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  • 1
    Online Resource
    Online Resource
    Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. 12 ( 2020-09-17), p. 1442-1455
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. 12 ( 2020-09-17), p. 1442-1455
    Abstract: Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2–based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2020005957
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 2
    Online Resource
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    B-Raf deficiency impairs tumor initiation and progression in a murine breast cancer model
    Springer Science and Business Media LLC ; 2019
    In:  Oncogene Vol. 38, No. 8 ( 2019-2), p. 1324-1339
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 38, No. 8 ( 2019-2), p. 1324-1339
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-018-0663-8
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
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  • 3
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    Abstract 1105: MET or SHP2 inhibition enhances targeted therapies and delays the emergence of resistance in oncogene-driven NSCLC
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1105-1105
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1105-1105
    Abstract: Background: Although advancements have been made in available targeted therapies for non-small cell lung cancer (NSCLC), most patients have an incomplete response and eventually acquire resistance. It is well known that MET signaling is a key pathway that mediates osimertinib resistance. Concurrently targeting multiple proteins in critical signaling pathways, including the MET receptor or SHP2, a key node downstream of receptor tyrosine kinases, may prevent or delay resistance. Here, we explore the promising concept of combining upfront targeted therapies with a selective MET inhibitor or SHP2 inhibitor as promising therapeutic strategies for oncogene-driven NSCLC. Methods: All cell lines were obtained from commercial vendors. Drugs were synthesized at Merck KGaA or purchased from commercial vendors. Cell viability upon inhibitor treatment was investigated by Resazurin Cell Viability Assay (R & D Systems), and the effect of the inhibitors on colony forming ability was assessed using colony formation assays. Western blot was conducted to analyze pathway activity. The emergence of resistance was investigated by measuring the cell surface confluence using the IncuCyte S3 system (Essen Bioscience). Results: The lung cancer cell lines used were NCI-H358 (KRAS G12C), HCC-827 (EGFR L858R), NCI-H2228 (ALK fusion), HCC-78 (ROS1 fusion), and NCI-H1781 (HER2 exon 20 insertion), with their respective targeted therapies sotorasib, osimertinib, alectinib, entrectinib, and poziotinib. The antiproliferative effects of targeted therapies combined with a MET or SHP2 inhibitor were assessed using combination dose matrices in 6-day viability assays. While MET inhibition did not further sensitize the already sensitive cells to the targeted therapies, synergism occurred when the drugs were combined with the SHP2 inhibitor. Similar results were obtained by colony formation assays lasting 2 weeks. Furthermore, the combination of the targeted therapies with the SHP2 inhibitor led to stronger ERK signaling abrogation than with single therapies. In a long-term proliferation assay, the combined inhibition of EGFR and MET receptor delayed the emergence of osimertinib resistance in the EGFR mutant HCC827 cells, which have MET protein overexpression and phosphorylation. Conclusions: Our data show that combining targeted therapies with a SHP2 inhibitor synergistically decreases the viability of oncogene-driven NSCLC cell lines, indicating that initial combination therapy may be an appealing approach to improve patient outcomes. The observed delay in the emergence of osimertinib resistance, from combining a MET inhibitor with osimertinib, provides preclinical evidence to support further investigating MET inhibition upfront to improve the long-term therapeutic efficacy of EGFR inhibitors. Citation Format: Nadine Reischmann, Lorenz Pudelko, Christopher Stroh, Nina Linde, Doreen Musch, Marina Keil, Linda Pudelko, Christina Esdar, Andree Blaukat, Karl M. Schumacher, Niki Karachaliou. MET or SHP2 inhibition enhances targeted therapies and delays the emergence of resistance in oncogene-driven NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1105.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1105
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
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    Online Resource
    Synthetic Biology: Programming Cells for Biomedical Applications
    Project MUSE ; 2012
    In:  Perspectives in Biology and Medicine Vol. 55, No. 4 ( 2012), p. 490-502
    Details
    In: Perspectives in Biology and Medicine, Project MUSE, Vol. 55, No. 4 ( 2012), p. 490-502
    Type of Medium: Online Resource
    ISSN: 1529-8795
    URL: Article
    DOI: 10.1353/pbm.2012.0042
    Language: English
    Publisher: Project MUSE
    Publication Date: 2012
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  • 5
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    Overcoming MET-mediated resistance in oncogene-driven NSCLC
