@article{BuckSerflingLindneretal.2022,
  author    = {Buck, Andreas K. and Serfling, Sebastian E. and Lindner, Thomas and H{\"a}nscheid, Heribert and Schirbel, Andreas and Hahner, Stefanie and Fassnacht, Martin and Einsele, Hermann and Werner, Rudolf A.},
  title     = {CXCR4-targeted theranostics in oncology},
  series = {European Journal of Nuclear Medicine and Molecular Imaging},
  volume    = {49},
  journal   = {European Journal of Nuclear Medicine and Molecular Imaging},
  number    = {12},
  doi       = {10.1007/s00259-022-05849-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324545},
  pages     = {4133-4144},
  year      = {2022},
  abstract  = {A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.},
  language  = {en}
}
@article{SerflingLapaDreheretal.2022,
  author    = {Serfling, Sebastian E. and Lapa, Constantin and Dreher, Niklas and Hartrampf, Philipp E. and Rowe, Steven P. and Higuchi, Takahiro and Schirbel, Andreas and Weich, Alexander and Hahner, Stefanie and Fassnacht, Martin and Buck, Andreas K. and Werner, Rudolf A.},
  title     = {Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT},
  series = {Molecular Imaging and Biology},
  volume    = {24},
  journal   = {Molecular Imaging and Biology},
  number    = {4},
  doi       = {10.1007/s11307-022-01717-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324622},
  pages     = {659-665},
  year      = {2022},
  abstract  = {Background CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. Methods Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. Results Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 - 10.55), 3.27 for the kidneys (range, 1.52 - 17.4), followed by bone marrow (1.76, range, 0.84 - 3.98), heart (1.66, range, 0.88 - 2.89), and liver (1.28, range, 0.73 - 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. Conclusions In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.},
  language  = {en}
}
@article{ButtHowardRaman2022,
  author    = {Butt, Elke and Howard, Cory M. and Raman, Dayanidhi},
  title     = {LASP1 in cellular signaling and gene expression: more than just a cytoskeletal regulator},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {23},
  issn      = {2073-4409},
  doi       = {10.3390/cells11233817},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297447},
  year      = {2022},
  abstract  = {LIM and SH3 protein 1 was originally identified as a structural cytoskeletal protein with scaffolding function. However, recent data suggest additional roles in cell signaling and gene expression, especially in tumor cells. These novel functions are primarily regulated by the site-specific phosphorylation of LASP1. This review will focus on specific phosphorylation-dependent interaction between LASP1 and cellular proteins that orchestrate primary tumor progression and metastasis. More specifically, we will describe the role of LASP1 in chemokine receptor, and PI3K/AKT signaling. We outline the nuclear role for LASP1 in terms of epigenetics and transcriptional regulation and modulation of oncogenic mRNA translation. Finally, newly identified roles for the cytoskeletal function of LASP1 next to its known canonical F-actin binding properties are included.},
  language  = {en}
}
@article{SubramaniyanSridharanHowardetal.2020,
  author    = {Subramaniyan, Boopathi and Sridharan, Sangita and Howard, Cory M. and Tilley, Augustus M.C. and Basuroy, Tupa and Serna, Ivana de la and Butt, Elke and Raman, Dayanidhi},
  title     = {Role of the CXCR4-LASP1 axis in the stabilization of Snail1 in triple-negative breast cancer},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {9},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12092372},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211217},
  year      = {2020},
  abstract  = {The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3β, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3β, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1.},
  language  = {en}
}
@article{WeichRogollGawlasetal.2021,
  author    = {Weich, Alexander and Rogoll, Dorothee and Gawlas, Sophia and Mayer, Lars and Weich, Wolfgang and Pongracz, Judit and Kudlich, Theodor and Meining, Alexander and Scheurlen, Michael},
  title     = {Wnt/β-catenin signaling regulates CXCR4 expression and [\(^{68}\)Ga] Pentixafor internalization in neuroendocrine tumor cells},
  series = {Diagnostics},
  volume    = {11},
  journal   = {Diagnostics},
  number    = {2},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics11020367},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228914},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{ButtStempfleListeretal.2020,
  author    = {Butt, Elke and Stempfle, Katrin and Lister, Lorenz and Wolf, Felix and Kraft, Marcella and Herrmann, Andreas B. and Viciano, Cristina Perpina and Weber, Christian and Hochhaus, Andreas and Ernst, Thomas and Hoffmann, Carsten and Zernecke, Alma and Frietsch, Jochen J.},
  title     = {Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia},
  series = {Cells},
  volume    = {9},
  journal   = {Cells},
  number    = {2},
  issn      = {2073-4409},
  doi       = {10.3390/cells9020444},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200638},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{WeichWernerBucketal.2021,
  author    = {Weich, Alexander and Werner, Rudolf A. and Buck, Andreas K. and Hartrampf, Philipp E. and Serfling, Sebastian E. and Scheurlen, Michael and Wester, Hans-J{\"u}rgen and Meining, Alexander and Kircher, Stefan and Higuchi, Takahiro and Pomper, Martin G. and Rowe, Steven P. and Lapa, Constantin and Kircher, Malte},
  title     = {CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas},
  series = {Diagnostics},
  volume    = {11},
  journal   = {Diagnostics},
  number    = {4},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics11040605},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234231},
  year      = {2021},
  abstract  = {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-na{\"i}ve 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.},
  language  = {en}
}
@article{HerrmannMuellerOrthetal.2020,
  author    = {Herrmann, Andreas B. and M{\"u}ller, Martha-Lena and Orth, Martin F. and M{\"u}ller, J{\"o}rg P. and Zernecke, Alma and Hochhaus, Andreas and Ernst, Thomas and Butt, Elke and Frietsch, Jochen J.},
  title     = {Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance},
  series = {Journal of Cellular and Molecular Medicine},
  volume    = {24},
  journal   = {Journal of Cellular and Molecular Medicine},
  number    = {5},
  doi       = {10.1111/jcmm.14910},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214122},
  pages     = {2942 -- 2955},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{ChifuHeinzeFussetal.2020,
  author    = {Chifu, Irina and Heinze, Britta and Fuss, Carmina T. and Lang, Katharina and Kroiss, Matthias and Kircher, Stefan and Ronchi, Cristina L. and Altieri, Barbara and Schirbel, Andreas and Fassnacht, Martin and Hahner, Stefanie},
  title     = {Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma},
  series = {Frontiers in Endocrinology},
  volume    = {11},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2020.597878},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216494},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{LapaSchrederSchirbeletal.2017,
  author    = {Lapa, Constantin and Schreder, Martin and Schirbel, Andreas and Samnick, Samuel and Kort{\"u}m, Klaus Martin and Herrmann, Ken and Kropf, Saskia and Einsele, Herrmann and Buck, Andreas K. and Wester, Hans-J{\"u}rgen and Knop, Stefan and L{\"u}ckerath, Katharina},
  title     = {[\(^{68}\)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [\(^{18}\)F]FDG and laboratory values},
  series = {Theranostics},
  volume    = {7},
  journal   = {Theranostics},
  number    = {1},
  doi       = {10.7150/thno.16576},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172106},
  pages     = {205-212},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}