Division of Hematology and Medical Oncology, New York University School of Medicine and Perlmutter Comprehensive Cancer Center, New York University Langone Health, New York, NY, USA.
Mayo Clinic, Scottsdale, AZ, USA.
Target Oncol. 2020 Apr;15(2):147-162. doi: 10.1007/s11523-020-00711-3.
Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology over the past decade. Recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies. The discovery of drugs that promote apoptosis in leukemic cells has translated to encouraging activity in clinical trials. B-cell lymphoma (BCL)-2 inhibition has been at the center of drug development efforts to target apoptosis in AML. Remarkable clinical success with venetoclax has revolutionized the ways we treat hematological malignancies. Several landmark trials have demonstrated the potent antitumor activity of venetoclax, and it is now frequently combined with traditional cytotoxic agents to treat AML. However, resistance to BCL-2 inhibition is emerging, and alternative strategies to address resistance mechanisms have become an important focus of research. A number of clinical trials are now underway to investigate a plurality of novel agents that were shown to overcome resistance to BCL-2 inhibition in preclinical models. Some of the most promising data come from studies on drugs that downregulate myeloid cell leukemia (MCL)-1, such as cyclin-dependent kinases (CDK) inhibitors. Furthermore, innovative approaches to target apoptosis via extrinsic pathways and p53 regulation have added new cytotoxic agents to the arsenal, including drugs that inhibit inhibitor of apoptosis protein (IAP) family proteins and murine double minute 2 (MDM2). This review provides a perspective on past and current treatment strategies harnessing various mechanisms of apoptosis to target AML and highlights some important promising treatment combinations in development.
急性髓系白血病（AML）是一种造血系统疾病，尽管在过去十年中我们对其癌症生物学的理解取得了进展，但仍然是治疗上的挑战。近年来，分子靶向治疗的发展在治疗白血病方面取得了令人鼓舞的成果，为新的治疗策略铺平了道路。发现能够促进白血病细胞凋亡的药物已转化为临床试验中的令人鼓舞的活性。B 细胞淋巴瘤（BCL）-2 抑制已成为药物开发努力的中心，旨在靶向 AML 中的细胞凋亡。Venetoclax 的显著临床成功彻底改变了我们治疗血液恶性肿瘤的方式。几项里程碑式的试验已经证明了 Venetoclax 的强大抗肿瘤活性，现在它经常与传统细胞毒性药物联合用于治疗 AML。然而，BCL-2 抑制的耐药性正在出现，解决耐药机制的替代策略已成为研究的重要焦点。目前正在进行多项临床试验，以研究多种新型药物，这些药物在临床前模型中显示出克服 BCL-2 抑制的耐药性。最有前途的数据来自于下调髓样细胞白血病（MCL）-1 的药物研究，如细胞周期蛋白依赖性激酶（CDK）抑制剂。此外，通过外在途径和 p53 调节靶向细胞凋亡的创新方法为武器库增加了新的细胞毒性药物，包括抑制凋亡蛋白（IAP）家族蛋白和鼠双微体 2（MDM2）的药物。这篇综述提供了利用各种细胞凋亡机制靶向 AML 的过去和当前治疗策略的视角，并强调了一些正在开发中的重要有前途的治疗组合。
