Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer

McPhillips, Fiona; Mullen, Peter; Monia, Brett P.; Ritchie, Alison; Dorr, F. Andrew; Smyth, John F.; Langdon, Simon P.

doi:10.1054/bjoc.2001.2139

Cited by 68 publications

(39 citation statements)

References 16 publications

(18 reference statements)

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“…For a long time, it was thought that constitutive activation of the mitogenic cascade, 80 e.g., by either mutational activation of RAS proteins 81 or by overexpression of C-RAF, 82 is the main mechanism contributing to tumor formation in humans. A couple of recent publications addressing the mutational status of A-RAF and C-RAF genes in more than 600 cancer cell lines and 500 primary human samples obtained from colorectal and gastric carcinoma, acute leukemias, gliomas, as well as lung, ovarian and testis tumors suggest that mutations in both RAF genes are very rare or nonexistent events.…”

Section: Raf Kinases and Human Cancermentioning

confidence: 99%

Raf kinases: Oncogenesis and drug discovery

Schreck

Rapp

2006

Intl Journal of Cancer

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Raf kinase signaling has been thoroughly investigated over the last 20 years. A-Raf, B-Raf and C-Raf, the 3 mammalian members of the Raf family, are involved in a variety of cellular processes such as growth, proliferation, survival, differentiation and transformation. The detection of B-RAF mutations in a wide variety of human cancers, the description of wildtype and mutant B-RAF as tumor antigens in melanoma and the promising outcome of clinical trials evaluating the Raf inhibitor Nexavar 1 (Sorafenib, BAY 43-9006) have sparked a broad interest in the scientific community. After a short historical detour and an introduction into Raf kinase signaling, we are going to discuss here recent outcomes of Raf kinase research with respect to tumor formation and give an overview on current efforts to develop anticancer therapies interfering with aberrant Raf kinase signaling. ' 2006 Wiley-Liss, Inc.Key words: cancer; clinical trials; transformation; drug delivery; signal transduction; mitogenic cascade; Raf kinases Raf kinases: The historyIn 1983, the cloning of the acutely transforming replication-defective mouse type C virus 3611-MSV and characterization of its acquired oncogene was reported. 1 Since 3611-MSV induces rapidly growing f ibrosarcoma in mice, the transduced oncogene was called v-raf, whereas its cellular homologue was named c-raf. 1 Shortly thereafter, Bister and coworkers described the cloning of the avian acute leukemia retrovirus Mil Hill No. 2 (MH2). 2 MH2 was found to carry a second potential oncogene in addition to vmyc, which was termed v-mil, whereas its cellular counterpart was called c-mil. 3 Already a hybridization analysis and the gross comparison of restriction maps of v-raf and v-mil pointed at sequence homologies between these 2 genes. 4 By direct sequencing of both genes it was finally proven that 3611-MSV and MH2 have integrated orthologues of the same gene into their genomes. 5 In the following we are going to use the nomenclature for Raf kinases as proposed in a recent review from Wellbrock et al. 6 In contrast to all other oncogene kinases known at that time, no tyrosine kinase activity was detected in C-Raf. 7 Indeed, it was found that C-Raf is a serine/threonine kinase. 8,9 This and the observation that Raf coexists with the Myc oncogene in retroviruses 10 led to two novel concepts: (i) There is a tyrosine to serine phosphorylation switch as the growth factor signal enters the cell, and (ii) the mechanistic basis for cooperation between nuclear and cytoplasmic oncogenes as well as for signal transduction from cell surface receptors to the nucleus is the phosphorylation of transcription factor class oncogenes such as Myc. 11-13 Growth factor abrogation and oncogene cooperation studies were performed to corroborate this signaling scheme. 14-17 Additional important early findings were (i) the cooperation between Raf and Myc in growth factor independent proliferation, immortalization and tumor induction, 14,18,19 leading to the Raf-Myc balance model, 20 and (ii) the cell lineage-switch ...

