title: Plerixafor Improves Primary Tumor Response and Reduces Metastases in Cervical Cancer Treated with Radio-Chemotherapy.
abstract: Purpose: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.Experimental Design: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.Results: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.Conclusions: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.Clin Cancer Res; 23(5); 1242-9. ©2016 AACR.
authors.affiliation: University Health Network, Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, Toronto, Canada.
authors.forename: Naz
authors.initials: N
authors.lastname: Chaudary
authors.affiliation: Department of Biostatistics, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.|Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Salomeh
authors.initials: S
authors.lastname: Jelveh
authors.affiliation: Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lindsay
authors.affiliation: University Health Network, Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, Toronto, Canada.|Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
authors.affiliation: Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada. mike.milosevic@rmp.uhn.ca.|Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
mesh_terms: D000818:Animals; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000235:genetics*; D059248:Chemoradiotherapy / Q000009:adverse effects; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D000080027:Cyclams; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000008:administration & dosage*; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D009367:Neoplasm Staging; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D002945:Cisplatin; C088327:plerixafor