Molecular Targeting to Expand the Therapeutic Ratio in Women with Curable Cervical Cancer

Introduction: Radiotherapy (RT) and/or chemotherapy (CT) resistant cervical tumors pose a clinical problem. Identification of potential new targets for overcoming RT resistance is needed. The CXCL12/CXCR4 chemokine axis has been shown to promote tumor growth, invasion, metastasis and RTCT resistance in different tumor sites. Plerixafor (AMD3100) is an inhibitor of the CXCR4/CXCL12 interaction that is currently clinically approved. We hypothesized that the addition of Plerixafor to RTCT in orthotopic cervical cancer xenografts can improve primary tumor response and improve cure rates.

Material and Method: Three primary cervical cancer xenografts (OCICx 3-13-20) with different levels of CXCR4 expression were implanted in the cervices of mice and treated with RT (30Gy/15 fractions or 50Gy/25 fractions) and weekly cisplatin (4mg/kg), with or without Plerixafor (5mg/kg/day). Treatment arms included five to seven mice each. Mice were monitored weekly for tumor growth by CT scan. A mixed effects linear model was fitted to the log of the tumor volumes to compare tumor growth and the Fisher’s exact test was used to compare control rates. Kidneys and gut were assessed after euthanasia for treatment related toxicity. In a separate experiment, mice were treated in the same way but sacrificed immediately at the end of treatment for biomarker assessment.

Results and Discussion: In the tumor model treated with 50Gy in 25 daily fractions, OCICx 3, there was a trend for higher radiological evidence of tumor cure when Plerixafor was added to RTCT compared to RTCT alone (43% vs. 14% respectively, p=0.2797). Tumor control was sustained for >8 weeks and proven by histopathology. Furthermore, the addition of Plerixafor to RTCT resulted in delayed tumor regrowth in all three tumor models. RTCT caused significant increases in tumor pCXCR4 expression relative to controls, consistent with a treatment-induced increase in signaling via the CXCL12/CXCR4 pathway. The addition of Plerixafor to RTCT significantly reduced pCXCR4 levels. The downstream receptors of CXCL12/CXCR4 pERK and pAKT, and the myeloid-derived suppressor cell marker Ly6G also had a reduced expression with RTCT+Plerixafor relative to RTCT alone, consistent with a downstream effect of CXCL12/CXCR4 inhibition. There were no changes in normal organ morphology to suggest increased late toxicity in any of the tumor models.

Conclusion: RTCT increases signaling via the CXLC12 pathway in cervical cancer. The addition of Plerixafor offsets this increase, improves primary tumor growth delay and tends to increase tumor cure without added toxicity. This combination warrants further investigation in phase I/II clinical trials.