University Health Network, Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, Toronto, Canada.
Department of Biostatistics, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.
Clin Cancer Res. 2017 Mar 1;23(5):1242-1249. doi: 10.1158/1078-0432.CCR-16-1730. Epub 2016 Oct 3.
There is an important need to improve the effectiveness of radio-chemotherapy (RTCT) for cervical cancer. The CXCL12/CXCR4 pathway can influence RT response by recruiting normal myeloid cells to the tumor microenvironment that in turn can exert radioprotective effects, and may promote metastases. The objective of this study was to explore the efficacy and toxicity of combining RTCT with CXCL12/CXCR4 inhibition in cervical cancer. CXCR4 expression was measured in 115 patients with cervical cancer. Two primary orthotopic cervical cancer xenografts (OCICx) with different levels of CXCR4 expression were treated with RT (30 Gy: 15 daily fractions) and weekly cisplatin (4 mg/kg), with or without the CXCR4 inhibitor Plerixafor (5 mg/kg/day). The endpoints were tumor growth delay and lymph node metastases. Acute intestinal toxicity was assessed using a crypt cell assay. There was a fivefold variation in CXCR4 mRNA expression in the patient samples, and good correlation between the expression in patients and in the xenografts. The combination of RTCT and Plerixafor produced substantial tumor growth delay and reduced lymph node metastases compared with RTCT alone in both of the xenograft models. There was a trend toward reduced acute intestinal toxicity with the addition of Plerixafor to RTCT. There were no changes in normal organ morphology to suggest increased late toxicity. This study demonstrates that the addition of Plerixafor to standard RTCT improves primary tumor response and reduces metastases in cervical cancer with no increase in toxicity. This combination warrants further investigation in phase I/II clinical trials. .
提高宫颈癌放化疗（RTCT）效果非常重要。趋化因子（C-X-C）配体 12/趋化因子受体 4（CXCL12/CXCR4）途径可通过将正常髓系细胞募集到肿瘤微环境，从而发挥放射保护作用，并可能促进转移，影响 RT 反应。本研究旨在探索联合 RTCT 和 CXCL12/CXCR4 抑制治疗宫颈癌的疗效和毒性。检测了 115 例宫颈癌患者的 CXCR4 表达。对具有不同 CXCR4 表达水平的两种原发性原位宫颈癌异种移植瘤（OCICx）分别采用 30 Gy（15 次分割）和每周顺铂（4 mg/kg）治疗，同时给予或不给予 CXCR4 抑制剂培哚普利（5 mg/kg/天）。终点是肿瘤生长延迟和淋巴结转移。采用隐窝细胞分析评估急性肠道毒性。患者样本中 CXCR4 mRNA 表达存在五倍差异，患者和异种移植瘤中的表达具有良好相关性。与 RTCT 单药治疗相比，RTCT 联合培哚普利治疗在两种异种移植瘤模型中均显著延迟肿瘤生长并减少淋巴结转移。与 RTCT 联合治疗相比，联合培哚普利治疗具有降低急性肠道毒性的趋势。正常器官形态无变化，提示晚期毒性增加。本研究表明，在标准 RTCT 中加入培哚普利可提高宫颈癌的原发病灶反应，减少转移，且毒性无增加。该联合治疗方案值得进一步进行 I/II 期临床试验研究。
