Princess Margaret Research Institute, Toronto, Canada.
Princess Margaret Research Institute, Toronto, Canada; Radiation Medicine Program, University Health, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada.
Int J Radiat Oncol Biol Phys. 2021 Aug 1;110(5):1317-1324. doi: 10.1016/j.ijrobp.2021.03.031. Epub 2021 Mar 23.
Cervical cancer is a global health problem. Despite the growth of prevention programs, there is an important need to improve the effectiveness of treatment for patients with invasive, locally advanced disease. In this study we examined (1) the efficacy of radiation therapy (RT) with cisplatin (RTCT) and an orally administered CXCR4 inhibitor suitable for clinical use, X4-136; (2) biomarkers of response to RTCT and X4-136; and (3) intestinal toxicity from RTCT and X4-136.
Orthotopic cervical cancer xenografts derived from our patients were treated with RT (30 Gy; 2 Gy/d) and cisplatin (4 mg/kg/wk intraperitoneally) with or without concurrent X4-136 (100 mg/kg/d orally) for 3 weeks. Mice were euthanized immediately after treatment for biomarker assessment or followed to evaluate primary tumor growth delay and metastases. In separate experiments, acute and late intestinal injury were assessed histologically.
RTCT alone increased CXCL12/CXCR4 signaling, intratumoral accumulation of myeloid cells, and PD-L1 expression. The addition of X4-136 during RTCT abrogated these effects, improved primary tumor response, and reduced metastases. Furthermore, X4-136 increased the proportion of surviving intestinal crypt cells after irradiation, in keeping with a reduction in acute RT toxicity, and reduced late histologic changes of late RT toxicity.
The combination of RTCT and the CXCR4 inhibitor X4-136 improves cervical cancer primary tumor control and reduces lymph node metastases, while also reducing normal tissue injury associated with adverse intestinal effects. Few if any pharmacologic strategies have expanded the therapeutic window with RT, suggesting that this combination warrants testing in clinical trials. These benefits might apply to other tumors where RTCT plays a curative role.
宫颈癌是一个全球性的健康问题。尽管预防计划有所增加，但仍有必要提高对患有侵袭性局部晚期疾病的患者的治疗效果。在这项研究中，我们研究了：（1）放射治疗（RT）联合顺铂（RTCT）和一种适用于临床的口服 CXCR4 抑制剂 X4-136 的疗效；（2）RTCT 和 X4-136 反应的生物标志物；（3）RTCT 和 X4-136 的肠道毒性。
源自我们患者的原位宫颈癌异种移植瘤接受 RT（30 Gy；2 Gy/d）和顺铂（4 mg/kg/wk 腹腔内）联合或不联合 X4-136（100 mg/kg/d 口服）治疗 3 周。治疗后立即处死小鼠进行生物标志物评估，或继续观察以评估原发肿瘤生长延迟和转移。在单独的实验中，通过组织学评估急性和晚期肠道损伤。
单独 RTCT 增加了 CXCL12/CXCR4 信号转导、肿瘤内髓样细胞的积累和 PD-L1 的表达。在 RTCT 期间添加 X4-136 可消除这些影响，提高原发肿瘤反应，并减少转移。此外，X4-136 增加了照射后存活的肠隐窝细胞的比例，这与急性 RT 毒性的降低以及晚期 RT 毒性的晚期组织学变化减少一致。
RTCT 联合 CXCR4 抑制剂 X4-136 可改善宫颈癌原发肿瘤控制并减少淋巴结转移，同时减少与不良肠道影响相关的正常组织损伤。几乎没有任何药物策略可以扩大 RT 的治疗窗口，这表明该联合治疗值得在临床试验中进行测试。这些益处可能适用于其他 RT 发挥治疗作用的肿瘤。
