15th European Molecular Imaging Meeting
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CXCR4 - A Multifaceted Target | joint session with the EANM

Session chair: Margret Schottelius (München, Germany); Erik Aarntzen (Nijmegen, Netherlands)
Shortcut: FS 02
Date: Thursday, 27 August, 2020, 5:30 p.m. - 7:00 p.m.
Session type: Focus Session

Focus Sessions are organized in co-operation with related societies or projects.


Abstract/Video opens by clicking at the talk title.

5:30 p.m. FS02-01

Molecular Biology of CXCR4 in cancer and inflammation

Stefania Scala1

1 Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Microenvironment Molecular Target, Napoli, Italy


CXCR4 is a seven-span transmembrane domains (352 amino acids, 48 kDa) G-protein coupled chemokine receptor, encoded on chromosome 2.1. CXCL12 binding to CXCR4 triggers multiple signal transduction pathways that regulate intracellular calcium flux, chemotaxis, transcription and cell survival. CXCL12 also binds CXCR7,  an atypical chemokine receptor (ACKR3) unable to trigger the canonical G protein-signaling and thus called decoy receptor. CXCL12 promotes tumor progression regulating cancer cell survival and migration in tumoral cells while  directing the recruitment of immune and stromal cells within the TME. CXCR4 is overexpressed and functional in the majority of human tumors where controls cell growth, migration and survival. A new family of CXCR4 peptide antagonist was developed through a rational design based on structural homology between CXCL12 and the vMIPII viral chemokine. Three Peptides R, S and I were identified as CXCR4 antagonist in vitro and in vivo with Peptide R the most efficient in vivo PCT/IB2011/000120/EP 2 528 936 B1/US2013/0079292A1. Peptide R potentiates the efficacy of standard treatment in colorectal cancer (5FU-OX and RT) targeting the EMT–treatment induced. Moreover Peptide  R improves the efficacy of anti PD-1 therapy in in vivo models of murine colon cancer and melanoma (MC38 and B16-hCXCR4). Combined treatment with Peptide R and anti PD-1 increases the number of cells Granzyme positive and decreases Foxp3 positive (Treg) cells within tumor microenvironment. Targeting CXCR4 affects Tregs function as demonstrated in renal cancer patients. Tregs isolated from renal cancer are more suppressive compared to Treg isolated from healthy donors and their function is impaired by CXCR4 antagonists. A biomarker clinical trial «REVOLUTION» (Transcan -2016-00000341)is actually ongoing to identify predictive markers of anti PD-1 response , Nivolumab. Preliminary results show that CXCR4 antagonist impairs Treg function as soon as after 2 weeks of treatment in Nivolumab responders patients. The optimized lead compound Peptide R54 reveals high affinity to CXCR4 (I.C.50: 15 nM). We are developing a  new PET tracer having as scaffold Peptide R54- Nota conjugated. Morever Peptide R54-tracer will be coupled  to nanovectors such as dendrimers ( Euronanomed 3 project NAN-4-TUM).

Keywords: CXCR4, cancer, inflammtion
5:50 p.m. FS02-02

Imaging CXCR4 – Tracer Development and Translation

Margret Schottelius1

1 CHUV/UNIL, Translational Radiopharmaceutical Sciences, Lausanne, Switzerland


The chemokine receptor CXCR4, a seven transmembrane G-protein coupled receptor, is widely expressed throughout the human body, both during development and adult life, with particularly high expression levels in the hematopoietic system. Physiologically, the interaction of CXCR4 with its cognate ligand, the chemokine CXCL12, plays a pivotal role in stem cell migration, retention, homing and differentiation during embryogenesis, organ development and healing and is centrally involved in the homeostasis of the adult hematopoietic system, mainly due to its involvement in the retention and trafficking of hematopoietic stem cells in the BM niche. Furthermore, the CXCR4/CXCL12 axis orchestrates an adequate response of the adoptive and innate immune system.

Pathologically, CXCR4 and CXCL12 are key players in various diseases. In cancer, their interaction plays a pivotal role in tumorigenesis, cancer progression and metastasis, and high CXCR4 expression has been documented for a broad spectrum of cancers, with a particular predominance in hematological cancers. Increasing evidence also points towards CXCL12 as a master driver of T-cell exclusion in solid tumors. Beyond its role in cancer, CXCR4 has been shown to mediate HIV-1 entry into T-cells as a co-receptor. Furthermore, it plays a central role in inflammatory diseases, ranging from rheumatoid arthritis and bone infection over atherosclerosis, where chronic inflammation of the arterial wall leads to atherosclerotic plaque development, to post-stroke and post-myocardial infarction inflammation.

