Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs
ABSTRACT The activation of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway is a known causal mechanism of oncogenesis and resistance to cancer treatments. The process of PI3K-Akt pathway activation is complex and includes receptor tyrosine kinase(RTK) activation, PIK3CA mutations, loss of phosphatase and tensin homolog (PTEN), Akt mutations, tuberous sclerosis complex (TSC) mutations, and Ras homologue enriched in brain (RHEB) gene amplifications. The blockage of mammalian target of rapamycin (mTOR), the key downstream pathway protein, has been successful in selected cancer types, with mTOR-targeting agents available for clinical use. Other novel drugs blocking this pathway such as PI3K inhibitors, Akt inhibitors and PDK-1 inhibitors are currently only available for investigational use, but have shown promise as cancer therapies in both preclinical and early phase clinical studies. The newer generations of these inhibitors are more specific and have improved potency and safety. The combinations of targeted treatments against this pathway, blocking multiple different steps, are under preliminary investigation. Further research is needed to identify the biomarkers that predict treatment response and resistance in order to optimize personalized medicine.
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ABSTRACT: Melanoma is the least common form of skin cancer, but it is responsible for the majority of skin cancer deaths. Traditional therapeutics and immunomodulatory agents have not shown much efficacy against metastatic melanoma. Agents that target the RAS/RAF/MEK/ERK (MAPK) signaling pathway-the BRAF inhibitors vemurafenib and dabrafenib, and the MEK1/2 inhibitor trametinib-have increased survival in patients with metastatic melanoma. Further, the combination of dabrafenib and trametinib has been shown to be superior to single agent therapy for the treatment of metastatic melanoma. However, resistance to these agents develops rapidly. Studies of additional agents and combinations targeting the MAPK, PI3K/AKT/mTOR (PI3K), c-kit, and other signaling pathways are currently underway. Furthermore, studies of phytochemicals have yielded promising results against proliferation, survival, invasion, and metastasis by targeting signaling pathways with established roles in melanomagenesis. The relatively low toxicities of phytochemicals make their adjuvant use an attractive treatment option. The need for improved efficacy of current melanoma treatments calls for further investigation of each of these strategies. In this review, we will discuss synthetic small molecule inhibitors, combined therapies and current progress in the development of phytochemical therapies. Copyright © 2015. Published by Elsevier Ireland Ltd.Cancer Letters 01/2015; 359(1). DOI:10.1016/j.canlet.2015.01.016 · 5.02 Impact Factor
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ABSTRACT: This paper examines the density, distribution and characteristics of mid-latitude cyclones in the oceans south of Africa in the GENESIS general circulation model (GCM). The latest version of the GENESIS GCM (version 2.0.a), as well as its predecessor (version 1.02), are evaluated to assess whether version 2.0.a is an improvement over version 1.02 in terms of mid-latitude cyclones. An automated cyclone finding program was used to identify cyclone centres. This program was applied to 5 years of twice daily GENESIS (versions 1.02 and 2.0.a) sea-level pressure data, as well as to 10 years of a gridded assimilation of observed data for the winter season (June, July, August).The results show that version 1.02 does not simulate the full meridional sea-level pressure range over the analysis window, whereas version 2.0.a is closer to that of the observed data. The circumpolar trough in version 1.02 is between 10 and 15 hPa too weak and it extends too far equatorward. The trough is captured better by version 2.0.a, probably due to its finer grid resolution (T31) compared with that of version 1.02 (R15 resolution). In both versions, cyclone densities north of 55°S are higher than observed and the high cyclone density band around the pole in version 1.02 is poorly defined. Discrepancies between the two versions, and the model and observed data, have been related to factors such as grid resolutions, topography, heat transport and sea-ice extent. Version 1.02 does not simulate the full meridional gradient of cyclone central pressures, whereas version 2.0.a is a better representation of the observed data. Both versions exhibit greater variability in the sea-level pressure field compared with the observed data. GENESIS version 2.0.a is a considerable improvement over its predecessor in terms of mid-latitude cyclones in the African region of the southern oceans.International Journal of Climatology 04/1997; 17(5):459-473. DOI:10.1002/(SICI)1097-0088(199704)17:53.0.CO;2-R · 3.40 Impact Factor
- Targeted Oncology 03/2011; 6(1):1-4. DOI:10.1007/s11523-011-0180-y · 3.46 Impact Factor