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

S V Hartimath; O Draghiciu; T Daemen; H W Nijman; A van Waarde; R A J O Dierckx; E F J de Vries

doi:10.1007/s11307-019-01447-x

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

Mol Imaging Biol. 2020 Aug;22(4):883-890. doi: 10.1007/s11307-019-01447-x.

Authors

S V Hartimath¹, O Draghiciu², T Daemen², H W Nijman³, A van Waarde¹, R A J O Dierckx¹, E F J de Vries⁴

Affiliations

¹ Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 31.001, 9713, GZ, Groningen, The Netherlands.
² Department of Medical Microbiology, Tumor Virology and Cancer Immunotherapy, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁴ Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 31.001, 9713, GZ, Groningen, The Netherlands. e.f.j.de.vries@umcg.nl.

Abstract

Purpose: Chemokine 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.

Procedure: TC-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.

Results: PET 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.

Conclusion: This 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.

Keywords: CXCR4 expression; Cervical cancer; Immune cell infiltration; Immunization; PET; Radiotherapy; Treatment monitoring.

MeSH terms

Animals
Carbon Radioisotopes / chemistry*
Cell Line, Tumor
Female
Mice, Inbred C57BL
Neoplasms / diagnostic imaging*
Neoplasms / metabolism
Positron-Emission Tomography*
Pyridines / chemistry*
Receptors, CXCR4 / metabolism*
Xenograft Model Antitumor Assays*

Substances

Carbon Radioisotopes
Carbon-11
N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine
Pyridines
Receptors, CXCR4