair diagnosis in tumor patients. The clinical trials showed that inhibitors of LSD1 have growing evidence of clinical efficacy which is very encouraging and promising. However, for some of the inhibitors such as GSK2879552, though selective, potent, and effective, its disease control was poor as the rate of adverse events (AEs) was high in tumor patients causing clinical trial termination, and continuation could not be supported by the risk-benefit profile. Therefore, we propose that, to attain excellent clinical results of inhibitors of LSD1, much attention is required in designing appropriate dosing regimens, developing in-depth in vitro/in vivo mechanistic works of LSD1 inhibitors, and developing inhibitors of LSD1 that are reversible, safe, potent, and selective which may offer safer profiles.

摘要

肿瘤是全球首要的死亡原因。因此,在癌症的研究、治疗方法和良好的维持治疗方面有了显著的进展。然而,许多肿瘤生物标志物的敏感性和特异性并不足够。因此,确定新的生物标志物以预测肿瘤的预后和治疗靶点具有极其重要的意义。本综述将赖氨酸特异性去甲基化酶1(LSD1)描述为不同肿瘤中的一种生物标志物。还讨论了临床试验中的LSD1抑制剂。最近的模式表明,LSD1参与了与具有精确DNA结合转录因子的多蛋白复合物相关的染色质区域,确立了LSD1作为一个良好的表观遗传靶点,并且还提供了大量治疗不同肿瘤的治疗靶点。本综述有力地支持了LSD1在不同肿瘤中的致癌可能性,表明LSD1水平可用于监测和识别不同肿瘤,并且可以成为肿瘤患者病情进展和准确诊断的有用生物标志物。临床试验表明,LSD1抑制剂的临床疗效证据越来越多,这非常令人鼓舞且前景广阔。然而,对于一些抑制剂,如GSK2879552,尽管具有选择性、强效且有效,但其疾病控制效果不佳,因为肿瘤患者的不良事件发生率很高,导致临床试验终止,且风险效益分析不支持继续进行。因此,我们建议,为了获得LSD1抑制剂优异的临床效果,在设计合适的给药方案、开展LSD1抑制剂深入的体外/体内作用机制研究以及开发可逆、安全、强效且选择性的LSD1抑制剂方面需要给予更多关注,这些抑制剂可能会提供更安全的情况。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1009/8018836/0cfb1a4de91f/JO2021-5512524.001.jpg

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