FGF Receptors: Cancer Biology and Therapeutics.

FGF Receptors: Cancer Biology and Therapeutics.

Med Res Rev. 2013 May 21;

Authors: Katoh M, Nakagama H

Abstract
Fibroblast growth factors (FGFs) are involved in a variety of cellular processes, such as stemness, proliferation, anti-apoptosis, drug resistance, and angiogenesis. Here, FGF signaling network, cancer genetics/genomics of FGF receptors (FGFRs), and FGFR-targeted therapeutics will be reviewed. FGF signaling to RAS-MAPK branch and canonical WNT signaling cascade mutually regulate transcription programming. FGF signaling to PI3K-AKT branch and Hedgehog, Notch, TGF?, and noncanonical WNT signaling cascades regulate epithelial-to-mesenchymal transition (EMT) and invasion. Gene amplification of FGFR1 occurs in lung cancer and estrogen receptor (ER)-positive breast cancer, and that of FGFR2 in diffuse-type gastric cancer and triple-negative breast cancer. Chromosomal translocation of FGFR1 occurs in the 8p11 myeloproliferative syndrome and alveolar rhabdomyosarcoma, as with FGFR3 in multiple myeloma and peripheral T-cell lymphoma. FGFR1 and FGFR3 genes are fused to neighboring TACC1 and TACC3 genes, respectively, due to interstitial deletions in glioblastoma multiforme. Missense mutations of FGFR2 are found in endometrial uterine cancer and melanoma, and similar FGFR3 mutations in invasive bladder tumors, and FGFR4 mutations in rhabdomyosarcoma. Dovitinib, Ki23057, ponatinib, and AZD4547 are orally bioavailable FGFR inhibitors, which have demonstrated striking effects in preclinical model experiments. Dovitinib, ponatinib, and AZD4547 are currently in clinical trial as anticancer drugs. Because there are multiple mechanisms of actions for FGFR inhibitors to overcome drug resistance, FGFR-targeted therapy is a promising strategy for the treatment of refractory cancer. Whole exome/transcriptome sequencing will be introduced to the clinical laboratory as the companion diagnostic platform facilitating patient selection for FGFR-targeted therapeutics in the era of personalized medicine.

PMID: 23696246 [PubMed - as supplied by publisher]

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Computational determination of the orientation of a heat repeat-like domain of DNA-PKcs.

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Computational determination of the orientation of a heat repeat-like domain of DNA-PKcs.

Comput Biol Chem. 2013 Feb;42:1-4

Authors: Lindert S, Stewart PL, Meiler J

Abstract
DNA dependent protein kinase catalytic subunit (DNA-PKcs) is an important regulatory protein in non-homologous end joining a process used to repair DNA double strand breaks. Medium resolution structures both from cryoEM and X-ray crystallography show the general topology of the protein and positions of helices in parts of DNA-PKcs. EM-Fold, an algorithm developed for building protein models into medium resolution density maps has been used to generate models for the heat repeat-like "Ring structure" of the molecule. We were able to computationally corroborate placement of the N-terminus of the domain that supports a previously published hypothesis. Targeted experiments are suggested to test the model.

PMID: 23246775 [PubMed - in process]

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Molecular markers of response and resistance to EGFR inhibitors in head and neck cancers.

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Molecular markers of response and resistance to EGFR inhibitors in head and neck cancers.

Front Biosci. 2013;18:520-42

Authors: Box C, Zimmermann M, Eccles S

Abstract
Receptor tyrosine kinases (RTK) are key targets for novel cancer therapeutics since they activate multiple oncogenic signalling pathways. Also, they are inherently 'druggable' due to their small ATP-dependent kinase domains (inhibitable by small molecules) and cell surface location which renders them accessible to monoclonal antibody-based therapies. The epidermal growth factor receptor (EGFR) is overexpressed in the majority of SCCHN cases and this review focuses primarily on the progress made in targeting the EGFR for the therapy of SCCHN by both small molecules and antibody-based therapies. We then discuss the overlapping and distinct molecular markers of response, innate or acquired resistance to each modality, and how these may be overcome. We also consider other RTKs overexpressed in this disease that may impact on responses and/or provide additional targets for combination therapy.

PMID: 23276940 [PubMed - in process]

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Image-based high-throughput screening for inhibitors of angiogenesis.

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Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

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Traditionally used Veronica officinalis inhibits proinflammatory mediators via the NF-?B signalling pathway in a human lung cell line.

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Traditionally used Veronica officinalis inhibits proinflammatory mediators via the NF-?B signalling pathway in a human lung cell line.

J Ethnopharmacol. 2013 Jan 9;145(1):118-26

Authors: Gr�ndemann C, Garcia-K�ufer M, Sauer B, Stangenberg E, K�ncz�l M, Merfort I, Zehl M, Huber R

