Lim Bora, Greer Yoshimi, Lipkowitz Stanley, Takebe Naoko
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Cancers (Basel). 2019 Jul 31;11(8):1087. doi: 10.3390/cancers11081087.
Evasion from apoptosis is an important hallmark of cancer cells. Alterations of apoptosis pathways are especially critical as they confer resistance to conventional anti-cancer therapeutics, e.g., chemotherapy, radiotherapy, and targeted therapeutics. Thus, successful induction of apoptosis using novel therapeutics may be a key strategy for preventing recurrence and metastasis. Inhibitors of anti-apoptotic molecules and enhancers of pro-apoptotic molecules are being actively developed for hematologic malignancies and solid tumors in particular over the last decade. However, due to the complicated apoptosis process caused by a multifaceted connection with cross-talk pathways, protein-protein interaction, and diverse resistance mechanisms, drug development within the category has been extremely challenging. Careful design and development of clinical trials incorporating predictive biomarkers along with novel apoptosis-inducing agents based on rational combination strategies are needed to ensure the successful development of these molecules. Here, we review the landscape of currently available direct apoptosis-targeting agents in clinical development for cancer treatment and update the related biomarker advancement to detect and validate the efficacy of apoptosis-targeted therapies, along with strategies to combine them with other agents.
逃避凋亡是癌细胞的一个重要特征。凋亡途径的改变尤为关键，因为它们赋予癌细胞对传统抗癌疗法（如化疗、放疗和靶向治疗）的抗性。因此，使用新型疗法成功诱导凋亡可能是预防复发和转移的关键策略。在过去十年中，尤其是针对血液系统恶性肿瘤和实体瘤，抗凋亡分子抑制剂和促凋亡分子增强剂正在积极研发。然而，由于凋亡过程与相互作用途径、蛋白质-蛋白质相互作用以及多种抗性机制存在多方面复杂联系，该类别内的药物研发极具挑战性。需要精心设计和开展临床试验，将预测性生物标志物与基于合理联合策略的新型凋亡诱导剂相结合，以确保这些分子的成功研发。在此，我们综述了目前正在临床开发用于癌症治疗的直接靶向凋亡药物的情况，并更新了相关生物标志物的进展，以检测和验证靶向凋亡疗法的疗效，以及将它们与其他药物联合使用的策略。
