Chen Helen H W, Kuo Macus Tien
Division of Clinical Radiation Oncology, Department of Radiation Oncology, National Cheng Kung University Hospital, Department of Radiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Oncotarget. 2017 Jun 8;8(37):62742-62758. doi: 10.18632/oncotarget.18409. eCollection 2017 Sep 22.
Effective radiotherapy for cancer has relied on the promise of maximally eradicating tumor cells while minimally killing normal cells. Technological advancement has provided state-of-the-art instrumentation that enables delivery of radiotherapy with great precision to tumor lesions with substantial reduced injury to normal tissues. Moreover, better understanding of radiobiology, particularly the mechanisms of radiation sensitivity and resistance in tumor lesions and toxicity in normal tissues, has improved the treatment efficacy of radiotherapy. Previous mechanism-based studies have identified many cellular targets that can affect radiation sensitivity, notably reactive oxygen species, DNA-damaging response signals, and tumor microenvironments. Several radiation sensitizers and protectors have been developed and clinically evaluated; however, many of these results are inconclusive, indicating that improvement remains needed. In this era of personalized medicine in which patients' genetic variations, transcriptome and proteomics, tumor metabolism and microenvironment, and tumor immunity are available. These new developments have provided opportunity for new target discovery. Several radiotherapy sensitivity-associated "gene signatures" have been reported although clinical validations are needed. Recently, several immune modifiers have been shown to associate with improved radiotherapy in preclinical models and in early clinical trials. Combination of radiotherapy and immunocheckpoint blockade has shown promising results especially in targeting metastatic tumors through abscopal response. In this article, we succinctly review recent advancements in the areas of mechanism-driven targets and exploitation of new targets from current radio-oncogenomic and radiation-immunotherapeutic approaches that bear clinical implications for improving the treatment efficacy of radiotherapy.
有效的癌症放射治疗依赖于在最大限度地根除肿瘤细胞的同时，将对正常细胞的杀伤降至最低。技术进步提供了先进的仪器设备，能够将放射治疗精确地输送到肿瘤病灶，同时大幅减少对正常组织的损伤。此外，对放射生物学的更深入理解，特别是肿瘤病灶中辐射敏感性和抗性的机制以及正常组织中的毒性，提高了放射治疗的疗效。先前基于机制的研究已经确定了许多可影响辐射敏感性的细胞靶点，特别是活性氧、DNA损伤反应信号和肿瘤微环境。已经开发并进行了几种辐射增敏剂和保护剂的临床评估；然而，许多结果尚无定论，这表明仍需改进。在这个个性化医疗的时代，患者的基因变异、转录组和蛋白质组学、肿瘤代谢和微环境以及肿瘤免疫情况都已明晰。这些新进展为新靶点的发现提供了机会。尽管需要临床验证，但已经报道了几种与放射治疗敏感性相关的“基因特征”。最近，在临床前模型和早期临床试验中，几种免疫调节剂已被证明与放射治疗效果的改善有关。放射治疗与免疫检查点阻断的联合应用已显示出有前景的结果，特别是通过远隔效应靶向转移性肿瘤。在本文中，我们简要回顾了机制驱动靶点领域以及当前放射肿瘤基因组学和放射免疫治疗方法中对新靶点的利用方面的最新进展，这些进展对提高放射治疗疗效具有临床意义。
