Abstract
Simple SummaryOnly 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.
Highlights
GLOBOCAN 2018 has confirmed for the oncological disorders the dubious distinction of being the second leading cause of death worldwide [1]
The cyclic-AMP response element-binding protein (CREB) inhibitor state-of-the-art is investigated extensively, including the histone lysine demethylases JMJD3/UTX inhibitor GSKJ4 that we newly identified as a promising CREB modulator in AML cells [16]
CREB has been proved to operate as an upstream effector of the CCAAT/enhancer-binding protein beta (C/EBPβ), a transcription factor frequently overexpressed in gastric cancer (GC) and associated with the suppression of the differentiation marker
Summary
GLOBOCAN 2018 has confirmed for the oncological disorders the dubious distinction of being the second leading cause of death worldwide [1]. Pancreatic cancer models, a reduced ITH of existing preclinical models is considered a causative element for targets failure in clinical [11,12]. Collective interactions among tumor, immune and stroma cells remain challenging to replicate in preclinical models, as well as their relative influence on ITH In light of these remarks, no existing preclinical model can perfectly forecast the patient outcomes in cancer. Only a combined multidisciplinary approach, aimed prior to examine the relevance of preclinical findings, could reduce phase II and III failure in cancer Verifying their relative targets and having a deep knowledge of the molecular mechanism of such anticancer drugs would help to propose more efficient therapy options in clinical [15]. Analyzing the strengths and weaknesses of targeting CREB, we attempt to figure out whether this therapeutic approach can represent a viable solution in cancer in the future
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