Search results for "PROTEIN KINASE"

3,4-Diarylmaleimides Effectively Inhibit Proliferation of FLT3-ITD-Positive Leukemic Cells, Induce Apoptosis and Show Additive Effects in Combination…

2007

Abstract Internal tandem duplication (ITD) mutations of FLT3 are present in leukemic blasts of approximately 30% of AML patients. ITD-mutations of FLT3 confer a worse prognosis and decreased overall survival. Therefore, FLT3-tyrosine kinase is considered an attractive drug target in AML and several FLT3-tyrosine kinase inhibitors (TKIs) are currently being tested in clinical trials (CEP701, MLN518, Sorafenib, PKC412). However, using these drugs as monotherapy, against the setting of remarkable efficacy has emerged the problem of short duration of remission indicating rapid development of secondary resistance. In addition, up to 30% of patients may show primary resistance to currently availa…

Sorafenib in advanced hepatocellular carcinoma

2008

none 25 BACKGROUND: No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. METHODS: In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Seconda…

Future perspectives in hepatocellular carcinoma.

2010

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide. Due to late diagnosis and advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefits have been available in up to 70% of patients. However, major progress has been achieved with regard to surveillance, early diagnosis, and multimodal treatment approaches during the last years leading to an improvement in prognosis. Particularly, the increasing knowledge of molecular hepatocarcinogenesis today provides the opportunity for targeted therapy. The multikinase inhibitor sorafenib has broadened the therapeutic horizon for patients with advanced disease and is current…

Transarterial chemoembolization and sorafenib in patients with intermediate-stage hepatocellular carcinoma: time to enter routine clinical practice?

2015

According to the guidelines of the European Association for the Study of the Liver (EASL), patients affected from hepatocellular carcinoma (HCC) can be classified according to the Barcelona Clinic Liver Cancer (BCLC) staging system. This classification system divides HCC patients in five stages (0, A, B, C and D) on the basis of a number of prognostic and treatment- related variables such as tumor status and liver function. A specific treat ment approach is then proposed for each of the above-mentioned stages. Transarterial chemoembolization (TACE) is recommended as first-line therapy in the treatment of patients with intermediate-stage (BCLC-B class) HCC [1]. The efficacy of this procedure…

Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond.

2018

The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago, with sorafenib demonstrating survival benefit in the first-line setting and becoming the first systemic therapy to be approved for HCC. More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). A key recommendation in the management of patients receiving sorafenib is to promote close communication between the patient and the physician so that adverse events (AEs) are detected early and severe AEs can b…

Immune oncology in hepatocellular carcinoma-hype and hope.

2017

The role of targeted therapy for gastrointestinal tumors

2014

Abstract: Many targeted drugs have been studied to target the molecular pathways involved in the development of gastrointestinal cancers. Anti-VEGF, anti-EGFR agents, and recently also multi-kinase inhibitor regorafenib, have already been available for the treatment of metastatic colorectal cancer patients. To date, Her-2 positive, gastric cancer patients, are also treated with trastuzumab, while the multi-targeted inhibitor, sorafenib, represents the standard treatment for hepatocellular carcinoma patients. Finally, sunitinib and everolimus, have been approved for the treatment of the neuroendocrine gastroenteropancreatic tumors. Actually a great number of further drugs are under preclinic…

Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy

2015

Abstract: Introduction: Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach. Areas covered: This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs i…

What links BRAF to the heart function? new insights from the cardiotoxicity of BRAF inhibitors in cancer treatment

2015

The RAS-related signalling cascade has a fundamental role in cell. It activates differentiation and survival. It is particularly important one of its molecules, B-RAF. B-RAF has been a central point for research, especially in melanoma. Indeed, it lacked effective therapeutic weapons since the early years of its study. Molecules targeting B-RAF have been developed. Nowadays, two classes of molecules are approved by FDA. Multi-target molecules, such as Sorafenib and Regorafenib, and selective molecules, such as Vemurafenib and Dabrafenib. Many other molecules are still under investigation. Most of them are studied in phase 1 trials. Clinical studies correlate B-RAF inhibitors and QT prolonga…

p38 MAPK activation is required for Paracentrotus lividus skeletogenesis

2008

We investigated the p38 MAPK role during sea urchin, Paracentrotus lividus, development. We found that at the morula stage, before the onset of skeletogenesis, p38 MAPK shows a peak of activity, and we tested whether p38 MAPK activity has any effect on skeletogenesis. By immunohistochemistry on whole-mount embryos we show the preferential localization of the active p38 form both in the presumptive PMCs and bilateral spiculo- genesis centers in control embryos, and in the radialized supernumerary spiculogenesis centers induced by NiCl2 treatment. By using SB203580, a p38 MAPK specific inhibitor, we show that p38 activity is required both for the initial triradiate spicule rudiments formation…