TY - JOUR
T1 - CXCR4-targeted PET imaging using 64Cu-AMD3100 for detection of Waldenström Macroglobulinemia
AU - Muz, Barbara
AU - Bandara, Nilantha
AU - Mpoy, Cedric
AU - Sun, Jennifer
AU - Alhallak, Kinan
AU - Azab, Feda
AU - Rogers, Buck E.
AU - Azab, Abdel Kareem
N1 - Funding Information:
We thank GEiC at Washington University in St. Louis for gene editing of RPCI-WM1 cells using CRISPR-Cas9 technology. We thank Lynne Marsala from Molecular Imaging Center, Department of Radiology for performing in vivo BLI imaging. We thank Amanda Klaas, Margaret Morris, Lori String, and Nicole Fettig from Preclinical Imaging Facility of Mallinckrodt Institute of Radiology for performing the PET imaging and biodistribution study on mice. The imaging studies were supported by NIH P50 CA094056 (Molecular Imaging Center) and NCI P30 CA091842 (Siteman Cancer Center Small Animal Cancer Imaging shared resource). Kinan Alhallak was supported by the National Center for Advancing Translational Sciences of the NIH under Award Number TL1TR002344.
Funding Information:
This work was supported by the International Waldenstrom?s Macroglobulinemia Foundation; National Center for Advancing Translational Sciences [U54CA199092]. The study was supported partially by a research grant from IWMF and by the award from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) and the National Cancer Institute of the NIH under (U54CA199092). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. We thank GEiC at Washington University in St. Louis for gene editing of RPCI-WM1 cells using CRISPR-Cas9 technology. We thank Lynne Marsala from Molecular Imaging Center, Department of Radiology for performing in vivo BLI imaging. We thank Amanda Klaas, Margaret Morris, Lori String, and Nicole Fettig from Preclinical Imaging Facility of Mallinckrodt Institute of Radiology for performing the PET imaging and biodistribution study on mice. The imaging studies were supported by NIH P50 CA094056 (Molecular Imaging Center) and NCI P30 CA091842 (Siteman Cancer Center Small Animal Cancer Imaging shared resource). Kinan Alhallak was supported by the National Center for Advancing Translational Sciences of the NIH under Award Number TL1TR002344.
Publisher Copyright:
© 2019, © 2019 Taylor & Francis Group, LLC.
PY - 2020/1/2
Y1 - 2020/1/2
N2 - Objective: Waldenström Macroglobulinemia (WM) is a rare B-cell malignancy characterized by secretion of immunoglobulin M and cancer infiltration in the bone marrow. Chemokine receptor such as CXCR4 and hypoxic condition in the bone marrow play crucial roles in cancer cell trafficking, homing, adhesion, proliferation, survival, and drug resistance. Herein, we aimed to use CXCR4 as a potential biomarker to detect hypoxic-metastatic WM cells in the bone marrow and in the circulation by using CXCR4-detecting radiopharmaceutical. Methods: We radiolabeled a CXCR4-inhibitor (AMD3100) with 64Cu and tested its binding to WM cells with different levels of CXCR4 expression using gamma counter in vitro. The accumulation of this radiopharmaceutical tracer was tested in vivo in subcutaneous and intratibial models using PET/CT scan. In addition, PBMCs spiked with different amounts of WM cells ex vivo were detected using gamma counting. Results: In vitro, 64Cu-AMD3100 binding to WM cell lines demonstrated a direct correlation with the level of CXCR4 expression, which was increased in cells cultured in hypoxia with elevated levels of CXCR4, and decreased in cells with CXCR4 and HIF-1α knockout. Moreover, 64Cu-AMD3100 detected localized and circulating CXCR4high WM cells with high metastatic potential. Conclusions: In conclusion, we developed a molecularly targeted system, 64Cu-AMD3100, which binds to CXCR4 and specifically detects WM cells with hypoxic phenotype and metastatic potential in the subcutaneous and intratibial models. These preliminary findings using CXCR4-detecting PET radiopharmaceutical tracer indicate a potential technology to predict high-risk patients for the progression to WM due to metastatic potential.
AB - Objective: Waldenström Macroglobulinemia (WM) is a rare B-cell malignancy characterized by secretion of immunoglobulin M and cancer infiltration in the bone marrow. Chemokine receptor such as CXCR4 and hypoxic condition in the bone marrow play crucial roles in cancer cell trafficking, homing, adhesion, proliferation, survival, and drug resistance. Herein, we aimed to use CXCR4 as a potential biomarker to detect hypoxic-metastatic WM cells in the bone marrow and in the circulation by using CXCR4-detecting radiopharmaceutical. Methods: We radiolabeled a CXCR4-inhibitor (AMD3100) with 64Cu and tested its binding to WM cells with different levels of CXCR4 expression using gamma counter in vitro. The accumulation of this radiopharmaceutical tracer was tested in vivo in subcutaneous and intratibial models using PET/CT scan. In addition, PBMCs spiked with different amounts of WM cells ex vivo were detected using gamma counting. Results: In vitro, 64Cu-AMD3100 binding to WM cell lines demonstrated a direct correlation with the level of CXCR4 expression, which was increased in cells cultured in hypoxia with elevated levels of CXCR4, and decreased in cells with CXCR4 and HIF-1α knockout. Moreover, 64Cu-AMD3100 detected localized and circulating CXCR4high WM cells with high metastatic potential. Conclusions: In conclusion, we developed a molecularly targeted system, 64Cu-AMD3100, which binds to CXCR4 and specifically detects WM cells with hypoxic phenotype and metastatic potential in the subcutaneous and intratibial models. These preliminary findings using CXCR4-detecting PET radiopharmaceutical tracer indicate a potential technology to predict high-risk patients for the progression to WM due to metastatic potential.
KW - Lymphoma
KW - PET imaging
KW - Waldenström Macroglobulinemia
KW - hypoxia
KW - metastasis
UR - http://www.scopus.com/inward/record.url?scp=85074034601&partnerID=8YFLogxK
U2 - 10.1080/15384047.2019.1665405
DO - 10.1080/15384047.2019.1665405
M3 - Article
C2 - 31571524
AN - SCOPUS:85074034601
SN - 1538-4047
VL - 21
SP - 52
EP - 60
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 1
ER -