Abstract
BackgroundThe CXCL12/CXCR4 chemokine pathway is involved in cervical cancer pathogenesis and radiation treatment (RT) response. We previously reported that radiochemotherapy (RTCT) and concurrent administration of the CXCR4 inhibitor plerixafor improved primary tumour response. The aims of this study were to determine optimal sequencing of RTCT and plerixafor, the mechanisms responsible for improved response and the effect of plerixafor on late intestinal toxicity.MethodsOrthotopic cervical cancer xenografts were treated with RTCT (30 Gy in 2 Gy fractions and cisplatin) with or without concurrent, adjuvant or continuous plerixafor. The endpoints were growth delay and molecular and immune cell changes at the end of treatment. Late intestinal toxicity was assessed by histologic examination of the rectum 90 days after a single 20 Gy fraction.ResultsRTCT increased CXCL12/CXCR4 signalling and the intratumoral accumulation of myeloid cells; the addition of plerixafor mitigated these effects. All of the RTCT and plerixafor arms showed prolonged tumour growth delay compared to RTCT alone, with the adjuvant arm showing the greatest improvement. Plerixafor also reduced late intestinal toxicity.ConclusionAdding Plerixafor to RTCT blunts treatment-induced increases in CXCL12/CXCR4 signalling, improves primary tumour response and reduces intestinal side effects. This combination warrants testing in future clinical trials.
Highlights
The CXCL12/CXCR4 chemokine pathway is involved in cervical cancer pathogenesis and radiation treatment (RT) response
Our group previously reported that concurrent treatment of cervical cancer patient-derived xenografts (PDXs) with radiotherapy and concurrent platinum-based chemotherapy (RTCT) and the CXCR4 inhibitor plerixafor (AMD3100) produced substantial tumour growth delay and reduced lymph node metastases without increasing early intestinal toxicity compared to RTCT alone.[4]
The tumour eradication experiments were done using OCICx 3. This PDX was selected because it has a radiation dose-response characteristic that results in a small proportion of tumour ‘cures’ with RTCT alone (50 Gy + concurrent cisplatin), making it better suited for evaluating long-term disease eradication with the addition of plerixafor
Summary
The CXCL12/CXCR4 chemokine pathway is involved in cervical cancer pathogenesis and radiation treatment (RT) response. The CXCL12/CXCR4 pathway has emerged as being of particular interest and relevance in cervical cancer as outlined in a recent review.[3] It has been implicated in HPV infection and cervical carcinogenesis, malignant progression, the development of metastases and RT response.[3] Our group previously reported that concurrent treatment of cervical cancer patient-derived xenografts (PDXs) with RTCT and the CXCR4 inhibitor plerixafor (AMD3100) produced substantial tumour growth delay and reduced lymph node metastases without increasing early (acute) intestinal toxicity compared to RTCT alone.[4] This report builds on these findings by investigating different ways of sequencing RTCT and plerixafor for optimal efficacy, and the mechanisms responsible for improved treatment response as a foundation for future phase I/II clinical trials. We evaluated long-term tumour control with the combination of RTCT and plerixafor, and the effect of plerixafor on late intestinal toxicity, the most common serious side effect of RTCT after treatment of cervical cancer
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