Abstract：
A majority of patients with cancer receive radiotherapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiotherapy has significant short-term and long-term toxicities for cancer survivors. Insights into molecular mechanisms involved in cellular responses to DNA breaks introduced by radiation or other cancer therapies have been gained in recent years and approaches to manipulate these responses to enhance tumor cell killing or reduce normal tissue toxicity are of great interest. Here, we report the identification and initial characterization of XRD-0394, a potent and specific dual inhibitor of two DNA damage response kinases, ATM and DNA-PKcs. This orally bioavailable molecule demonstrates significantly enhanced tumor cell kill in the setting of therapeutic ionizing irradiation in vitro and in vivo. XRD-0394 also potentiates the effectiveness of topoisomerase I inhibitors in vitro. In addition, in cells lacking BRCA1/2 XRD-0394 shows single-agent activity and synergy in combination with PARP inhibitors. A phase Ia clinical trial (NCT05002140) with XRD-0394 in combination with radiotherapy has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with radiotherapy, PARP inhibitors, and targeted delivery of topoisomerase I inhibitors.
摘要：
大多数癌症患者接受放射治疗作为其治疗方案的一部分，无论是使用外部束治疗还是局部递送的放射性同位素。虽然通常有效，一些肿瘤的放疗控制不充分,放疗对癌症幸存者有显著的短期和长期毒性.近年来,已经获得了对通过放射或其他癌症疗法引入的DNA断裂的细胞应答中所涉及的分子机制的见解,并且操纵这些应答以增强肿瘤细胞杀伤或降低正常组织毒性的方法是非常感兴趣的。这里,我们报告了XRD-0394的鉴定和初步表征，这是一种有效和特异性的两种DNA损伤反应激酶的双重抑制剂，ATM和DNA-PKcs。这种口服生物可利用的分子在体外和体内治疗性电离辐射的背景下显示出显著增强的肿瘤细胞杀伤作用。XRD-0394还增强了拓扑异构酶I抑制剂在体外的有效性。此外,在缺乏BRCA1/2的细胞中，XRD-0394显示出单一试剂活性和与PARP抑制剂组合的协同作用。使用XRD-0394与RT组合的Ia期临床试验(NCT05002140)已经完成。这些结果为XRD-0394与RT结合的未来临床试验提供了理论基础。PARP抑制剂和拓扑异构酶I抑制剂的靶向递送。
