Lenz Heinz-Josef, Kahn Michael
USC Norris Comprehensive Cancer Center, USC Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, California, USA.
Cancer Sci. 2014 Sep;105(9):1087-92. doi: 10.1111/cas.12471. Epub 2014 Sep 6.
Throughout our life, long-lived somatic stem cells (SSC) regenerate adult tissues both during homeostatic processes and repair after injury. The role of aberrant regulation of SSC has also recently gained prominence in the field of cancer research. Following malignant transformation, so termed cancer stem cells (CSC), endowed with the same properties as SSC (i.e. the ability to both self-renew and generate differentiated progenitors), play a major part in tumor initiation, therapy resistance and ultimately relapse. The same signaling pathways involved in regulating SSC maintenance are involved in the regulation of CSC. CSC exist in a wide array of tumor types, including leukemias, and brain, breast, prostate and colon tumors. Consequently, one of the key goals in cancer research over the past decade has been to develop therapeutic strategies to safely eliminate the CSC population without damaging the endogenous SSC population. A major hurdle to this goal lies in the identification of the key mechanisms that distinguish CSC from the normal endogenous tissue stem cells. This review will discuss the discovery of the specific CBP/catenin antagonist ICG-001 and the ongoing clinical development of the second generation CBP/catenin antagonist PRI-724. Importantly, specific CBP/catenin antagonists appear to have the ability to safely eliminate CSC by taking advantage of an intrinsic differential preference in the way SSC and CSC divide.
在我们的一生中，长寿的体细胞干细胞（SSC）在稳态过程以及损伤后的修复过程中都会使成体组织再生。最近，SSC异常调节的作用在癌症研究领域也备受关注。恶性转化后，所谓的癌症干细胞（CSC）具有与SSC相同的特性（即自我更新和产生分化祖细胞的能力），在肿瘤起始、治疗抗性以及最终的复发中起主要作用。调节SSC维持的相同信号通路也参与CSC的调节。CSC存在于多种肿瘤类型中，包括白血病以及脑、乳腺、前列腺和结肠肿瘤。因此，在过去十年中癌症研究的关键目标之一就是开发治疗策略，以安全地消除CSC群体而不损害内源性SSC群体。实现这一目标的主要障碍在于确定区分CSC与正常内源性组织干细胞的关键机制。本综述将讨论特异性CBP/连环蛋白拮抗剂ICG-001的发现以及第二代CBP/连环蛋白拮抗剂PRI-724正在进行的临床开发。重要的是，特异性CBP/连环蛋白拮抗剂似乎能够通过利用SSC和CSC分裂方式的内在差异偏好来安全地消除CSC。
