TY - THES
A1 - Messerschmidt, Konstantin Felix
T1 - Einfluss der PSMA-Expression auf die Docetaxel-Sensitivität sowie systemischer Medikamente auf die Expression von PSMA, CXCR4 und SSTR2
T1 - Influence of PSMA expression on docetaxel sensitivity and of systemic drugs on PSMA, CXCR4 and SSTR2 expression
N2 - Für das klinische Management des Prostatakarzinoms werden nuklearmedizinische Verfahren zunehmend relevant. Bildgebung und Therapie, welche gegen das Prostataspezifische Membranantigen (PSMA) gerichtet sind, werden bereits im klinischen Alltag angewendet. Weitere potenzielle Biomarker des Prostatakarzinoms, wie beispielsweise der CXC-Motiv-Chemokinrezeptor 4 (CXCR4) und der Somatostatinrezeptor Typ 2 (SSTR2), werden zudem als nuklearmedizinische Zielstrukturen diskutiert. Vorangegangene Arbeiten legten einen Zusammenhang zwischen dem Ausmaß der PSMA-Expression und der Sensitivität gegenüber Docetaxel in Prostatakarzinomzellen nahe. Ein Ziel der vorliegenden Arbeit war, diesen Mechanismus genauer zu untersuchen. Dabei wurden die Aktivität onkogener Signalwege, die Proliferation und die CXCR4- sowie die Androgenrezeptor (AR)- Expression in Prostatakarzinomzelllinien mit unterschiedlicher PSMA-Expression durchflusszytometrisch quantifiziert. Im zweiten Projektteil sollte der Einfluss von Metformin und verschiedener, bereits in der Prostatakarzinomtherapie angewandter Medikamente (Docetaxel, Dexamethason, Abirateron und Enzalutamid), auf die Expression von PSMA, CXCR4 und SSTR2 untersucht werden. Die Quantifizierung der Expression erfolgte mittels Durchflusszytometrie. Ein kausaler Mechanismus für den Zusammenhang zwischen PSMA-Expression und Docetaxel-Sensitivität konnte in dieser Arbeit schließlich nicht hergestellt werden. Es zeigten sich jedoch vor allem Expressionsmodulationen von PSMA und CXCR4. Mittels Docetaxel konnte z.B. bei C4-2 Zellen eine Verdopplung der PSMA-Expression und eine Verdreifachung der CXCR4-Expression erreicht werden. Darüber hinaus zeigte die Behandlung mit Abirateron eine deutliche Heraufregulation der PSMA- Expression bei LNCaP und C4-2 Zellen, sowie eine Zunahme der CXCR4- Expression bei allen untersuchten Zelllinien. Sollte sich der Einfluss der medikamentösen Behandlung auf die Expression von PSMA und CXCR4 bestätigen, kann dies zukünftig zur verbesserten und individualisierten Diagnostik und Therapie von Prostatakarzinompatienten beitragen.
N2 - Nuclear medicine methods are becoming increasingly relevant for the clinical management of prostate carcinoma. Imaging and therapy directed against the prostate specific membrane antigen (PSMA) are already used in clinical practice. Other potential biomarkers of prostate cancer, such as CXC motif chemokine receptor 4 (CXCR4) and somatostatin receptor type 2 (SSTR2), are also being discussed as nuclear medicine targets. Previous work suggested a relationship between the level of PSMA expression and sensitivity to docetaxel in prostate cancer cells. One aim of the present work was to further investigate this mechanism. The activity of oncogenic signalling pathways, proliferation and CXCR4 expression as well as androgen receptor (AR) expression in prostate carcinoma cell lines with different PSMA expression were quantified by flow cytometry. In the second part of the study, the influence of metformin and various drugs already used in prostate carcinoma therapy (docetaxel, dexamethasone, abiraterone and enzalutamide) on the expression of PSMA, CXCR4 and SSTR2 was assessed. Expression was quantified by flow cytometry analysis. A causal mechanism for the connection between PSMA expression and docetaxel sensitivity could, eventually, not be established in this work. However, expression modulations were primarily found for PSMA and CXCR4. Using docetaxel, for instance, a doubling of PSMA expression and a tripling of CXCR4 expression could be achieved in C4-2 cells. In addition, treatment with abiraterone showed a significant upregulation of PSMA expression in LNCaP and C4-2 cells, as well as an increase in CXCR4 expression in all cell lines examined. If the influence of drug treatment on the expression of PSMA and CXCR4 is confirmed, this may contribute to improved and individualised diagnostics and therapy of prostate cancer patients.
