Amongst the three forms of Raf kinases, the B-type Raf kinase would be the most potent activator on the MAPK kinase pathway.6 Mutations inside the B-Raf gene are the most common genetic alteration found in patients with thyroid cancer, occurring in about 45% of sporadic Vicriviroc ic50 selleck chemicals PTCs.eight Of those, the V600E mutation inside the exon 15 represents >90% of B-Raf mutations and is present in 77.8% of individuals with recurrent illness.eight B-Raf mutation in PTC has been independently associated with the absence of tumor capsule and tumor iodine avidity, tumor recurrence, and treatment failure of recurrent disease.9,10 In vitro, inhibitors of Raf kinase activity have shown to efficiently inhibit the development of poorly differentiated thyroid cancer cell lines that harbor mutations in RET or Raf.11 Sorafenib.Sorafenib is definitely an orally active multi-kinase inhibitor that targets B-Raf, vascular endothelial growth issue receptors 1 and 2 , RET, and c-Kit.It could possibly be a potentially beneficial agent for patients with thyroid cancer because of its effects around the B-Raf pathway , RET, and angiogenesis.Two phase II clinical trials applying sorafenib in patients with metastatic iodinerefractory thyroid carcinoma have already been published.
The 1st trial was conducted by Kloos et al,12 in which 56 individuals had been enrolled; partial response was seen in six of the 41 sufferers, with PTC incorporated, and stable illness >6 months in 23 patients.The median duration of partial response was 7.5 months and median progression-free survival was 15 months.Grade 3 adverse events included hand?foot skin reaction, musculoskeletal discomfort, and fatigue.Interestingly, a high incidence of B-Raf mutation was identified in 17 of 22 PTCs analyzed, with 14 of those mutations becoming V600E, whereas three other sufferers PD0332991 selleck chemicals had a K601E mutation.No patients with MTC have been integrated and no partial responses had been reported in non-PTC patients.The second phase II trial was carried out by Gupta-Abramson et al13 in 30 individuals who had been treated with sorafenib 400 mg orally twice every day.Seven individuals had partial response lasting 18 to 84 weeks, and 16 sufferers had steady illness lasting 14 to 89 weeks; median PFS was 79 weeks.Of note, 95% patients for whom serial thyroglobulin levels had been offered showed a reduce in thyroglobulin levels, having a imply decrease of 70%.In terms of toxicity, a single patient died of liver failure that was probably treatment-related.13 Although the presence of B-Raf mutation has been related with poor outcome and also the outcomes of these trials are encouraging, the correlation in between the presence of B-RafV600E mutation and clinical response to sorafenib has but to be elucidated.Preliminary benefits of a different open-label phase II study of sorafenib in 55 patients with metastatic, iodinerefractory thyroid carcinoma presented within the 2009 .