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)

BAY 43-9006 is an oral inhibitor of CRAF, wild-type BRAF, mutant V599E BRAF, vascular endothelial growth factor receptor (VEGFR) 2, VEGFR3, mVEGFR2, FLT-3, platelet-derived growth factor receptor, p38, and c-kit among other kinases. A Phase I study of BAY 43-9006 identified 400 mg orally twice daily as the recommended Phase II dose. The Phase II results of a study of BAY 43-9006 at 400 mg orally twice daily were particularly interesting in patients with renal cell carcinoma. Data from the first 41 patients with renal cell carcinoma showed that 30% of patients had stable disease (defined as between 25% reduction and 25% growth), 40% had responded (defined as >25% reduction), and 30% had progressed. Disease could be stabilized for periods in excess of a year. Some lesions became cystic and could actually enlarge while developing a low attenuation core. This phenomenon is recognized in the treatment of gastrointestinal stromal tumors with imatinib mesylate. The toxic effects of BAY 43-9006 were manageable and included hypertension, edema, diarrhea, hand and foot syndrome, rash, and hair loss where the rash involved the scalp. There was an impression of tachyphylaxis such that patients who required a dose reduction could be restored to full dose after a few months. A Phase III randomized, placebo-controlled trial of BAY 43-9006 has started for patients whose renal cell carcinoma has progressed within 6 months of immunotherapy. Combination studies with interferon, interleukin 2, bevacizumab, and chemotherapy are under consideration. The therapeutic targets of BAY 43-9006 in renal cell carcinoma remain unclear. Unlike melanoma, BRAF mutations have not been found in renal cell carcinoma. Other candidate targets include VEGFR2 and VEGFR3.
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PMID:Kinase inhibition with BAY 43-9006 in renal cell carcinoma. 1544 36

Mastocytosis refers to a group of disorders characterized by the pathologic proliferation of mast cells. We present a 70-year-old white man with a rare presentation of nodular mastocytosis, characterized by disseminated nodular lesions, myelodysplastic syndrome, and a c-kit V560G receptor mutation. The patient presented to the clinic after initial presentation 6 months earlier, with ear pruritus, associated hearing loss, and widespread rash.
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PMID:Nodular mastocytosis. 1684 28

Treatments for metastatic renal cell carcinoma (MRCC) are limited. RCCs frequently overexpress epithelial growth factor receptor and express c-Kit and platelet-derived growth factor receptor-beta. Combination of interferon with tyrosine kinase inhibitors of epithelial growth factor receptor [gefitinib (Iressa)] or c-Kit and platelet-derived growth factor receptor-beta [imatinib (Gleevec)] was evaluated for efficacy and safety. Patients with MRCC received 12-week cycles of interferon [3 million units (MU) subcutaneously thrice in week 1 and 6 MU thrice weekly thereafter] and either gefitinib (500 mg daily) or imatinib (600 mg daily). The gefitinib/imatinib dose was reduced as needed owing to toxicity. The primary endpoint was objective tumor response. Secondary endpoints were time to tumor progression, overall survival, and safety. Seventeen patients were enrolled. Most had clear cell [36% (6/17)] or papillary [36% (6/17)] tumors. Most (n=14) were treated on the gefitinib arm, including two patients who crossed over from the imatinib arm after experiencing disease progression. Objective tumor responses were evaluable in 14 patients (82%). Of these 14, partial responses occurred in three (21%), stable disease in seven (50%), and progressive disease in four (29%). The most frequent treatment-related adverse events were skin rash, flu-like symptoms, and fatigue (both treatment arms); diarrhea (gefitinib arm only); and thrombocytopenia and leukopenia (imatinib arm only). Median time to tumor progression (range) for patients on the gefitinib arm only was 4.27 (1.13-15.97) months and median overall survival (range) was 11.42+ (1.13-29.07+) months. Combination of gefitinib with interferon safely delays progression of refractory MRCC. Further studies in this setting are warranted.
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PMID:Interferon-alpha in combination with either imatinib (Gleevec) or gefitinib (Iressa) in metastatic renal cell carcinoma: a phase II trial. 1841 19

Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG+imatinib mesylate in AML patients. Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5mg/m(2) days 3-7, Cytarabine 2gm/m(2) days 3-7, G-CSF 300mcg days 2-7, and escalating doses of imatinib mesylate given on days 1-15. The level 1 Gleevec dose was 400mg, while level 2 was 600mg and the level 3 dose 800mg. A total of 16 patients were enrolled, 15 AML and 1 CML myeloid blast crisis. The dose escalation occurred as planned and there was no clear evidence of added toxicity due to imatinib mesylate. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy however no other deaths occurred within 30 days of starting therapy. One patient had a Grade 3 skin rash at dose level 2. The most common toxicities encountered during induction therapy were nausea, vomiting, rash and diarrhea that were transient and/or reversible. At the 800mg dose 1 patient developed a decline in cardiac ejection fraction on day 20 who later died of sepsis, so this was considered a dose limiting toxicity. Of 16 evaluable patients 11 achieved a hypocellular marrow after initial induction with 1 additional patient achieving a hypocellular marrow following a second course of the same regimen. Four patients (25%) achieved a complete morphologic response with normal cytogenetics, 2 patients (12.5%) achieved a complete morphologic response only and 1 patient had a complete response in the bone marrow but incomplete blood count recovery. The overall response rate was 43.8%. The median overall survival was 175 days (95% CI 16.24-333.76) and the median relapse free survival was 76 days. The addition of imatinib mesylate to CLAG was well tolerated with acceptable toxicities and response rates comparable to other salvage regimens. To assess the efficacy of imatinib mesylate in combination with CLAG, a larger phase II trial is now planned.
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PMID:Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML. 1857 21

Diffuse cutaneous mastocytosis is a rare variant of mast cell disease with widespread erythroderma, which is normally clinically apparent in early infancy. We report the case of a neonate who presented with diffuse erythrodermic rash and bullous lesions. Biopsy specimens showed a dense dermal infiltrate of mast cells. Serum histamine and tryptase levels were elevated. No somatic mutation of the c-kit gene was found. Blistering ceased at 5 months of age, but atopic dermatitis appeared at 6 months and allergic workup revealed a high level of food-specific IgE. Herein, we describe the case and provide the first review of the literature on neonatal onset diffuse cutaneous mastocytosis to clarify the prognosis of this condition.
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PMID:Neonatal onset diffuse cutaneous mastocytosis: a case report and review of the literature. 2067 92

Treatment options for patients suffering from indolent forms of mastocytosis remain inadequate with the hyperactivation of mast cells responsible for many of the disease's systemic manifestations. Masitinib is a potent and highly selective oral tyrosine kinase inhibitor. A combined inhibition of c-Kit and Lyn make it particularly efficient in controlling the activity of mast cells and therefore, of potential therapeutic benefit in mastocytosis. Masitinib was administered to 25 patients diagnosed as having systemic or cutaneous mastocytosis with related handicap (i.e., disabilities associated with flushes, depression, pruritus and quality-of-life) at the initial dose levels of 3 or 6 mg/kg/day over 12 weeks. In accordance with the AFIRMM study, response was based upon change of clinical symptoms associated with patient handicap at week 12 relative to baseline, regardless of disease subtype. Improvement was observed in all primary endpoints at week 12 including a reduction of flushes, Hamilton rating, and pruritus as compared with baseline by 64% (P = 0.0005), 43% (P = 0.0049), and 36% (P = 0.0077), respectively. An overall clinical response was observed in 14/25 patients (56%; [95%CI = 37%-75%]), with sustainable improvement observed throughout an extension phase (>60 weeks). Common adverse events were edema (44%), nausea (44%), muscle spasms (28%), and rash (28%), the majority of which were of mild or moderate severity with a significant decline in frequency observed after 12 weeks of treatment. One patient experienced a serious adverse event of reversible agranulocytosis. Masitinib is a promising treatment for indolent forms of mastocytosis with handicap and indicates acceptable tolerability for long-term treatment regimens.
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PMID:Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. 2110 25