KW - Prostatakrebs
KW - Docetaxel
KW - Dexamethason
KW - Metformin
KW - Nuklearmedizin
KW - PSMA
KW - CXCR4
KW - SSTR2
KW - Akt
KW - ERK1/2
KW - p38
KW - Abirateron
KW - Enzalutamid
KW - LNCaP
KW - PC3
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283364
ER -
TY - JOUR
A1 - Weich, Alexander
A1 - Rogoll, Dorothee
A1 - Gawlas, Sophia
A1 - Mayer, Lars
A1 - Weich, Wolfgang
A1 - Pongracz, Judit
A1 - Kudlich, Theodor
A1 - Meining, Alexander
A1 - Scheurlen, Michael
T1 - Wnt/β-catenin signaling regulates CXCR4 expression and [\(^{68}\)Ga] Pentixafor internalization in neuroendocrine tumor cells
JF - Diagnostics
N2 - Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [\(^{68}\)Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [\(^{68}\)Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified.
KW - neuroendocrine tumor
KW - NET
KW - Wnt
KW - β-catenin
KW - CXCR4
KW - [\(^{68}\)Ga] Pentixafor
KW - BON-1
KW - QGP-1
KW - MS-18
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228914
SN - 2075-4418
VL - 11
IS - 2
ER -
TY - THES
A1 - Nattmann, Anja Maria
T1 - ADAM9 und CXCR4 – neue Angriffspunkte in der Pathogenese des Vestibularisschwannoms
T1 - ADAM9 and CXCR4 – new targets in vestibular schwannoma pathogenesis
N2 - Obwohl es sich bei Vestibularisschwannomen (VS) um benigne Tumoren handelt, können sie die Lebensqualität der betroffenen Patienten deutlich beeinträchtigen. Gerade bei Patienten, die an einer NF 2 leiden und sich daher wiederholt operativen Eingriffen unterziehen müssen, ist es notwendig, eine medikamentöse Therapiealternative anbieten zu können, die ohne die Notwendigkeit einer operativen Intervention auskommt und gleichzeitig schwerwiegenden Folgen der Tumorerkrankung – wie dem drohenden Hörverlust – Einhalt gebietet. Die vorliegende Arbeit hatte zum Ziel, sich dieser medikamentösen Therapiealternative einen Schritt anzunähern, indem molekulare Pathomechanismen, die dem VS zugrunde liegen könnten, untersucht wurden. Im Mittelpunkt standen der Chemokinrezeptor CXCR4, das Tumorsuppressorprotein Merlin und die Metalloprotease ADAM9. Für CXCR4 ließen sich keine Effekte in Bezug auf die Aktivierung der ERK- und AKT-Signalwege erkennen. Auch beeinflusste eine Merlinüberexpression in VS-Zellen die CXCR4- und ADAM9-Proteinexpression nicht. Für ADAM9 zeigte sich eine potenzielle Relevanz für die Pathogenese des VS: Wurde die ADAM9-Konzentration durch einen knock-down reduziert, hatte dies eine verminderte VS-Zellzahl zur Folge. Des Weiteren scheint Integrin α6 ein Substrat von ADAM9 zu sein, das möglicherweise in die Zytoskelettmodifikation durch ADAM9 involviert ist. Somit stellt die ADAM9-Inhibition einen interessanten Angriffspunkt für eine mögliche medikamentöse Behandlung von VS dar. Ferner wurden Cytokine gefunden, die bisher nicht in einen Zusammenhang mit dem VS gebracht worden waren. Vor allem die Bedeutung der Cytokine TIMP-2 und CXCL7 sollte für das VS näher untersucht werden. Somit konnte diese Arbeit weitere Aspekte aufdecken, die für die Pathogenese des VS relevant sein könnten und an die zukünftige Forschung anknüpfen sollte.
