4 results on '"Stangl, Stefan"'
Search Results
2. Selective In Vivo Imaging of Syngeneic, Spontaneous, and Xenograft Tumors Using a Novel Tumor Cell-Specific Hsp70 Peptide-Based Probe.
- Author
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Stangl, Stefan, Varga, Julia, Freysoldt, Bianca, Trajkovic-Arsic, Marija, Siveke, Jens T., Greten, Florian R., Ntziachristos, Vasilis, and Multhoff, Gabriele
- Subjects
- *
TUMORS , *CANCER cells , *METASTASIS , *XENOGRAFTS , *LABORATORY mice - Abstract
Although in vivo targeting of tumors using fluorescently labeled probes has greatly gained in importance over the last few years, most of the clinically applied reagents lack tumor cell specificity. Our novel tumor cell-penetrating peptide-based probe (TPP) recognizes an epitope of Hsp70 that is exclusively present on the cell surface of a broad variety of human and mouse tumors and metastases, but not on normal tissues. Because of the rapid turnover rate of membrane Hsp70, fluorescently labeled TPP is continuously internalized into syngeneic, spontaneous, chemically/genetically induced and xenograft tumors following intravenous administration, thereby enabling site-specific labeling of primary tumors and metastases. In contrast with the commercially available nonpeptide small molecule αvβ3-integrin antagonist IntegriSense, TPP exhibits a significantly higher tumor-to-background contrast and stronger tumor-specific signal intensity in all tested tumor models. Moreover, in contrast with IntegriSense, TPP reliably differentiates between tumor cells and cells of the tumor microenvironment, such as tumor-associated macrophages and fibroblasts, which were found to be membrane-Hsp70 negative. Therefore, TPP provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. TPP might also be a promising platform for tumor-specific drug delivery and other Hsp70-based targeted therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
3. The Chemokine CX3CL1 Improves Trastuzumab Efficacy in HER2 Low-Expressing Cancer In Vitro and In Vivo .
- Author
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Dreyer TF, Kuhn S, Stange C, Heithorst N, Schilling D, Jelsma J, Sievert W, Seitz S, Stangl S, Hapfelmeier A, Noske A, Wege AK, Weichert W, Ruland J, Schmitt M, Dorn J, Kiechle M, Reuning U, Magdolen V, Multhoff G, and Bronger H
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents, Immunological therapeutic use, Breast Neoplasms mortality, Breast Neoplasms pathology, Chemokine CX3CL1 metabolism, Cohort Studies, Drug Resistance, Neoplasm genetics, Drug Resistance, Neoplasm immunology, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic immunology, Humans, Kaplan-Meier Estimate, Killer Cells, Natural immunology, Lung Neoplasms secondary, Mice, Middle Aged, Prognosis, Receptor, ErbB-2 analysis, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 metabolism, Signal Transduction immunology, Trastuzumab therapeutic use, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Young Adult, Antineoplastic Agents, Immunological pharmacology, Breast Neoplasms drug therapy, Chemokine CX3CL1 genetics, Lung Neoplasms drug therapy, Trastuzumab pharmacology
- Abstract
A crucial mode of action of trastuzumab is the labeling of HER2-positive (HER2
+ ) tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therapy. ADCC requires both sufficient lymphocytic infiltration and close binding of the immune cells to the antibody-tagged tumor cells. We hypothesized that the chemokine CX3CL1 could improve both processes, as it is synthesized as a membrane-bound, adhesive form that is eventually cleaved into a soluble, chemotactic protein. Here, we show that CX3CL1 overexpression is a positive prognostic marker in breast cancer. CX3CL1 overexpression attracted tumor-suppressive lymphocytes, including NK cells, and inhibited tumor growth and lung metastasis in the syngeneic 4T1 breast cancer mouse model. In HER2+ SKBR3, MDA-MB-453, and HT-29 tumor cells, CX3CL1 overexpression increased NK cell-mediated cytotoxicity in vitro and acted synergistically with trastuzumab. Even though CX3CL1 did not further improve trastuzumab efficacy in vivo in the trastuzumab-sensitive MDA-MB-453 model, it compensated for NK-cell depletion and prolonged survival. In the HER2 low-expressing HT-29 model, however, CX3CL1 overexpression not only prolonged survival time but also overcame trastuzumab resistance in a partly NK cell-dependent manner. Taken together, these findings identify CX3CL1 as a feasible pharmacologic target to enable trastuzumab therapy in HER2 low-expressing cancers and render it a potential predictive biomarker to determine therapy responders., (©2021 American Association for Cancer Research.)- Published
- 2021
- Full Text
- View/download PDF
4. Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG 24 -DFO[ 89 Zr] for Tumor-Specific PET/CT Imaging.