Given the undisputed clinical relevance of CXCR4 as a molecular target, a multitude of CXCR4 targeted peptidic and non-peptidic antagonists have been developed for CXCR4-targeted therapies during the last two decades. Based on these developments and to meet the clinical need for pre-therapeutic quantification of CXCR4 expression, intense efforts have also been directed towards the development of suitable CXCR4-targeted molecular imaging agents. Amongst the mentioned CXCR4-targeted antagonists, three structurally diverse classes of compounds have been extensively evaluated with respect to their suitability as in vivo CXCR4 imaging agents, including radiolabeled analogs of the bicyclams AMD3100 and AMD3465,18F- or 68Ga-labeled T-140-based peptides for PET imaging as well as corresponding nuclear/fluorescent ligands for optical/SPECT imaging, and various radiolabeled FC-131-based cyclic pentapeptides. From all three classes, highly promising candidates with high CXCR4 affinity and excellent CXCR4 targeting properties in vitro and in vivo in preclinical studies have emerged.

This talk will summarize the recent advances in tracer development, encompassing the entire scope of CXCR4 targeted imaging agents under development. Major focus, however, will be directed towards examples, which have been successfully translated into clinical application, for example CXCR4-targeted theranostics based on the complementary agents [68Ga]Pentixafor and [177Lu]Pentixather. Furthermore, and overview over the most promising “next generation” tracers and their potential to further improve CXCR4-targeted imaging and therapy will be provided.
Keywords: CXCR4, Chemokine receptor, Pentixafor, Pentixather, theranostics
6:10 p.m. FS02-03

CXCR4 - a Multifaceted Target The Clinical Experience: Cancer

Constantin Lapa1

1 University Hospital Augsburg, Department of Nuclear Medicine, Augsburg, Germany


The C-X-C chemokine receptor 4 (CXCR4) and its natural ligand CXCL12 are key factors in the process of cell migration, homing of hematopoietic stem cells to the bone marrow, and represent important mediators of angiogenesis and cell proliferation.

In a pathological condition, involvement in the process of metastasis and homing of cancer cells to a protective niche has been described, making CXCR4 an attractive target for imaging and treatment of malignant diseases.

Recently, radiolabeled analogs of CXCR4 antagonists have been introduced which can be used for non-invasive imaging of CXCR4 expression in animal models and humans using positron emission tomography. In addition, beta emitter-labeled antagonists have been used in small patient cohorts for treatment of hematological neoplasms such as lymphoma, multiple myeloma and acute myeloid leukemia.

This talk reports on the current experience with CXCR4-directed theranostics in human malignant diseases.

Keywords: PET, theranostics, nuclear medicine, chemokines, cancer
6:30 p.m. FS02-04

CXCR4 - a Multifaceted Target - The Clinical Experience: Cardiovascular

Fabien Hyafil1, Bertrand Tavitian2

1 Bichat University Hospital, Nuclear Medicine, Paris, France
2 Université Paris Descartes, PARCC, Inserm U970, Paris, France


68Ga-Pentixafor is a PET agent that exhibits high affinity and selectivity for C-X-C chemokine receptor type 4 (CXCR4). The CXCR4 is a constitutive cytokine receptor involved in several biological processes including the entry of human immunodeficiency virus, the development of metastasis and the evolution of different autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. CXCR4 plays also a pivotal role in the trafficking of inflammatory cells by mediating the homing of progenitor cells in the bone marrow and regulating their mobilization into peripheral tissues upon injury. In fact, the small molecular antagonist AMD3100 (plerixafor) blocks the CXCR4 receptor and allows for mobilization of hematopoietic stem and progenitor cells in the bone marrow for autografting upon myeloablative treatment. Owing to the over-expression of CXCR4 at the surface of cells involved in the inflammatory process an under hypoxic conditions, 68Ga-pentixafor appears as a promising candidate for the detection of intense inflammatory reaction in hypoxic areas in cardiovascular tissues.  
Specific binding of 68Ga-pentixafor has been evidenced in plaques in a rabbit model of atherosclerosis and then confirmed in human carotid plaques of patients with recent acute ischemic stroke and in coronary plaques of patients with recent acute myocardial infarction. On autoradiography, radiolabeled pentixafor was found to accumulate primarily in regions of in atherosclerotic plaques with CXCR4-expressing macrophages on histology. 68Ga-pentixafor accumulation has also been detected in the heart early after acute myocardial infarction. In a mice model of acute myocardial infarction, an upregulation of CXCR4 could be identified in the infarcted area with a peak of signal at day one and complete resolution of the signal at day 7. The intensity and persistence of 68Ga-pentixafor uptake in the infarcted area detected with 68Ga-pentixafor-PET imaging predicted deleterious cardiac remodeling and poor outcome. Based on 68Ga-pentixafor PET imaging, a therapeutic strategy of CXCR4 inhibition one hour after acute MI has been tested and resulted into a dramatic reduction of the number of LV rupture and improved late cardiac function. This illustrates how 68Ga-pentixafor-PET imaging can offer to monitor in vivo molecular expression of CXCR4 in cardiovascular organs and help identify the best timing for medical intervention.
Hence, 68Ga-pentixafor appears as a promising radiopharmaceutical for the more specific identification of macrophages in atherosclerotic plaques and in the heart with PET by overcoming the current limitations of FDG for the detection of inflammation in cardiovascular tissues. Future studies will need to be carried out to understand more in depth the origin, meaning and changes of CXCR4 expression in tissues taking place during inflammatory processes.

Keywords: PET, CXCR4, molecular imaging, coronary artery disease, atherosclerosis