N2 - Although they are benign tumors, vestibular schwannomas have the potential to noticeably impair the patients’ quality of life. Especially patients suffering from neurofibromatosis type 2 develop multiple schwannomas and therefore often require repeated surgery. Thus, a non-invasive and effective pharmacotherapy is urgently needed to prevent severe consequences of vestibular schwannoma such as hearing loss. The aim of this thesis was to investigate pathological mechanisms of vestibular schwannoma to identify potential druggable targets. Especially the chemokine receptor CXCR4, the tumor suppressor protein Merlin and the metalloproteinase ADAM9 were in the focus of interest.
Neither inhibition, nor stimulation of CXCR4 affected the activity of ERK and AKT signaling pathways, respectively. Similarly, Merlin overexpression did not change CXCR4 or ADAM9 protein expression in vestibular schwannoma. However, ADAM9 appeared to be potentially important for the pathogenesis of vestibular schwannoma: An ADAM9 knock-down led to reduced vestibular schwannoma cell numbers. Moreover, integrin α6 appeared to be a substrate of ADAM9 and might be involved in its mediation of cytoskeleton alterations. Thus, pharmacological inhibition of ADAM9 could be a promising therapeutic strategy to target vestibular schwannoma.
In addition, a cytokine screen revealed the tissue inhibitor of metalloproteinases 2 (TIMP-2) and the chemokine ligand CXCL7 as hitherto unknown factors with putative relevance for the vestibular schwannoma pathogenesis.
To conclude, this thesis revealed new perspectives on pathological mechanisms of vestibular schwannoma which deserve further investigation.
KW - Akustikustumor
KW - Vestibularisschwannom
KW - ADAM9
KW - CXCR4
KW - Merlin
KW - vestibular schwannoma
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-278086
ER -
TY - JOUR
A1 - Butt, Elke
A1 - Stempfle, Katrin
A1 - Lister, Lorenz
A1 - Wolf, Felix
A1 - Kraft, Marcella
A1 - Herrmann, Andreas B.
A1 - Viciano, Cristina Perpina
A1 - Weber, Christian
A1 - Hochhaus, Andreas
A1 - Ernst, Thomas
A1 - Hoffmann, Carsten
A1 - Zernecke, Alma
A1 - Frietsch, Jochen J.
T1 - Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia
JF - Cells
N2 - The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.
KW - LASP1
KW - CXCR4
KW - AKT1
KW - CML
KW - breast cancer
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200638
SN - 2073-4409
VL - 9
IS - 2
ER -
TY - JOUR
A1 - Weich, Alexander
A1 - Werner, Rudolf A.
A1 - Buck, Andreas K.
A1 - Hartrampf, Philipp E.
A1 - Serfling, Sebastian E.
A1 - Scheurlen, Michael
A1 - Wester, Hans-Jürgen
A1 - Meining, Alexander
A1 - Kircher, Stefan
A1 - Higuchi, Takahiro
A1 - Pomper, Martin G.
A1 - Rowe, Steven P.
A1 - Lapa, Constantin
A1 - Kircher, Malte
T1 - CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas
JF - Diagnostics
N2 - We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer \(^{68}\)Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard \(^{18}\)F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent \(^{18}\)F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. \(^{68}\)Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while \(^{18}\)F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, \(^{18}\)F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher 18F-FDG uptake as compared to \(^{68}\)Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUVmax: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUVmean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard \(^{18}\)F-FDG PET/CT.
