Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale , Novara, Italy.
Expert Opin Ther Targets. 2020 Dec;24(12):1239-1250. doi: 10.1080/14728222.2020.1832465. Epub 2020 Oct 19.
Genomic studies have allowed to identify molecular predictors for chronic lymphocytic leukemia (CLL) treatment tailoring. disruption is the strongest predictor of chemo-refractoriness and its assessment is the first decisional node in the disease treatment algorithm.
The review covers the p53 biological pathway, its genetic alterations and clinical implications in CLL, and its druggable targets. The potential therapeutic options for disrupted patients are described, including: agents circumventing disruption; targeted therapies restoring the physiological function of mutant p53; and medicines potentiating p53 function.
The key approach to improve CLL outcome is treatment tailoring in individual patients. BCR and BCL2 inhibitors have significantly improved CLL survival, however disrupted patients still have a less favorable outcome than wild type cases, possibly because these novel drugs do not directly target p53 and do not restore the function of the disrupted p53 pathway. Emerging innovative molecules in cancer are able to restore the p53 mutant protein and/or potentiate the activity of the p53 wild type protein. If these compounds were confirmed as efficacious also for CLL, they would represent another step forward in the care of high risk CLL patients with abnormalities.
基因组研究使得能够识别慢性淋巴细胞白血病（CLL）治疗个体化的分子预测因子。 破坏是化疗耐药性的最强预测因子，其评估是疾病治疗算法中的第一个决策节点。
本综述涵盖了 p53 生物学途径、CLL 中的遗传改变及其临床意义，以及其可成药的靶点。描述了针对 破坏患者的潜在治疗选择，包括：绕过 破坏的药物；恢复突变型 p53生理功能的靶向治疗；以及增强 p53 功能的药物。
改善 CLL 预后的关键方法是对个体患者进行治疗个体化。BCR 和 BCL2 抑制剂显著改善了 CLL 的生存，但 破坏的患者的预后仍不如野生型病例，这可能是因为这些新型药物不能直接靶向 p53，也不能恢复 破坏的 p53 途径的功能。癌症中新兴的创新药物能够恢复突变型 p53 蛋白和/或增强野生型 p53 蛋白的活性。如果这些化合物被证实对 CLL 也有效，它们将代表高危 CLL 患者伴 异常治疗的又一个进步。
