Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update.
Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update.
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DOI：
10.3390/cancers12113166
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发表时间：
2020-10-28
期刊：
影响因子：
5.2
通讯作者：
Naviglio S
中科院分区：
文献类型：
--
作者：
Sapio L;Salzillo A;Ragone A;Illiano M;Spina A;Naviglio S
目前，只有5%的药物相关靶点从临床前转移到癌症临床，其中只有一部分实现了患者的床边治疗。其中，肿瘤内异质性和临床前癌症模型的局限性实际上是这种失败的主要原因。环磷酸腺苷反应元件结合蛋白（cyclic-AMP response element-binding protein，CREB）是一种存在于不同肿瘤类型中的原癌基因，参与肿瘤的维持和发展。由于其在肿瘤病理生理学中的相关性，多年来已经开发和测试了许多CREB抑制剂化合物。在此，我们研究了CREB和CREB抑制剂在癌症中的最新技术水平，回顾了过去几年的一些最重要的发现。虽然科学声明赋予CREB在癌症中的积极作用，但其治疗潜力仍停留在实验室工作台上。因此，在临床上追求每一个具体的结果来实现CREB抑制可能会给全世界的癌症患者带来机会和未来。肿瘤内异质性（ITH）被认为是癌症治疗中的主要迷失因素。作为随机遗传和表观遗传改变的结果，分支进化形状的出现赋予肿瘤可塑性，导致复发和不利的临床预后。越来越多的癌症发现证据向我们提出了“巨大的悖论”，其中包括不断发现的无数潜在靶点和少数对人类患者有效的候选人。其中，环磷酸腺苷反应元件结合蛋白（CREB）已被认为是支持肿瘤发生、发展和转移的原癌基因。CREB的过度表达和过度活化经常在癌症中观察到，而CREB的遗传和药理学下调影响增殖和凋亡。值得注意的是，本综述旨在研究CREB靶向治疗癌症的可行性。特别是，从癌症病理生理学中最新的CREB证据开始，我们评估了CREB抑制剂设计的进展状态，包括我们新发现的组蛋白赖氨酸脱甲基酶JMJD 3/UTX抑制剂GSKJ 4，它是白血病细胞中有前途的CREB调节剂。此外，还对优势和劣势进行了准确的分析，以确定CREB是否真的可以代表治疗候选药物，或者只是无数临床前癌症靶点之一。
Only 5% of all drug-related targets currently move from preclinical to clinical in cancer, and just some of them achieve patient’s bedside. Among others, intratumor heterogeneity and preclinical cancer model limitations actually represent the main reasons for this failure. Cyclic-AMP response element-binding protein (CREB) has been defined as a proto-oncogene in different tumor types, being involved in maintenance and progression. Due to its relevance in tumor pathophysiology, many CREB inhibitor compounds have been developed and tested over the years. Herein, we examine the current state-of-the-art of both CREB and CREB inhibitors in cancer, retracing some of the most significant findings of the last years. While the scientific statement confers on CREB a proactive role in cancer, its therapeutic potential is still stuck at laboratory bench. Therefore, pursuing every concrete result to achieve CREB inhibition in clinical might give chance and future to cancer patients worldwide. Intratumor heterogeneity (ITH) is considered the major disorienting factor in cancer treatment. As a result of stochastic genetic and epigenetic alterations, the appearance of a branched evolutionary shape confers tumor plasticity, causing relapse and unfavorable clinical prognosis. The growing evidence in cancer discovery presents to us “the great paradox” consisting of countless potential targets constantly discovered and a small number of candidates being effective in human patients. Among these, cyclic-AMP response element-binding protein (CREB) has been proposed as proto-oncogene supporting tumor initiation, progression and metastasis. Overexpression and hyperactivation of CREB are frequently observed in cancer, whereas genetic and pharmacological CREB downregulation affects proliferation and apoptosis. Notably, the present review is designed to investigate the feasibility of targeting CREB in cancer therapy. In particular, starting with the latest CREB evidence in cancer pathophysiology, we evaluate the advancement state of CREB inhibitor design, including the histone lysine demethylases JMJD3/UTX inhibitor GSKJ4 that we newly identified as a promising CREB modulator in leukemia cells. Moreover, an accurate analysis of strengths and weaknesses is also conducted to figure out whether CREB can actually represent a therapeutic candidate or just one of the innumerable preclinical cancer targets.
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影响因子：
--
作者：
Daures M;Idrissou M;Judes G;Rifaï K;Penault-Llorca F;Bignon YJ;Guy L;Bernard-Gallon D
通讯作者：
Bernard-Gallon D
影响因子：
15.9
作者：
Daniel, Paul M.;Filiz, Gulay;Mantamadiotis, Theo
通讯作者：
Mantamadiotis, Theo
影响因子：
5.6
作者：
Choi MH;Jo HG;Yang JH;Ki SH;Shin HJ
通讯作者：
Shin HJ
DOI：
10.1007/978-3-319-62817-2_2
发表时间：
2017-01-01
期刊：
PLASTIC BRAIN
影响因子：
--
作者：
Belgacem, Yesser H.;Borodinsky, Laura N.
通讯作者：
Borodinsky, Laura N.
影响因子：
50.3
作者：
Bender, Sebastian;Tang, Yujie;Pfister, Stefan M.
通讯作者：
Pfister, Stefan M.