KW - CXCR4
KW - NET
KW - NEC
KW - 68Ga-Pentixafor
KW - 18F-FDG
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234231
SN - 2075-4418
VL - 11
IS - 4
ER -
TY - THES
A1 - Bögelein, Anna
T1 - Einfluss systemischer Therapeutika auf die CXCR4-Expression von Myelomzellen
T1 - Influence of therapeutic agents on CXCR4 expression of myeloma cells
N2 - Im Zuge der Bemühungen um neue, tumorspezifische Therapieansätze für die Myelomerkrankung hat sich der C-X-C-Chemokinrezeptor 4 (CXCR4) aufgrund seiner zentralen Rolle in der Tumorgenese als vielversprechender Angriffspunkt hervorgetan. Im Sinne eines theranostischen Konzepts wird der Rezeptor mithilfe eines radioaktiv markierten Liganden quantifiziert und anschließend von rezeptorspezifischen Radiotherapeutika als Zielstruktur genutzt. Die CXCR4-Expression ist allerdings ein höchst dynamischer Prozess mit großer inter- und intraindividueller Heterogenität, der u.a. durch eine begleitende Chemotherapie beeinflusst werden kann. Ob sich therapieinduzierte Veränderungen der Rezeptorexpression gezielt nutzen lassen, um die CXCR4-Expression zu optimieren und so die Effektivität der CXCR4-gerichteten Strategien zu steigern, wurde bislang nicht untersucht.
Vor diesem Hintergrund wurden in der vorliegenden Arbeit verschiedene, in der Myelomtherapie etablierte Substanzen sowohl einzeln als auch in Kombination hinsichtlich ihres Einflusses auf die CXCR4-Expression von MM-Zelllinien und primären MM-Zellen unter in vitro Bedingungen analysiert.
In den durchgeführten Experimenten zeigte sich eine hohe Variabilität der CXCR4-Expression der MM-Zellen nach Therapieinduktion, die sich als substanz-, dosis- und zeitabhängig herausstellte. Die Ergebnisse bestätigten das große Potenzial der therapieinduzierten Modulation der CXCR4-Expression. Im weiteren Verlauf sind translationale Forschungsansätze gerechtfertigt, die die Übertragbarkeit der in vitro gewonnenen Ergebnisse auf die komplexen Vorgänge im lebenden Organismus überprüfen. Langfristiges Ziel ist der Entwurf eines patientenzentrierten, multimodalen Therapiekonzepts, welches das CXCR4-gerichtete theranostische Konzept mit einer individuell angepassten, medikamentösen MM-Therapie kombiniert.
N2 - In the course of developing new tumor specific therapeutic approaches for non-yet curable myeloma disease C-X-C chemokine receptor 4 (CXCR4) has emerged as a promising target due to its crucial role in myeloma tumorigenesis. Within a theranostic concept CXCR4 is quantified using radioactively labeled ligands and afterwards targeted by receptor-specific radiopharmaceuticals. However, CXCR4 expression is a very dynamic process with a high inter- and intraindividual heterogeneity which can be influenced by concomitant chemotherapy. Whether therapy induced changes in receptor expression can be used to enhance CXCR4 expression and thus to improve efficacy of CXCR4-based theranostics has not been examined so far.
In this context the present study evaluated the effect of several anti-myeloma drugs (bortezomib, cyclophosphamide, dexamethasone, doxorubicin, lenalidomide) on CXCR4 expression of different human myeloma cell lines as well as patient-derived CD138+ plasma cells under in vitro conditions.
Findings disclosed a high variability of CXCR4 expression on myeloma cells after drug application which turned out to be substance-, dose- and time-dependent. The results confirmed the high potential of therapy-induced modulation of CXCR4 expression. In further course, translational research approaches are justified to verify the transferability of the in vitro findings to the complex macro- and microenvironment in vivo. Long-term goal is the development of a patient-centered, multimodal therapy concept which combines CXCR4 based theranostics with a personalized drug-based therapy.
KW - Plasmozytom
KW - In vitro
KW - Multiples Myelom
KW - Theranostik
KW - CXCR4
KW - Gallium-68 Pentixafor
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241746
ER -
TY - THES
A1 - Martellotta, Donato Daniel
T1 - Stellenwert von CXCL12 und CXCR4 in der Pathogenese des Vestibularisschwannomes
T1 - Significance of CXCL12 and CXCR4 in the pathogenesis of vestibular schwannoma
N2 - CXCR4 ist der spezifische Rezeptor für das Chemokin CXCL12 und ist überexprimiert in Vestibularisschwannomzellen.