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Section: Raf Kinases and Human Cancermentioning

confidence: 99%

Raf kinases: Oncogenesis and drug discovery

Schreck

Rapp

2006

Intl Journal of Cancer

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“…6,7 In the present study, we extend these investigations by comparing the effects of first-generation ASOs with second-generation ASOs and also with siRNAs targeted against Raf-1 mRNA. We demonstrate the importance of a high level of transfection for effective target mRNA reduction and blockade of downstream signaling resulting in growth inhibition.…”

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confidence: 78%

“…4 Raf-1 is frequently activated in many tumors, either through mutation or through overexpression, and is essential for the regulation of cellular proliferation. Since overexpression of Raf-1 is associated with reduced survival in ovarian cancer, 6,7 we have explored strategies to reduce its expression.…”

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confidence: 99%

Comparison of strategies targeting Raf-1 mRNA in ovarian cancer

et al. 2005

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In this study, we characterize the uptake and specificity of a firstgeneration Raf-1 antisense oligonucleotide (ASO) (ISIS 5132) and compare it with a second-generation ASO (ISIS 13650) and an RNA interference approach. All three approaches resulted in inhibition of both Raf-1 expression and cellular growth. Specificity of the Raf-1 ASOs was confirmed by comparison with ASOs targeted against another Raf isoform (B-Raf) as well as mismatch sequences. Cellular uptake studies with FAM-labelled ISIS 5132 revealed that whilst the majority of cells treated at a low-intermediate plating density were labelled within 3 hr, cells treated at high density demonstrated neither Raf-1 protein knockout nor significant growth inhibition, following similar treatment. This lack of response at high cell densities was associated with reduced pERK and Raf-1 inhibition. Cell cycle analysis revealed that whilst SKOV-3 cells both accumulated in the S-phase of the cell cycle and showed enhanced annexin V levels, following Raf-1 ASO treatment; these effects were also demonstrated with first-generation but not second-generation mismatch oligonucleotides. Bromodeoxyuridine incorporation analysis suggested that these effects may indeed be partly attributable to sequence nonspecific effects. Finally, the combination of ISIS 5132 with either carboplatin or taxol showed enhanced growth inhibition, supporting the view that such ASOs may have a more effective clinical role when used in combination with cytotoxic agents. ' 2005 Wiley-Liss, Inc.

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“…Raf-1 activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase pathway inhibits apoptosis in cancer cells and MEK inhibitors may abrogate the antiapoptotic function of Raf-1 (31,32). There are only episodic reports of Raf-1-positive expression, particularly in ovarian and head and neck cancer (33,34). Although the roles of Raf-1 in BTC carcinogenesis and progression are not fully understood, our results, demonstrating a high rate of Raf-1 expression, may indicate activation of the IGFR-IR̸Ras̸Raf pathway.…”

Section: A B C Dmentioning

confidence: 99%

Expression of insulin-like growth factor I receptor as a biomarker for predicting prognosis in biliary tract cancer patients

Suzuki

Roa

Kawamoto

et al. 2015

Molecular and Clinical Oncology

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Abstract. Carcinomas of the gallbladder (GBCa) and bile ducts are aggressive tumors with poor survival and it is, therefore, essential to elucidate the molecular mechanisms of the various signaling pathways in order to develop effective therapies. In this study, tumor specimens from 40 GBCa patients, 12 extrahepatic bile duct carcinoma patients and 26 intrahepatic bile duct carcinoma patients from the USA and Japan were investigated for insulin-like growth factor I receptor (IGF-IR), mammalian target of rapamycin (mTOR) and rapidly accelerated fibrosarcoma-1 (Raf-1) expression by immunohistochemistry; in addition, the correlations with histological type, pathological stage and patient outcome were analyzed. Positive expression of IGF-IR, mTOR and Raf-1 were identified in 68, 73 and 85% of the specimens, respectively. There was no association with histological type and pathological stage, although the positive expression rate of Raf-1 was higher in advanced-stage GBCa. Moreover, patients with positive expression of IGF-IR exhibited significantly reduced survival compared to those with negative IGF-IR expression. In conclusion, IGF-IR, mTOR and Raf-1 were highly expressed in biliary tract cancer and targeted therapy against IGF-IR may be an effective strategy. Among these molecules, IGF-IR expression was found to be a useful biomarker for identifying patients who may benefit from additional treatment.

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Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer

Cited by 68 publications

References 16 publications

Raf kinases: Oncogenesis and drug discovery

Raf kinases: Oncogenesis and drug discovery

Comparison of strategies targeting Raf-1 mRNA in ovarian cancer

Expression of insulin-like growth factor I receptor as a biomarker for predicting prognosis in biliary tract cancer patients

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