- Author
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Stangl S, Tei L, De Rose F, Reder S, Martinelli J, Sievert W, Shevtsov M, Öllinger R, Rad R, Schwaiger M, D'Alessandria C, and Multhoff G
- Subjects
- Animals, Antibodies, Monoclonal metabolism, Binding, Competitive, Cell Line, Tumor, Cell-Penetrating Peptides metabolism, Epitopes chemistry, Fibroblasts metabolism, Fluorescein-5-isothiocyanate chemistry, Gene Expression Regulation, Neoplastic, Humans, Immunoconjugates chemistry, Inhibitory Concentration 50, Kinetics, Mice, Microscopy, Fluorescence, Tissue Distribution, Zirconium chemistry, Drug Screening Assays, Antitumor methods, HSP70 Heat-Shock Proteins metabolism, Peptides chemistry, Positron Emission Tomography Computed Tomography methods, Radioisotopes chemistry
- Abstract
High precision in vivo PET/CT imaging of solid tumors improves diagnostic credibility and clinical outcome of patients. An epitope of the oligomerization domain of Hsp70 is exclusively exposed on the membrane of a large variety of tumor types, but not on normal cells, and thus provides a universal tumor-specific target. Here we developed a novel PET tracer TPP-PEG
24 -DFO[89 Zr] based on the tumor cell-penetrating peptide probe TPP, which specifically recognizes membrane Hsp70 (mHsp70) on tumor cells. The implemented PEG24 moiety supported tracer stability and improved biodistribution characteristics in vivo The Kd of the tracer ranged in the low nanomolar range (18.9 ± 11.3 nmol/L). Fluorescein isothiocyanate (FITC)-labeled derivatives TPP-[FITC] and TPP-PEG24 -[FITC] revealed comparable and specific binding to mHsp70-positive 4T1, 4T1+ , a derivative of the 4T1 cell line sorted for high Hsp70 expression, and CT26 tumor cells, but not to mHsp70-negative normal fibroblasts. The rapid internalization kinetics of mHsp70 into the cytosol and the favorable biodistribution of the peptide-based tracer TPP-PEG24 -DFO[89 Zr] in vivo enabled a tumor-specific accumulation with a high tumor-to-background contrast and renal body clearance. The tumor-specific enrichment of the tracer in 4T1+ (6.2 ± 1.1%ID/g), 4T1 (4.3 ± 0.7%ID/g), and CT26 (2.6 ± 0.6%ID/g) mouse tumors with very high, high, and intermediate mHsp70 densities, respectively, reflected mHsp70 expression profiles of the different tumor types, whereas benign mHsp70-negative fibroblastic hyperplasia showed no tracer accumulation (0.2 ± 0.03%ID/g). The ability of our chemically optimized peptide-based tracer TPP-PEG24 -DFO[89 Zr] to detect mHsp70 in vivo suggests its broad applicability in targeting and imaging with high specificity for any tumor type that exhibits surface expression of Hsp70. Significance: A novel peptide-based PET tracer against the oligomerization domain of Hsp70 has potential for universal tumor-specific imaging in vivo across many tumor type. Cancer Res; 78(21); 6268-81. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
- Full Text
- View/download PDF
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