Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The introduction of novel targeted therapies into the clinic in recent years has had a considerable impact on the management of several neoplastic diseases--such as gastrointestinal stromal tumors, hepatocellular carcinomas and renal cell carcinomas--considered until recently refractory to systemic therapies. We describe here two such novel biological agents, sunitinib and sorafenib, as a paradigm of the successful clinical application of new concepts. Sunitinib and sorafenib are small molecule tyrosine kinase inhibitors that target vascular endothelial growth factor receptor, platelet-derived growth factor receptor, C-Kit and others. Both agents are administered orally; sunitinib is tyically given in cycles for 4 consecutive weeks with 2 weeks off, while sorafenib is given continually. Side effects occur in most patients, similar for both agents; they may affect several systems and organs but are mostly mild and easily manageable, rarely requiring discontinuation of the drug. However, these toxicities mandate prompt attention and intervention. The most frequently observed effects are hypertension, nausea, anorexia, asthenia and cutaneous manifestations; cardiac abnormalities may include congestive failure. Sunitinib, and markedly less frequently sorafenib, may cause thyroid gland dysfunction, mainly hypothyroidism. Antitumor activity has been shown for renal cell carcinoma in pivotal trials, for sunitinib as first-line treatment and for sorafenib in previously treated patients as second-line. Sunitinib is now approved as second-line therapy for patients with GIST refractory to imatinib; sorafenib has resulted in a significant prolongation in median survival in patients with hepatocellular carcinoma. Ongoing clinical trials will further define the spectrum of these agents' antitumor activity, their role in combination with other drugs, as well as their optimal dose and schedule of administration.
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PMID:Novel multitargeted anticancer oral therapies: sunitinib and sorafenib as a paradigm. 2109 May 21

The prognosis of patients with metastatic uveal melanoma is poor and there are limited therapeutic options. C-kit is expressed in the majority of patients with metastatic uveal melanoma. In this pilot trial, we examined the toxicity and efficacy of sunitinib malate, a multitarget tyrosine kinase inhibitor, in patients with metastatic uveal melanoma. Twenty patients with metastatic uveal melanoma expressing c-kit, 17 of whom failed previous treatments, were included in this study. Patients received sunitinib malate 37.5 mg daily continuously in 4-week cycles. The evaluation of response was carried out every 8 weeks. The overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier survival curves and differences in survivals were tested using the log-rank test. There was one partial response and 12 stable disease (SD) after sunitinib treatment. The median OS and PFS were 8.2 and 4.2 months, respectively. Three patients had SD for more than 12 months with sunitinib after failing previous treatments. The most common adverse events were fatigue (90%), diarrhea (60%), hemorrhage (55%), anorexia (45%), hand-foot syndrome (25%), hypothyroidism (25%), and rash (25%). Eleven patients required a dose reduction to 25 mg daily secondary to grade 3 adverse events. The degree of c-kit expression in melanoma cells was not associated with longer PFS or OS. Patients who developed systemic metastases after more than 5 years of their initial diagnosis had better PFS (median PFS: 5.8 vs. 2.6 months, P=0.005). Sunitinib was safely administered and showed potential clinical benefit in patients with metastatic uveal melanoma. The lack of a correlation between c-kit expression and clinical outcomes requires further investigation on the mechanism of sunitinib in metastatic uveal melanoma.
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PMID:A pilot study of sunitinib malate in patients with metastatic uveal melanoma. 2311 4