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

Abstract

Approximately 30-40% of cervical cancer patients treated with radio(chemo)therapy (RTCT) develop recurrence that can be difficult to treat. New approaches for overcoming treatment failures are needed. The CXCL12/CXCR4 chemokine pathway promotes tumor growth and metastasis in various tumor sites and we have observed the pathway is upregulated in RT treated cervical cancers. Plerixafor, an inhibitor of this pathway, is approved clinically and our initial studies showed the addition of plerixafor to RTCT enhanced primary tumor response. The current studies examined: 1. Different ways of sequencing RTCT and plerixafor to maximize efficacy 2. Biomarkers of response to RTCT and plerixafor 3. Effects of plerixafor with RTCT on intestinal toxicity, an important dose-limiting consequence of treatment in these patients. Orthotopic cervix xenografts were treated with RT (30 Gy; 2 Gy/day) and weekly cisplatin (4mg/kg) with or without plerixafor (5mg/kg/day). Plerixafor was administered concurrently with RTCT (3 wks), adjuvantly after RTCT (3 wks) or continuously (6 wks). Biomarker response was evaluated at the end of the concurrent and adjuvant treatments. Tumor growth delay was assessed at later times. Tumor control was assessed after 50 Gy (2Gy/day-5 wks) with cisplatin and plerixafor. Late intestinal toxicity was assessed by histologic examination of the colorectal junction 90 days after treatment. Plerixafor, whether administered concurrently or adjuvantly, prolonged tumor growth delay following RTCT (30 Gy). Adjuvant plerixafor was associated with longer growth delay. Tumor cure was achieved at a higher RT dose of 50 Gy with RTCT+plerixafor. RTCT alone increased CXCL12/CXCR4 signalling, PD-L1 (immune checkpoint marker) expression and the tumor accumulation of myeloid cells. The addition of plerixafor during or after RTCT abrogated these effects. This suggests: 1) RTCT upregulation of the CXCL12/CXCR4 pathway leads to recruitment of immune populations into the tumor that confer treatment resistance and 2) RTCT-induced increases in PD-L1 expression may promote an immunosuppressed tumor microenvironment that impairs treatment response. Plerixafor reduced RT-related intestinal injury, suggesting a protective effect that may relate to modifications of immune cell infiltrates involved with the mobilization of mesenchymal stem cells from the marrow. Further investigation is needed to assess mechanisms underlying these radio-protective effects. Adding plerixafor to RTCT blunts RTCT-induced upregulation of the CXCL12/CXCR4 pathway and reduces the increase in tumor-associated myeloid cells. These benefits may apply to other tumors where RT plays a curative role. Plerixafor protects normal tissue from RT injury. Few if any drugs have been identified previously that both improve the effectiveness of RT and prevent side effects. The combination of RT and plerixafor warrants testing in clinical trials to validate these findings.