1 University of Rome Tor Vergata, Tor Vergata University Clinical Center, Department of Systems Medicine, Medical Oncology , Viale Oxford 81, 00133 Rome , Italy +39 0620908190 ; +39 0620903504 ;
Expert Opin Investig Drugs. 2015;24(7):929-47. doi: 10.1517/13543784.2015.1035708. Epub 2015 Apr 9.
Despite the emergence of several new effective treatments for metastatic castration-resistant prostate cancer patients, disease progression inevitably occurs, leading scientific community to carefully look for novel therapeutic targets of prostate cancer. Kallikrein (KLK)-related peptidases have been demonstrated to facilitate prostate tumorigenesis and disease progression through the development of an oncogenic microenvironment for prostate cells.
This review first summarizes the large amount of preclinical data showing the involvement of KLKs in prostate cancer pathobiology. In the second part, the authors assess the current status and future directions for KLK-targeted therapy and briefly describe the advances and challenges implicated in the design of effective manufactured drugs. The authors then focus on the preclinical data and on Phase I/II studies of the most promising KLK-targeted agents in prostate cancer. The drugs discussed here are divided on the basis of their mechanism of action: KLK-engineered inhibitors; KLK-activated pro-drugs; KLK-targeted microRNAs and small interfering RNAs(-/)small hairpin RNAs; KLK vaccines and antibodies.
Targeting KLK expression and/or activity could be a promising direction in prostate cancer treatment. Future human clinical trials will help us to evaluate the real benefits, toxicities and the consequent optimal use of KLK-targeted drugs, as mono-therapy or in combination regimens.
尽管出现了几种新的有效治疗转移性去势抵抗性前列腺癌患者的方法，但疾病的进展不可避免，这促使科学界仔细寻找前列腺癌的新治疗靶点。激肽释放酶（KLK）相关肽酶已被证明通过为前列腺细胞发展致癌微环境来促进前列腺肿瘤发生和疾病进展。
这篇综述首先总结了大量的临床前数据，表明 KLKs 参与了前列腺癌的病理生物学。在第二部分，作者评估了 KLK 靶向治疗的现状和未来方向，并简要描述了在设计有效药物方面所涉及的进展和挑战。然后，作者将重点放在前列腺癌中最有前途的 KLK 靶向药物的临床前数据和 I/II 期研究上。这里讨论的药物根据其作用机制进行分类：KLK 工程抑制剂；KLK 激活的前药；KLK 靶向 microRNAs 和小干扰 RNA(-)/小发夹 RNA；KLK 疫苗和抗体。
靶向 KLK 的表达和/或活性可能是前列腺癌治疗的一个有前途的方向。未来的人类临床试验将帮助我们评估 KLK 靶向药物的真正益处、毒性以及随后的最佳使用，无论是单独使用还是联合使用。
