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      Disclosing the CXCR4 Expression in Lymphoproliferative Diseases by Targeted Molecular Imaging

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          Abstract

          Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [ 68Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [ 68Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [ 68Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [ 68Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders.

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          A molecular imaging primer: modalities, imaging agents, and applications.

          Michelle L James, Sanjiv Gambhir (2012)
          Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.
          Article 0 comments Cited 297 times – based on 0 reviews     Review now
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            CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment.

            Jan A Burger, Thomas J Kipps (2006)
            Signals from the microenvironment have a profound influence on the maintenance and/or progression of hematopoietic and epithelial cancers. Mesenchymal or marrow-derived stromal cells, which constitute a large proportion of the non-neoplastic cells within the tumor microenvironment, constitutively secrete the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). CXCL12 secretion by stromal cells attracts cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and nonhematopoietic tumor cells. CXCR4 promotes tumor progression by direct and indirect mechanisms. First, CXCR4 is essential for metastatic spread to organs where CXCL12 is expressed, and thereby allows tumor cells to access cellular niches, such as the marrow, that favor tumor-cell survival and growth. Second, stromal-derived CXCL12 itself can stimulate survival and growth of neoplastic cells in a paracrine fashion. Third, CXCL12 can promote tumor angiogenesis by attracting endothelial cells to the tumor microenvironment. CXCR4 expression is a prognostic marker in various types of cancer, such as acute myelogenous leukemia or breast carcinoma. Promising results in preclinical tumor models indicate that CXCR4 antagonists may have antitumor activity in patients with various malignancies. Collectively, these observations reveal that CXCR4 is an important molecule involved in the spread and progression of a variety of different tumors. As such, CXCR4 antagonists, although initially developed for treatment of AIDS, actually may become effective agents for the treatment of neoplastic disease.
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              A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia.

              John DiPersio, Michael Rettig, A Cashen … (2012)
              The interaction of acute myeloid leukemia (AML) blasts with the leukemic microenvironment is postulated to be an important mediator of resistance to chemotherapy and disease relapse. We hypothesized that inhibition of the CXCR4/CXCL12 axis by the small molecule inhibitor, plerixafor, would disrupt the interaction of leukemic blasts with the environment and increase the sensitivity of AML blasts to chemotherapy. In this phase 1/2 study, 52 patients with relapsed or refractory AML were treated with plerixafor in combination with mitoxantrone, etoposide, and cytarabine. In phase 1, plerixafor was escalated to a maximum of 0.24 mg/kg/d without any dose-limiting toxicities. In phase 2, 46 patients were treated with plerixafor 0.24 mg/kg/d in combination with chemotherapy with an overall complete remission and complete remission with incomplete blood count recovery rate (CR + CRi) of 46%. Correlative studies demonstrated a 2-fold mobilization in leukemic blasts into the peripheral circulation. No evidence of symptomatic hyperleukocytosis or delayed count recovery was observed with the addition of plerixafor. We conclude that the addition of plerixafor to cytotoxic chemotherapy is feasible in AML, and results in encouraging rates of remission with correlative studies demonstrating in vivo evidence of disruption of the CXCR4/CXCL12 axis.
              Article 0 comments Cited 142 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Theranostics
                Journal ID (iso-abbrev): Theranostics
                Journal ID (publisher-id): thno
                Title: Theranostics
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1838-7640
                Publication date Collection: 2015
                Publication date (Electronic): 1 March 2015
                Volume: 5
                Issue: 6
                Pages: 618-630
                Affiliations
                1. Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany
                2. III. Medical Department, Technische Universität München, Munich, Germany
                3. Department of Nuclear Medicine, Technische Universität München, Munich, Germany
                4. Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
                5. Institute of Pathology, Helmholtz Zentrum München, Munich, Germany
                6. Institute of Pathology, Universität Würzburg, Comprehensive Cancer Center Mainfranken, Würzburg, Germany
                7. Institute for Advanced Study, Department of Chemistry, Technische Universität München, Garching, Germany
                8. Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
                Author notes
                ✉ Corresponding author: Hans-Jürgen Wester: phone +49-89-2891 2212; fax +49-89-2391 2204; E-mail: h.j.wester@ 123456tum.de

                # Current address: Ulm University, Department of Nuclear Medicine; Ulm, Germany.

                * Current address: Scintomics GmbH, Fuerstenfeldbruck, Germany.

                Competing interests: Hans-J. Wester is founder, owner and CEO, of Scintomics GmbH, Fuerstenfeldbruck, Germany. Jakub Šimeček is research associate at Scintomics GmbH, Fuerstenfeldbruck, Germany. All other authors have declared that no competing interest exists.

                Article
                Publisher ID: thnov05p0618
                DOI: 10.7150/thno.11251
                PMC ID: 4377730
                PubMed ID: 25825601
                SO-VID: 3ffd2d81-19ec-47ba-9ff7-0ac92b75cb1a
                Copyright © © 2015 Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.
                History
                Date received : 6 December 2014
                Date accepted : 6 February 2015
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Molecular medicine
                Keywords: cxcr4,chemokine receptor,positron emission tomography,lymphoma, in vivo imaging
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: cxcr4, chemokine receptor, positron emission tomography, lymphoma, in vivo imaging

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