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2013年6月18日星期二

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

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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Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines.

Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines.

Mol Biol Rep. 2013 Jan;40(1):269-79

Authors: Shin YM, Jung HJ, Choi WY, Lim CJ

Abstract
Ginsenoside Rg3 is one of ginsenosides that are the well-known bioactive principles of Panax ginseng. Among the two stereoisomeric forms of Rg3, 20(S)-ginsenoside Rg3 [20(S)-Rg3] is predominant. 20(S)-Rg3 is capable of suppressing the nitric oxide (NO), reactive oxygen species (ROS) and prostaglandin E2 (PGE2) productions induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells in a concentration-dependent manner. In the same stimulated macrophages, 20(S)-Rg3 was able to suppress matrix metalloproteinase-9 (MMP-9) activity and suppress cyclooxygenase-2 (COX-2) expression. It suppressed the production of some proinflammatory cytokines, such as TNF-?, IL-1? and IL-6, and the cell mobility enhanced by LPS in the macrophage cells. 20(S)-Rg3 displayed suppressive effect on the ROS level but not on the NO level, and down-regulating effect on MMP-9 but not on MMP-2 in non-stimulated HaCat keratinocytes. 20(S)-Rg3 also exhibited suppressive effect on the MMP-9 gelatinolytic activity enhanced in the HaCat keratinocytes stimulated with tumor necrosis factor-? (TNF-?), one of the major proinflammatory cytokines. However, 20(S)-Rg3 was not able to modulate the NO level even in the presence of TNF-?. Taken together, anti-inflammatory and related antioxidative and MMP-9 inhibitory activities of 20(S)-Rg3, the major stereoisomeric form of ginsenoside Rg3, are confirmed in macrophage and keratinocyte cell lines.

PMID: 23054007 [PubMed - indexed for MEDLINE]

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Current evidence on the relationship between three polymorphisms in the XRCC7 gene and cancer risk.

Current evidence on the relationship between three polymorphisms in the XRCC7 gene and cancer risk.

Mol Biol Rep. 2013 Jan;40(1):81-6

Authors: Zhang J, Wu XH, Gan Y

Abstract
Inconsistency of the association of polymorphisms of XRCC7 with cancer is noted. Three commonly studied XRCC7 polymorphisms including rs7003908 (T>G), rs7830743 (A>G), and rs10109984 (T>C) were selected to explore their association with risk of development of cancer by meta-analysis of published case-control studies. The results showed that no significant associations with cancer risk were found in any model in terms of rs7003908, rs7830743 and rs10109984 when all studies were pooled into the meta-analysis. But when stratified by cancer type, statistically significantly elevated cancer risk was only found in prostate cancer for rs7003908 (GG vs. TT: OR = 1.845, 95 % CI = 1.178-2.888; dominant model: OR = 1.423, 95 % CI = 1.050-1.929; recessive model: OR = 1.677, 95 % CI = 1.133-2.482). In the subgroup analysis by ethnicity or study design, no significantly increased risks were found for all three polymorphisms. This meta-analysis suggests that XRCC7 rs7003908 polymorphism may contribute to cancer susceptibility for prostate cancer, which is recommended to be included in future large-sample studies and functional assays.

PMID: 23108991 [PubMed - in process]

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2013年6月17日星期一

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

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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