4.5 Article

CXCR4-targeted PET imaging using 64Cu-AMD3100 for detection of Waldenstr?m Macroglobulinemia

Journal

CANCER BIOLOGY & THERAPY
Volume 21, Issue 1, Pages 52-60

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/15384047.2019.1665405

Keywords

Lymphoma; Waldenstr?m Macroglobulinemia; hypoxia; PET imaging; metastasis

Categories

Funding

  1. International Waldenstrom's Macroglobulinemia Foundation
  2. National Center for Advancing Translational Sciences [U54CA199092]
  3. IWMF
  4. National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH)
  5. National Cancer Institute of the NIH [U54CA199092]

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Objective: ?Waldenstr?m?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 Cu-64 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, Cu-64-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-1? knockout. Moreover, Cu-64-AMD3100 detected localized and circulating CXCR4(high) WM cells with high metastatic potential. Conclusions: In conclusion, we developed a molecularly targeted system, Cu-64-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.

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