    Elsevier BV ; 2023
    In:  iScience Vol. 26, No. 7 ( 2023-07), p. 107006-
    Details
    In: iScience, Elsevier BV, Vol. 26, No. 7 ( 2023-07), p. 107006-
    Type of Medium: Online Resource
    ISSN: 2589-0042
    URL: Article
    DOI: 10.1016/j.isci.2023.107006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 6
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    Abstract 2854: Reconstruction of BRAFV600E driven colorectal carcinogenesis and identification of novel drug combinations involving BRAF and RTK inhibitors
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2854-2854
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2854-2854
    Abstract: BRAF mutations are found in approximately 10% of colorectal cancers (CRC) and are associated with an aggressive, less-differentiated and therapy-resistant phenotype. Inhibitors targeting BRAFV600E elicit only limited survival benefits when used as single agents. This unresponsiveness was mechanistically attributed to the relief of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated dual and triple combinatorial trials. These trials often involve the combination of BRAF inhibitors (BRAFi) and/or MEK inhibitors with anti-EGFR antibodies such as cetuximab or panitumumab. Although first results of these dual or triple therapies demonstrated improved efficacy, the response rates still were heterogeneous. Here, we show that BRAFi upregulate a variety of receptor tyrosine kinases (RTK) in CRC cell lines, including not only the EGFR, but also human epidermal growth factor receptor (HER) 2 and HER3. Importantly, combination of BRAFi (vemurafenib, dabrafenib or encorafenib) with inhibitors dually targeting the EGFR and HER2 (lapatinib, canertinib or afatinib) significantly reduced the metabolic activity and proliferation of CRC cells. Similarly, genetic depletion of HER2 and HER3 re-sensitized CRC cells to BRAF inhibition. Interestingly, BRAF inhibition also led to increased levels of the GRB2-associated binders (Gab) 1 and Gab2, two important mediators of RTK signaling. The Gab2 upregulation was directly dependent on the loss of BRAFV600E signaling and not caused by “off-target” effects, as demonstrated by allele-specific shRNA mediated BRAFV600E knockdown. These findings suggest new escape mechanisms for current treatment regimens and indicate that targeted therapy in BRAF mutant CRC could benefit from broad RTK pathway blockade. Importantly, the BRAF/HER family inhibitor combination was also more effective in murine intestinal MouseT1 cells (originating from a Vil-Cre;BrafLSL-V637E/+;Tp53LSL-R172H/+ mouse model), which indicates a species-independent phenomenon. These novel and our previous findings that BRAFV600E suppresses features of epithelial differentiation and effector function prompted us to establish crypt organoid cultures from mice carrying conditional BraffloxV600E/+ and/or Tp53LSL-R172H/+ knock-in alleles, either singly or in combination. Using a Vil-CreERT2 transgene, we were able to induce expression of oncogenic BRAF and dominant-negative p53R172H in organoids by 4-hydroxy-tamoxifen mediated Cre activation. We demonstrate that the sudden expression of BRAFV600E and TP53R172H induce marked morphological and molecular changes in small and large intestinal crypts. This organoid model system represents an excellent tool to better understand key characteristics of BRAF mutant CRC such as intrinsic aggressiveness, poor differentiation and resistance to BRAFi. Citation Format: Nadine Reischmann, Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer. Reconstruction of BRAFV600E driven colorectal carcinogenesis and identification of novel drug combinations involving BRAF and RTK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2854.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2854
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
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    Abstract 1106: Detection of MET alterations at the DNA, RNA and protein levels in NSCLC patients progressing on ALK and ROS1 targeted therapies
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1106-1106
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1106-1106
    Abstract: Background: ALK and ROS1 fusion-positive NSCLC patients derive clinical benefit from tyrosine kinase inhibitors (TKIs) but ultimately relapse. Acquired resistance mechanisms include on-target secondary mutations or copy number gains and activation of bypass signaling. Although MET amplification has been described as a bypass resistance mechanism to ALK and ROS1 inhibitors, there are limited data on MET gene and protein overexpression. Aims: (i) detection of MET alterations at the DNA, mRNA and protein levels in ALK and ROS1 fusion-positive NSCLC patients progressing on TKIs, and (ii) establishment of primary cultures using samples from those patients. Methods: MET alterations were studied in 12 patients after progression on TKIs, 10 ALK and 2 ROS1 fusion-positive. Informed consent was obtained from all patients. NGS and FISH were used to detect resistance mutations and amplifications. MET mRNA expression levels were determined by nCounter. Total and phospho-MET levels were assessed by IHC