Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[11C]Methyl-AMD3465 PET

Sv Hartimath,R.A.J.O Dierckx,A Van Waarde,H.W Nijman,E.F.J De Vries,T Daemen,O Draghiciu

doi:10.1007/s11307-019-01447-x

Sv Hartimath, R.A.J.O Dierckx + Show 5 more

Open Access

https://doi.org/10.1007/s11307-019-01447-x

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Abstract

PurposeChemokine CXCL12 and its receptor CXCR4 are constitutively overexpressed in human cancers. The CXCL12-CXCR4 signaling axis plays an important role in tumor progression and metastasis, but also in treatment-induced recruitment of CXCR4-expressing cytotoxic immune cells. Here, we aimed to demonstrate the feasibility of N-[11C]methyl-AMD3465 positron emission tomography (PET) to monitor changes in CXCR4 density in tumors after single-fraction local radiotherapy or in combination with immunization.ProcedureTC-1 cells expressing human papillomavirus antigens E6 and E7 were inoculated into the C57BL/6 mice subcutaneously. Two weeks after tumor cell inoculation, mice were irradiated with a single-fraction 14-Gy dose of X-ray. One group of irradiated mice was immunized with an alpha-viral vector vaccine, SFVeE6,7, and another group received daily injections of the CXCR4 antagonist AMD3100 (3 mg/kg -intraperitoneal (i.p.)). Seven days after irradiation, all animals underwent N-[11C]methyl-AMD3465 PET.ResultsPET imaging showed N-[11C]methyl-AMD3465 uptake in the tumor of single-fraction irradiated mice was nearly 2.5-fold higher than in sham-irradiated tumors (1.07 ± 0.31 %ID/g vs. 0.42 ± 0.05 % ID/g, p < 0.01). The tumor uptake was further increased by 4-fold (1.73 ± 0.17 % ID/g vs 0.42 ± 0.05 % ID/g, p < 0.01) in mice treated with single-fraction radiotherapy in combination with SFVeE6,7 immunization. Administration of AMD3100 caused a 4.5-fold reduction in the tracer uptake in the tumor of irradiated animals (0.24 ± 0.1 % ID/g, p < 0.001), suggesting that tracer uptake is indeed due to CXCR4-mediated chemotaxis.ConclusionThis study demonstrates the feasibility of N-[11C]methyl-AMD3465 PET imaging to monitor treatment-induced changes in the density of CXCR4 receptors in tumors and justifies further evaluation of CXCR4 as a potential imaging biomarker for evaluation of anti-tumor therapies.

Highlights

CXCR4 is a seven-transmembrane G-protein coupled receptor, which is overexpressed by stromal cells and tumor cells in more than 20 different human cancers types [1]
This hypothesis was supported by animal studies, showing that CXCR4-positive tumor cells migrated from their primary region to these CXCL12 secreting organs [10, 11]
We demonstrate the feasibility to monitor the effect of radiation and cancer immunization on CXCR4 receptor expression in the tumor using positron emission tomography (PET) imaging

Summary

Introduction

CXCR4 is a seven-transmembrane G-protein coupled receptor, which is overexpressed by stromal cells and tumor cells in more than 20 different human cancers types [1]. It is believed that organs with high levels of CXCL12, such as lymph nodes, lungs, liver, and bones, are the first destination of metastatic tumor cells expressing CXCR4 receptors. This hypothesis was supported by animal studies, showing that CXCR4-positive tumor cells migrated from their primary region to these CXCL12 secreting organs [10, 11]. Increased secretion of CXCL12 by the tumor, for example, as a result of hypoxia or treatment, stimulates the infiltration of CXCR4 expressing immune cells [14, 15]

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