Das Ziel dieser Arbeit war es den Effekt des spezifischen Inhibitors AMD3100 auf die CXCR4 vermittelte Proliferation und Migration der Vestibularisschwannomzellen in verschiedenen Zellkuturmodellen zu analysieren.
Die nachgewiesene Inhibition von CXCR4 deutet auf einen möglichen Einsatz von AMD3100 in der systemischen Therapie von NF-2 Patienten hin.
N2 - CXCR4 is the specific receptor for the chemokine CXCL12 and is hyperexpressed in vestibular schwannoma cells.
The aim was to analyse the influence of the specific inhibitor AMD 3100 on the CXCR4 stimulated proliferation and migration of vestibular schwannoma cells in different cell culture models.
The demonstrated inhibition of CXCR4 suggests the use of AMD3100 in the systemic therapy of NF-2 patients.
KW - CXCL12
KW - Vestibularisschwannom
KW - CXCR4
KW - NF-2
KW - 3D-Modell
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241454
ER -
TY - JOUR
A1 - Herrmann, Andreas B.
A1 - Müller, Martha‐Lena
A1 - Orth, Martin F.
A1 - Müller, Jörg P.
A1 - Zernecke, Alma
A1 - Hochhaus, Andreas
A1 - Ernst, Thomas
A1 - Butt, Elke
A1 - Frietsch, Jochen J.
T1 - Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance
JF - Journal of Cellular and Molecular Medicine
N2 - Chronic myeloid leukaemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR‐ABL tyrosine kinase. The LIM and SH3 domain protein 1 (LASP1) has recently been identified as a novel BCR‐ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore, LASP1 was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential LASP1‐mediated pathways and related factors that may help to further eradicate minimal residual disease (MRD), the effect of LASP1 on processes involved in progression and maintenance of CML was investigated. The present data indicate that not only overexpression of CXCR4, but also knockout of LASP1 contributes to proliferation, reduced apoptosis and migration as well as increased adhesive potential of K562 CML cells. Furthermore, LASP1 depletion in K562 CML cells leads to decreased cytokine release and reduced NK cell‐mediated cytotoxicity towards CML cells. Taken together, these results indicate that in CML, reduced levels of LASP1 alone and in combination with high CXCR4 expression may contribute to TKI resistance.
KW - BCR‐ABL
KW - CML
KW - CXCR4
KW - LASP1
KW - nilotinib
KW - precursor cells
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214122
VL - 24
IS - 5
SP - 2942
EP - 2955
ER -
TY - JOUR
A1 - Chifu, Irina
A1 - Heinze, Britta
A1 - Fuss, Carmina T.
A1 - Lang, Katharina
A1 - Kroiss, Matthias
A1 - Kircher, Stefan
A1 - Ronchi, Cristina L.
A1 - Altieri, Barbara
A1 - Schirbel, Andreas
A1 - Fassnacht, Martin
A1 - Hahner, Stefanie
T1 - Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma
JF - Frontiers in Endocrinology
N2 - Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (p=0.01) and local recurrences (p=0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, p=0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=−0.254, p=0.03) but positively with tumor size (r=0.3, p=0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.
KW - chemokine receptor
KW - prognosis
KW - adrenocortical carcinoma
KW - CXCR4
KW - CXCR7
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216494
SN - 1664-2392
VL - 11
ER -
TY - JOUR
A1 - Lapa, Constantin
A1 - Schreder, Martin
A1 - Schirbel, Andreas
A1 - Samnick, Samuel
A1 - Kortüm, Klaus Martin
A1 - Herrmann, Ken
A1 - Kropf, Saskia
A1 - Einsele, Herrmann
A1 - Buck, Andreas K.
A1 - Wester, Hans-Jürgen
A1 - Knop, Stefan
A1 - Lückerath, Katharina
T1 - [\(^{68}\)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [\(^{18}\)F]FDG and laboratory values
JF - Theranostics
N2 - Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies.
Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity.
[\(^{68}\)Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018).
[\(^{68}\)Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.
KW - medicine
KW - multiple myeloma
KW - FDG
KW - molecular imaging
KW - CXCR4
KW - PET
KW - radionuclide therapy
KW - theranostics
Y1 - 2017
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172106
VL - 7
IS - 1
ER -