Du Fang-Yu, Zhou Qi-Fan, Sun Wen-Jiao, Chen Guo-Liang
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China.
World J Stem Cells. 2019 Jul 26;11(7):398-420. doi: 10.4252/wjsc.v11.i7.398.
In recent decades, cancer stem cells (CSCs) have been increasingly identified in many malignancies. CSC-related signaling pathways and their functions provide new strategies for treating cancer. The aberrant activation of related signaling pathways (., Wnt, Notch, and Hedgehog pathways) has been linked to multiple types of malignant tumors, which makes these pathways attractive targets for cancer therapy. CSCs display many characteristic features, such as self-renewal, differentiation, high tumorigenicity, and drug resistance. Therefore, there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication, survival, and differentiation. Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape. Therefore, multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs. Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials, and some inhibitors, such as vismodegib, sonidegib, and glasdegib, have been approved. Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein. The signal transducers and activators of transcription 3 (STAT3) inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers. Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development, which is another strategy for CSC therapy. In addition to the potential pharmacological inhibitors targeting CSC-related signaling pathways, other methods of targeting CSCs are available, such as nano-drug delivery systems, mitochondrion targeting, autophagy, hyperthermia, immunotherapy, and CSC microenvironment targeting. In addition, we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.
近几十年来，在许多恶性肿瘤中越来越多地发现了癌症干细胞（CSCs）。与CSC相关的信号通路及其功能为癌症治疗提供了新策略。相关信号通路（如Wnt、Notch和Hedgehog通路）的异常激活与多种恶性肿瘤有关，这使得这些通路成为有吸引力的癌症治疗靶点。CSCs表现出许多特征，如自我更新、分化、高致瘤性和耐药性。因此，迫切需要开发新的治疗策略来靶向这些通路，以控制干细胞的复制、存活和分化。不同信号通路之间存在显著的串扰，并可能导致代偿性逃逸。因此，多靶点抑制剂将是克服CSCs耐药性的主要方法之一。许多CSCs中信号通路成分的小分子抑制剂已进入临床试验，一些抑制剂，如维莫德吉、索尼德吉和格拉斯吉布，已获批准。由于Smo蛋白发生突变，肿瘤细胞对索尼德吉和维莫德吉耐药。信号转导和转录激活因子3（STAT3）抑制剂BBI608正在进行针对多种癌症的III期试验评估。BBI608的结构衍生物是STAT3抑制剂开发的主要重点，这是CSC治疗的另一种策略。除了针对CSC相关信号通路的潜在药理抑制剂外，还有其他靶向CSCs的方法，如纳米药物递送系统、线粒体靶向、自噬、热疗、免疫疗法和CSC微环境靶向。此外，我们总结了靶向CSC相关信号通路的药物以及其他靶向CSCs方法在临床开发方面的最新进展。
