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Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging.

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 [(68)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [(68)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [(68)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [(68)Ga]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.

SUBMITTER: Wester HJ

PROVIDER: S-EPMC4377730 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging.

Wester Hans Jürgen HJ Keller Ulrich U Schottelius Margret M Beer Ambros A Philipp-Abbrederis Kathrin K Hoffmann Frauke F Šimeček Jakub J Gerngross Carlos C Lassmann Michael M Herrmann Ken K Pellegata Natalia N Rudelius Martina M Kessler Horst H Schwaiger Markus M

Theranostics 20150301 6

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 [(68)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expres ...[more]

PMID: 25825601

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Project description:PurposeRecent studies investigating a tumor-sink effect in solid tumors reported on decreasing uptake in normal organs in patients with higher tumor burden. This phenomenon, however, has not been evaluated yet for theranostic radiotracers applied to hematological neoplasms. As such, we aimed to determine a potential "lymphoma-sink effect" in patients with marginal zone lymphoma (MZL) imaged with C-X-C motif chemokine receptor (CXCR) 4-directed PET/CTs.ProceduresWe retrospectively analyzed 73 patients with MZL who underwent CXCR4-directed [68Ga]Ga-PentixaFor PET/CT. Normal unaffected organ uptake (heart, liver, spleen, bone marrow, kidneys) was quantified using volumes of interests (VOIs) and mean standardized uptake values (SUVmean) were derived. MZL manifestations were also segmented to determine the maximum and peak standardized uptake values SUV (SUVmax/peak) and volumetric parameters, including lymphoma volume (LV), and fractional lymphoma activity (FLA, defined as LV*SUVmean of lymphoma burden). This approach resulted in 666 VOIs to capture the entire MZL manifestation load. We used Spearman's rank correlations to determine associations between organ uptake and CXCR4-expressing lymphoma lesions.ResultsWe recorded the following median SUVmean in normal organs: heart, 1.82 (range, 0.78-4.11); liver, 1.35 (range, 0.72-2.99); bone marrow, 2.36 (range, 1.12-4.83); kidneys, 3.04 (range, 2.01-6.37); spleen, 5.79 (range, 2.07-10.5). No relevant associations between organ radiotracer uptake and MZL manifestation were observed, neither for SUVmax (ρ ≤ 0.21, P ≥ 0.07), SUVpeak (ρ ≤ 0.20, P ≥ 0.09), LV (ρ ≤ 0.13, P ≥ 0.27), nor FLA (ρ ≤ 0.15, P ≥ 0.33).ConclusionsInvestigating a lymphoma-sink effect in patients with hematological neoplasms, we observed no relevant associations between lymphoma burden and uptake in normal organs. Those observations may have therapeutic implications, e.g., for "cold" SDF1-pathway disrupting or "hot," CXCR4-directed radiolabeled drugs, as with higher lymphoma load, normal organ uptake seems to remain stable.

Project description:PURPOSE:CXCR4 is overexpressed on tumor cells from many types of human cancers. A high level of CXCR4 expression often correlates with poor prognosis, chemotherapy resistance, and metastasis. The development of CXCR4-specific radiotracers for positron emission tomography (PET) imaging will allow in vivo evaluation of receptor expression level for diagnosis or therapeutic evaluation. PROCEDURES:Two new (18)F-labeled radiotracers based on an Ac-TC14012 peptide, [(18)F]FP-Ac-TC14012 and [(18)F]FB-Ac-TC14012, were synthesized and characterized. The affinities of the 2-fluoropropionate (FP)-conjugated or 4-fluorobenzoate (FB)-conjugated peptides to CXCR4-transfected Chinese hamster ovarian (CHO) cells were evaluated in a competitive binding assay with [(125)I]CXCL12 radioligand. The cell uptake and retention of [(18)F]FP-labeled and [(18)F]FB-labeled peptides were measured. The tumor targetability and pharmacokinetics of these two tracers were also evaluated by microPET imaging and biodistribution studies. RESULTS:The labeled peptides retained high binding affinity to CXCR4 and showed much higher uptake in CXCR4-positive CHO cells than in CXCR4-negative cells in vitro. The smaller and more hydrophilic [(18)F]FP prosthetic group resulted in higher affinity and lower nonspecific cell uptake compared to the [(18)F]FB-labeled peptide. Both radiotracers showed much higher accumulation in CXCR4-positive than CXCR4-negative tumor xenografts in mice and allowed clear visualization of CXCR4 expression by PET. Among the two, [(18)F]FP-Ac-TC14012 showed higher tumor uptake and better tumor-to-background contrast. Unlike their N-terminal 4-F-benzoate analogs, these two tracers had minimal blood retention, likely due to reduced red blood cell binding. Metabolic organs, such as the liver and kidney, also showed high uptake. When blocked with low-dose cold peptide (10 ?g), the tumor uptake was significantly increased, most likely due to the increased concentration in blood circulation, as evidenced by decreased liver uptake. CONCLUSION:These results demonstrate that the [(18)F]FP-labeled Ac-TC14012 peptide with high tumor uptake, low nonspecific binding, and good tumor-to-background contrast promises [(18)F]FP-Ac-TC14012 as a PET tracer for in vivo PET imaging of CXCR4 expression.

Project description:PURPOSE:CXCR4 is one of several "chemokine" receptors expressed on malignant tumors (including GBM and PCNSL) and hematopoietic stem cells. Although 68Ga-pentixafor and 68Ga-NOTA-NFB have been shown to effectively image CXCR4 expression in myeloma and other systemic malignancies, imaging CXCR4 expression in brain tumors has been more limited due to the blood-brain barrier (BBB) and a considerable fraction of CXCR4 staining is intracellular. METHODS:We synthesized 6 iodinated and brominated cyclam derivatives with high affinity (low nM range) for CXCR4, since structure-based estimates of lipophilicity suggested rapid transfer across the BBB and tumor cell membranes. RESULTS:We tested 3 iodinated and 3 brominated cyclam derivatives in several CXCR4(+) and CXCR4(-) cell lines, with and without cold ligand blocking. To validate these novel radiolabeled cyclam derivatives for diagnostic CXCR4 imaging efficacy in brain tumors, we established appropriated murine models of intracranial GBM and PCNSL. Based on initial studies, 131I-HZ262 and 76Br-HZ270-1 were shown to be the most avidly accumulated radioligands. 76Br-HZ270-1 was selected for further study in the U87-CXCR4 and PCNSL #15 intracranial tumor models, because of its high uptake (9.5?±?1.3 %ID/g, SD) and low non-specific uptake (1.6?±?0.7 %ID/g, SD) in the s.c. U87-CXCR4 tumor models. However, imaging CXCR4 expression in intracranial U87-CXCR4 and PCNSL #15 tumors with 76Br-HZ270-1 was unsuccessful, following either i.v. or spinal-CSF injection. CONCLUSIONS:Imaging CXCR4 expression with halogenated cyclam derivatives was successful in s.c. located tumors, but not in CNS located tumors. This was largely due to the following: (i) the hydrophilicity of the radiolabeled analogues-as reflected in the "measured" radiotracer distribution (LogD) in octanol/PBS-which stands in contrast to the structure-based estimate of LogP, which was the rationale for initiating the study and (ii) the presence of a modest BTB in intracranial U87-CXCR4 gliomas and an intact BBB/BTB in the intracranial PCNSL animal model.

Dataset Information

Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging.

Publications

Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging.

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