Targeting TP53 disruption in chronic lymphocytic leukemia: Current strategies and future directions

IF 3.3 4区医学 Q2 HEMATOLOGY

Hematological Oncology Pub Date : 2023-11-08 DOI:10.1002/hon.3238

Stefano Molica, Constantine Tam, David Allsup, Aaron Polliack

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引用次数: 0

Abstract

In the modern era of Chronic Lymphocytic Leukemia (CLL) targeted therapy, the loss of p53 function due to genetic abnormalities remains a significant challenge. This is because even targeted agents, which are currently the mainstay of treatment for CLL, do not directly target p53 or restore its disrupted pathway. Consequently, resistance to therapy and unfavorable clinical outcomes often accompany these p53-related abnormalities. An essential goal of future clinical research should be to address the ostensibly “undruggable” p53 pathway. Currently, multiple therapeutic approaches are being explored to tackle TP53 dysfunction and improve outcomes in high-risk CLL. These approaches include the use of oncoprotein murine double minute 2 inhibitors, small-molecule p53 reactivators, exportin 1 (XPO1) inhibitors, and ataxia-telangiectasia mutated and Rad3-related (ATR) inhibitors. Combinations of these p53-targeting strategies, along with established novel therapies such as B-cell receptor or B-cell lymphoma-2 (BCL-2) inhibitors, may shape the future of therapeutic trials in this challenging-to-treat disease.

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靶向慢性淋巴细胞白血病中TP53破坏：当前策略和未来方向。

在现代慢性淋巴细胞白血病（CLL）靶向治疗中，由于基因异常导致的p53功能丧失仍然是一个重大挑战。这是因为即使是目前治疗CLL的主要靶向药物，也不能直接靶向p53或恢复其被破坏的途径。因此，对治疗的耐药性和不利的临床结果往往伴随着这些p53相关的异常。未来临床研究的一个重要目标应该是解决表面上“不可治愈”的p53通路。目前，正在探索多种治疗方法来解决TP53功能障碍并改善高危CLL的预后。这些方法包括使用肿瘤蛋白鼠双分钟2抑制剂、小分子p53再激活剂、出口蛋白1（XPO1）抑制剂、共济失调毛细血管扩张突变和Rad3相关（ATR）抑制剂。这些p53靶向策略的组合，以及已建立的新疗法，如B细胞受体或B细胞淋巴瘤-2（BCL-2）抑制剂，可能会影响这种具有挑战性的疾病治疗试验的未来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Hematological Oncology 医学-血液学

CiteScore

4.20

自引率

6.10%

发文量

147

审稿时长

>12 weeks

期刊介绍： Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.