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Extracts from Veronica officinalis L. are traditionally used for the treatment of lung diseases; however, the effective compounds and the mode of action are still unknown.
AIM OF THE STUDY: Here we analyzed the effects of a standardized Veronica extract on genes expression and signalling protein production associated with the development of inflammatory lung diseases.
MATERIAL AND METHODS: The degranulation capacity of primary mast cells, as well as gene expression and release of inflammatory mediators from human lung epithelial cells (A549 cells) were analyzed in relation to the synthetic drugs azelastine and dexamethasone. Gene and protein expression of cyclooxygenase-2 were investigated by semi-quantitative RT-PCR and western blotting, respectively. The involvement of phosphorylated mitogen-activated protein kinases and NF-?B signaling in regulation of these molecules were characterized by western blotting and electrophoretic mobility shift assays. Characteristic extract components were identified by LC-MS and verminoside was quantified by HPLC analysis.
RESULTS: We demonstrated that Veronica officinalis has a small influence on the degranulation capacity of mast cells but rather inhibits gene and protein expression of the chemokine eotaxin in A549 lung epithelial cells, which is essential for recruitment of inflammatory-associated cells in lung diseases. Furthermore, release of the inflammatory mediator PGE(2) was diminished through inhibition of COX-2 expression via the NF-?B signaling pathway in TNF-?-activated A549 cells. Phytochemical analysis identified verproside and verminoside as the most abundant iridoid glycosides.
CONCLUSION: Our results are a contribution to explaining the observed anti-inflammatory effects of Veronica offcinalis extract on a molecular level. However, its clinical potency has at first to be proven in animals and subsequently in clinical trials.

PMID: 23142555 [PubMed - indexed for MEDLINE]

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Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer.

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Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer.

Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):E1301-10

Authors: Knight JF, Lesurf R, Zhao H, Pinnaduwage D, Davis RR, Saleh SM, Zuo D, Naujokas MA, Chughtai N, Herschkowitz JI, Prat A, Mulligan AM, Muller WJ, Cardiff RD, Gregg JP, Andrulis IL, Hallett MT, Park M

Abstract
Triple-negative breast cancer (TNBC) accounts for ?20% of cases and contributes to basal and claudin-low molecular subclasses of the disease. TNBCs have poor prognosis, display frequent mutations in tumor suppressor gene p53 (TP53), and lack targeted therapies. The MET receptor tyrosine kinase is elevated in TNBC and transgenic Met models (Met(mt)) develop basal-like tumors. To investigate collaborating events in the genesis of TNBC, we generated Met(mt) mice with conditional loss of murine p53 (Trp53) in mammary epithelia. Somatic Trp53 loss, in combination with Met(mt), significantly increased tumor penetrance over Met(mt) or Trp53 loss alone. Unlike Met(mt) tumors, which are histologically diverse and enriched in a basal-like molecular signature, the majority of Met(mt) tumors with Trp53 loss displayed a spindloid pathology with a distinct molecular signature that resembles the human claudin-low subtype of TNBC, including diminished claudins, an epithelial-to-mesenchymal transition signature, and decreased expression of the microRNA-200 family. Moreover, although mammary specific loss of Trp53 promotes tumors with diverse pathologies, those with spindloid pathology and claudin-low signature display genomic Met amplification. In both models, MET activity is required for maintenance of the claudin-low morphological phenotype, in which MET inhibitors restore cell-cell junctions, rescue claudin 1 expression, and abrogate growth and dissemination of cells in vivo. Among human breast cancers, elevated levels of MET and stabilized TP53, indicative of mutation, correlate with highly proliferative TNBCs of poor outcome. This work shows synergy between MET and TP53 loss for claudin-low breast cancer, identifies a restricted claudin-low gene signature, and provides a rationale for anti-MET therapies in TNBC.

PMID: 23509284 [PubMed - in process]

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Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer.

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Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer.

Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):E1301-10

Authors: Knight JF, Lesurf R, Zhao H, Pinnaduwage D, Davis RR, Saleh SM, Zuo D, Naujokas MA, Chughtai N, Herschkowitz JI, Prat A, Mulligan AM, Muller WJ, Cardiff RD, Gregg JP, Andrulis IL, Hallett MT, Park M

Abstract
Triple-negative breast cancer (TNBC) accounts for ?20% of cases and contributes to basal and claudin-low molecular subclasses of the disease. TNBCs have poor prognosis, display frequent mutations in tumor suppressor gene p53 (TP53), and lack targeted therapies. The MET receptor tyrosine kinase is elevated in TNBC and transgenic Met models (Met(mt)) develop basal-like tumors. To investigate collaborating events in the genesis of TNBC, we generated Met(mt) mice with conditional loss of murine p53 (Trp53) in mammary epithelia. Somatic Trp53 loss, in combination with Met(mt), significantly increased tumor penetrance over Met(mt) or Trp53 loss alone. Unlike Met(mt) tumors, which are histologically diverse and enriched in a basal-like molecular signature, the majority of Met(mt) tumors with Trp53 loss displayed a spindloid pathology with a distinct molecular signature that resembles the human claudin-low subtype of TNBC, including diminished claudins, an epithelial-to-mesenchymal transition signature, and decreased expression of the microRNA-200 family. Moreover, although mammary specific loss of Trp53 promotes tumors with diverse pathologies, those with spindloid pathology and claudin-low signature display genomic Met amplification. In both models, MET activity is required for maintenance of the claudin-low morphological phenotype, in which MET inhibitors restore cell-cell junctions, rescue claudin 1 expression, and abrogate growth and dissemination of cells in vivo. Among human breast cancers, elevated levels of MET and stabilized TP53, indicative of mutation, correlate with highly proliferative TNBCs of poor outcome. This work shows synergy between MET and TP53 loss for claudin-low breast cancer, identifies a restricted claudin-low gene signature, and provides a rationale for anti-MET therapies in TNBC.

PMID: 23509284 [PubMed - in process]

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