Imatinib mesylate is a tyrosine kinase inhibitor which targets Bcr-Abl-protein, c-Kit, and platelet-derived growth factor receptor. The drug was originally developed for treatment of chronic myeloid leukemia but is also regarded as first-line treatment of patients with metastatic gastrointestinal stromal tumours (GIST). Dermatologic side effects are common, with superficial edema and rash as the most frequent. In addition, imatinib mesylate treatment is often associated with hypopigmentation. Intraoral side effects are very rare. The present paper demonstrates 1 patient with GIST and 2 patients with chronic myeloid leukemia treated with imatinib mesylate for 5-6 years. All 3 patients presented with diffuse solitary bluish-brown pigmentations in the hard palate. The lesions persisted at follow-ups. There were no other pigmentations in the oral mucosa. The histopathologic examination showed depositions of melanin pigment in the lamina propria. The possible relationship between the observed melanotic maculae and imatinib mesylate treatment is discussed.
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PMID:Oral pigmentation in the hard palate associated with imatinib mesylate therapy: a report of three cases. 2177 89

We report a case of a 48-year-old Indian male who presented with swelling and firmness in his left upper part of the abdomen of one month duration with anorexia and weight loss. Initial examination revealed an intra abdominal mass of around 16.8x11.0x24.5cm with minimal left sided pleural effusion. A biopsy from the mass confirmed the diagnosis of gastrointestinal stromal tumour (GISTs) as supported by immmunohistochemistry results which showed strong positivity for c-kit while stains for smooth muscle actin, desmin, myoglobin, S100 Protein and cytokerstin remained negative. The patient was not suitable for surgical intervention in view of advanced tumor, and Imatinib Mesylate 400mg daily was started with the aim of making the tumor operable. Such therapy lasted for twenty months and was tolerated well by the patient. It then resulted in gradual tumor regression, following which the patient underwent successful tumor resection. Post surgical resection patient had no radiological evidence of intra abdominal tumor but mild left sided pleural effusion with left lower lobe atelectasis. The patient had uneventful post operative recovery and he is currently on Imatinib mesylate and tolerating treatment well with mild skin rash. The experience with preoperative imatinib on surgical resection rates and post operative outcomes is limited especially with primary locally advanced GISTs. In our case successful surgical resection was possible for a huge locally advanced GIST with unusually prolonged treatment of twenty months with imatinib preoperatively.
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PMID:Successful surgical resection of advanced gastrointestinal stromal tumor post neoadjuvent therapy. 2148 16

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

We present a case of perforating folliculitis in a patient treated with nilotinib, a kinase inhibitor. A 48-year-old man presented with a severely pruritic follicular rash for several months that started after reaching a complete molecular response of his myeloid chronic while treated with nilotinib. Clinical examination showed predominantly follicular pinpoint papules on trunk and proximal extremities and a biopsy showed a slightly dilated hair follicle with a focal disruption of the infundibular follicular epithelium. Other diseases related with perforating folliculitis were ruled out. The temporary relationship between the treatment and the appearance of the lesions suggests some pathogenic role of nilotinib. Relationship with nilotinib is also supported by previous similar cases related with sorafenib therapy. Both drugs inhibit c-kit and PDGF-R. PDGF-R has been previously involved in murine and human in vitro models of hair follicle cycle. So, our case supports in vivo the previous evidence of the importance of PDGF-R, a kinase, in the normal hair follicle development.
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PMID:Perforating folliculitis in a patient treated with nilotinib: a further evidence of C-kit involvement. 2361 33


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