Abstract
Adrenocortical carcinomas (ACCs) are rather rare endocrine tumors that often have a poor prognosis. The reduced survival rate associated with these tumors is due to their aggressive biological behavior, combined with the scarcity of effective treatment options that are currently available. The recent identification of the genomic alterations present in ACC have provided further molecular mechanisms to develop consistent strategies for the diagnosis, prevention of progression and treatment of advanced ACCs. Taken together, molecular and genomic advances could be leading the way to develop personalized medicine in ACCs similarly to similar developments in lung or breast cancers. In this review, we focused our attention to systematically compile and summarize the alterations in the cell cycle regulation that were described so far in ACC as they are known to play a crucial role in cell differentiation and growth. We have divided the analysis according to the major transition phases of the cell cycle, G1 to S and G2 to M. We have analyzed the most extensively studied checkpoints: the p53/Rb1 pathway, CDC2/cyclin B and topoisomerases (TOPs). We reached the conclusion that the most important alterations having a potential application in clinical practice are the ones related to p53/Rb1 and TOP 2. We also present a brief description of on-going clinical trials based on molecular alterations in ACC. The drugs have targeted the insulin-like growth factor receptor 1, TOP 2, polo-like kinase1, cyclin-dependent kinase inhibitors, p53 reactivation and CDC25.
Highlights
Adrenocortical carcinomas (ACCs) are rather rare tumors, and this constituted a major limitation to conduct wide and comprehensive molecular characterization studies
Since alterations in the cell cycle regulators were pointedout as very important ACC drivers by the already mentioned pan-genomic studies and by several smaller studies, we decided to gather the current knowledge on cell cycle dysregulation in ACCs in this review
Eight ACC patients (NCT01262235) received two cycles of the treatment and four patients showed a good response in stabilizing disease including a 13% reduction of tumor size in one patient, suggesting that the role of PLK1 inhibition for ACC treatment should be further investigated [149]
Summary
Adrenocortical carcinomas (ACCs) are rather rare tumors, and this constituted a major limitation to conduct wide and comprehensive molecular characterization studies. A relatively large number of studies identified a wide array of molecular alterations, but usually in a relatively limited number of ACC samples. Molecular studies that aimed to characterize the cell cycle deregulations found in adrenocortical tumors (ACTs) are the subject of this systematic review. This comprehensive review aims to clarify some apparently contradictory results and rather complex molecular interactions. The data presented in this review intends to be a useful working resource for researchers interested in ACC to identify new diagnostic, prognostic and therapeutic tools to improve outcomes for ACC patients
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