Targeting the DNA damage response to enhance radiotherapy in soft tissue sarcomas

IF 5.5 2区 医学 Q1 HEMATOLOGY
Bauke H.G. van Riet , Sanne Venneker , Judith V.M.G. Bovée , Neeltje Steeghs , Rick L. Haas
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Abstract

Radiotherapy plays an important role in treating non-metastatic soft tissue sarcomas by inducing DNA damage and subsequent cell death. However, all cells possess defence mechanisms to repair DNA damage via DNA damage response (DDR) pathways. Inhibition of these DDR pathways may enhance tumour sensitivity to radiation, potentially improving treatment outcomes. This review assesses the potential of DDR inhibition to enhance radiosensitivity in soft tissue sarcomas, by evaluating both preclinical and clinical studies that combined DDR inhibitors and radiotherapy. Studies were identified by searching literature databases, clinical trial registries and conference abstracts, and focused on the relevance for combining DDR inhibitors and radiotherapy in soft tissue sarcoma treatment. Targeting DDR pathways through key proteins like PARP, ATM and ATR appears to be a promising approach to increase the radiosensitivity of soft tissue sarcomas in preclinical studies with minimal increased toxicity. Although phase I and II clinical trials observed that DDR inhibitors are mostly well tolerated, phase II trials observed limited to no improvement in disease control or overall survival. Moreover, some trials observed increased severe toxicities, especially at higher radiation doses or accelerated schedules. Nevertheless, DDR inhibitors have a great potential to sensitize soft tissue sarcomas to radiotherapy. Unfortunately, the currently developed DDR inhibitors have shown limited effect on overall survival and recurrence rates. Therefore, efforts should be made to either improve their efficacy or to reduce radiation doses through DDR inhibitor-mediated radiosensitization while maintaining efficacy.
靶向DNA损伤反应增强软组织肉瘤放疗
放射治疗通过诱导DNA损伤和随后的细胞死亡在治疗非转移性软组织肉瘤中起重要作用。然而,所有细胞都具有通过DNA损伤反应(DDR)途径修复DNA损伤的防御机制。抑制这些DDR通路可能会增强肿瘤对辐射的敏感性,从而潜在地改善治疗结果。本综述通过评估DDR抑制剂联合放疗的临床前和临床研究,评估了DDR抑制剂增强软组织肉瘤放射敏感性的潜力。通过检索文献数据库、临床试验注册库和会议摘要来确定研究,重点关注DDR抑制剂与放疗在软组织肉瘤治疗中的相关性。在临床前研究中,通过关键蛋白如PARP、ATM和ATR靶向DDR通路似乎是一种有希望的方法,可以增加软组织肉瘤的放射敏感性,同时毒性增加最小。尽管I期和II期临床试验观察到DDR抑制剂大多耐受性良好,但II期试验观察到的疾病控制或总生存期的改善有限或没有改善。此外,一些试验观察到严重毒性增加,特别是在较高的辐射剂量或加速的时间表下。然而,DDR抑制剂有很大的潜力使软组织肉瘤对放疗敏感。不幸的是,目前开发的DDR抑制剂对总生存率和复发率的影响有限。因此,在保持疗效的同时,应努力提高其疗效或通过DDR抑制剂介导的放射增敏来降低辐射剂量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.00
自引率
3.20%
发文量
213
审稿时长
55 days
期刊介绍: Critical Reviews in Oncology/Hematology publishes scholarly, critical reviews in all fields of oncology and hematology written by experts from around the world. Critical Reviews in Oncology/Hematology is the Official Journal of the European School of Oncology (ESO) and the International Society of Liquid Biopsy.
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