and Western blotting. Results: A total of 21 samples were available from the 12 patients, including tumor biopsies (n=5), plasma (n=10), pleural effusions (n=3) and cerebrospinal fluids (n=3). MET alterations were detected in 4 patients, 3 ALK fusion-positive progressing on lorlatinib and one ROS1 fusion-positive patient progressing on crizotinib. The 3 ALK fusion-positive patients had MET amplification detected in liquid biopsy (n=2) or tumor tissue (n=1), collected after progression on lorlatinib. In the patient with tissue biopsy available, the increased MET copy number was in line with the presence of MET protein and RNA overexpression. MET amplification was not present on the pre-treatment biopsy available for one of the 3 patients. In primary cultures established from pleural effusion samples of 2 ALK fusion-positive patients, MET amplification was maintained, particularly if the cells were cultured in presence of an ALK TKI. Although the ROS1 fusion-positive patient had no MET amplification after progression on crizotinib, MET and phospho-MET upregulation were detected by IHC. These alterations were also present in primary culture that could be established from a pleural effusion sample of the patient. Conclusions: We found MET alterations in 4 out of 12 (33%) fusion-positive patients after progression on TKIs. Three of them had MET amplification and one MET protein overexpression in the absence of MET copy number gain. Despite the small size of the cohort, our results suggest that testing not only at the DNA but also at the RNA and protein levels, discovers amplification-negative patients with MET alterations who may derive benefit from a MET targeted therapy. Finally, our findings highlight the potential of pleural effusion as a source of material for the establishment of primary cultures. Citation Format: Núria Jordana-Ariza, Nadine Reischmann, Carlos Esparré, Ruth Román, Cristina Aguado-Esteban, Silvia García-Román, Christopher Stroh, Andrés Aguilar Aguilar, Rafael Rosell, Niki Karachaliou, Miguel A. Molina-Vila. Detection of MET alterations at the DNA, RNA and protein levels in NSCLC patients progressing on ALK and ROS1 targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1106.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1106
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
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    Measurement and modeling of transcriptional noise in the cell cycle regulatory network
    Informa UK Limited ; 2013
    In:  Cell Cycle Vol. 12, No. 19 ( 2013-10), p. 3392-3407
    Details
    In: Cell Cycle, Informa UK Limited, Vol. 12, No. 19 ( 2013-10), p. 3392-3407
    Type of Medium: Online Resource
    ISSN: 1538-4101 , 1551-4005
    URL: Article
    DOI: 10.4161/cc.26257
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2013
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  • 9
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    Abstract PR07: A biosensor mouse to predict the dissociation and spread of pancreatic cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 2_Supplement ( 2017-01-15), p. PR07-PR07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 2_Supplement ( 2017-01-15), p. PR07-PR07
    Abstract: E-cadherin-mediated cell-cell junctions play a physical role in maintaining normal epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here, we have generated an E-cadherin-GFP(FRAP) biosensor mouse, which enables intravital photobleaching and quantification of E-cadherin mobility in live tissue, without affecting normal biology. We demonstrate using FRAP or FLIP, the broad applications of this mouse to examine E-cadherin regulation in multiple tissues including mammary, brain, liver and kidney, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue, upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment, and reveal new insights into the dynamic remodeling of E-cadherin during in situ cancer progression. Photobleaching in the E-cadherin-GFP(FRAP) mouse correlate directly with epithelial integrity and mechanical strength making the biosensor mouse a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native micro-environments. This abstract is also being presented as Poster B23. Citation Format: David Herrmann, Zahra Erami, Sean Warren, Max Nobis, Astrid Magenau, Morghan Lucas, Claire Vennin, Ewan J. McGhee, Wilfred Leung, Nadine Reischmann, Agata Mrowinska, Juliane P. Schwarz, Shereen Kadir, Saadia A. Karim, Andrew D. Campbell, David Gallego-Ortega, Jeffry Evans, Owen J. Sansom, Jennifer P. Morton, Kurt I. Anderson, Paul Timpson. A biosensor mouse to predict the dissociation and spread of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.EPSO16-PR07
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 10
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    The Atypical Kinase RIOK1 Promotes Tumor Growth and Invasive Behavior
    Elsevier BV ; 2017
    In:  EBioMedicine Vol. 20 ( 2017-06), p. 79-97
    Details
    In: EBioMedicine, Elsevier BV, Vol. 20 ( 2017-06), p. 79-97
    Type of Medium: Online Resource
    ISSN: 2352-3964
    URL: Article
    DOI: 10.1016/j.ebiom.2017.04.015
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
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