Abstract A10: Plerixafor inhibits myeloid cell recruitment and improves the radioresponse in patient-derived cervix cancer xenograft models
Authors: Chaudary Naz , Pintilie Melania , Hill Richard , Milosevic Michael 
Published: March 2017

Abstract
Background: Standard treatment for women who are diagnosed with stage IIB through IVA cervical cancer consists of radiation and cisplatin-based chemotherapy (RTCT) with a control rate of approximately 60% depending on stage. Current options for patients with recurrent and metastatic disease are limited, and their median overall survival from recurrence is &lt;12 months. To date, biologic therapy has had little impact on survival, so identification of potential new targets is urgently required to develop novel therapeutic strategies. Equally developing relevant animal models is important to further enhance our understanding of the characteristics of human cervix cancers and for assessment of novel therapies. We have established a panel of orthotopically-passaged xenografts (OCICx) by implanting cervix tumor pieces from patient biopsies directly into the cervices of mice. These tumors grow and metastasize to the para-aortic lymphnodes in a manner similar to that in patients. These models have been shown to mirror the clinical and biological behavior of cervical cancer in patients in regards to the tumor microenvironmental parameters including epithelial and stromal content, vascularity, proliferation, lymphatics, hypoxia and interstitial fluid pressure.
Purpose: Cervical cancers recruit myeloid cells from the bone marrow via the CXCL12/CXCR4 pathway, which in turn influences vascular function and radiotherapy response. The objective of our study was to explore combined treatment with Plerixafor (a CXCL12/CXCR4 inhibitor) and standard RTCT on primary tumor response and the development of metastases, using orthotopic xenografts derived directly from patients with cervical cancer.
Methods: Two primary cervix (OCICx13 and OCICx20) and ME180 (human cervix cancer; cell line derived) xenografts were grown in the cervices of immune deficient mice. To simulate clinical treatment, image-guided radiotherapy (30 Gy in 15 daily fractions) and concurrent weekly cisplatin (4 mg/kg) were administered, with or without Plerixafor (5 mg/kg/day). Plerixafor treatments were administered either concurrently with RTCT or immediately subsequent to RTCT (for 3 weeks post RTCT).The primary endpoints were tumor growth delay and the frequency of lymph node metastases. Chemokine expression and neutrophil recruitment were evaluated by immunohistochemistry. Acute gut toxicity was assessed using the crypt cell assay. Blood and normal organs were examined for late toxicity.
Results: The combination of RTCT and Plerixafor (administered either concurrently with or subsequent to RTCT) produced enhanced tumor growth delay and reduced metastases compared to standard RTCT alone in both the ME180 and the patient-derived xenograft models. There was a reduction in chemokine signaling (CXCL12/CXCR4) and myeloid cell infiltration (GCSF, CD11b) with combination treatment compared to RTCT alone. There was no effect of Plerixafor on acute GI toxicity, nor were there changes in blood counts or organ morphology to indicate increased late hematological or normal tissue toxicity. Late gut toxicity studies are underway. There was no difference between concurrent and subsequent treatment with Plerixafor in tumor growth delay and metastasis. Further studies examining the genetic characterization of the OCICx models and the associated patient cervix biopsies are underway.
Conclusion: The OCICx orthotopic xenografts represent unique models to test strategies for targeting essential pathways in cervix cancer and metastasis. This preclinical study demonstrates that the addition of Plerixafor to standard RTCT for cervical cancer improves local tumor response and reduced metastases with no increase in toxicity. Plerixafor is commercially available for other indications, which will facilitate translation of these findings to phase I/II clinical studies.
Citation Format: Naz Chaudary, Melania Pintilie, Richard Hill, Michael Milosevic. Plerixafor inhibits myeloid cell recruitment and improves the radioresponse in patient-derived cervix cancer xenograft models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A10.