Background Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors. Methods We conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor. We assessed antitumor response and the safety and tolerability of the drug. Pharmacokinetics were assessed in a subgroup of patients. Results A total of 147 patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53.7 percent) had a partial response, 41 patients (27.9 percent) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8 percent). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow...

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Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.

Protein-tyrosine kinases (PTKs) are important regulators of intracellular signal-transduction pathways mediating development and multicellular communication in metazoans Their activity is normally tightly controlled and regulated Perturbation of PTK signalling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation The lipid kinase phosphoinositide 3-OH kinase (PI(3)K) and some of its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70S6K), are crucial effectors in oncogenic PTK signalling This review emphasizes how oncogenic conversion of protein kinases results from perturbation of the normal autoinhibitory constraints on kinase activity and provides an update on our knowledge about the role of deregulated PI(3)K/Akt and mammalian target of rapamycin/p70S6K signalling in human malignancies

Oncogenic kinase signalling

Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

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A quantitative analysis of kinase inhibitor selectivity.

Purpose: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. Patients and Methods: GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome. Results: Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation ...

Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor

Protein phosphorylation regulates most aspects of cell life, whereas abnormal phosphorylation is a cause or consequence of disease. A growing interest in developing orally active protein-kinase inhibitors has recently culminated in the approval of the first of these drugs for clinical use. Protein kinases have now become the second most important group of drug targets, after G-protein-coupled receptors. Here, I give a personal view of some of the most important advances that have shaped this field.

Protein kinases--the major drug targets of the twenty-first century?

Gastrointestinal stromal tumors are a group of mesenchymal neoplasms that arise from precursors of the connective-tissue cells of the gastrointestinal tract.1 They occur predominantly in middle-aged and older persons, and approximately 70 percent of the tumors are found in the stomach, 20 to 30 percent are found in the small intestine, and less than 10 percent are found elsewhere in the gastrointestinal tract.1 Recent studies have shown that cells in gastrointestinal stromal tumors express a growth factor receptor with tyrosine kinase activity termed c-kit. This receptor, the product of the proto-oncogene c-kit, can be detected by immunohistochemical staining for . . .

Effect of the Tyrosine Kinase Inhibitor STI571 in a Patient with a Metastatic Gastrointestinal Stromal Tumor

Between 1977 and 1987, posterior (n=29) or posterolateral (n=73) fusion was performed for mild to moderate (slip <50%) isthmic spondylolisthesis on 102 patients (46 females, 56 males). The patients’ average age at the time of operation was 15.9 (range, 8.1–19.8) years. Clinical (physical examination and Oswestry disability index (ODI)) and radiological (MRI and plain radiographs) examinations were performed on these patients after an average follow-up time of 21.0 (range, 26.2–15.1) years. In the radiographs, the mean slip preoperatively was 27% (range, 5–50%) and at the last follow-up visit 26% (range, 5–78%). Inside the fusion, there were a total of 148 intervertebral discs, 121 (82%) of them had decreased signal intensity in T2-weighted MR images and 113 (76%) were narrowed. Above the fusion level, 27 (27%) discs were speckled and 27 (27%) were black; 21 (21%) intervertebral disc spaces were narrowed. Two levels above the fusion level the numbers were 8 (8%), 16 (16%) and 16 (16%), respectively. Six (6%) patients had a prolapse. Degenerative facet joint hypertrophy above fusion was seen at 80 (79%) of the levels studied. When compared to healthy subjects higher frequency of disc and facet joint degeneration was found. In MR images, none of the patients had lumbar spinal stenosis inside or above the fusion. Narrowing of one or both of the neural foramina at the level of the L5–S1 interververtebral disc was noted in 32 (31%) patients. Seventeen (17%) of the patients had, usually mild, muscular atrophy of the psoas and 33 (32%) of the paraspinal muscles. There was no difference in frequency of abnormal MRI findings between patients (n=93) with ODI 20 or less compared with patients (n=9) with ODI more than 20. In situ fusion due to isthmic spondylolsthesis at adolescence is associated with moderate degenerative changes in the lumbar spine during a 20-year follow-up. Changes were most commonly found at the level of the spondylolisthesis and above fusion level. Neural foramina stenosis seems to be associated with spondylolisthesis and its severity to severity of the slip. Muscle atrophy tended to be mild. However, there was no correlation between patient outcome (ODI) and abnormal lumbar MRI findings.

No correlation between patient outcome and abnormal lumbar MRI findings 21 years after posterior or posterolateral fusion for isthmic spondylolisthesis in children and adolescents.

Pekka Tervahartiala

Papers

Effect of the Tyrosine Kinase Inhibitor STI571 in a Patient with a Metastatic Gastrointestinal Stromal Tumor

No correlation between patient outcome and abnormal lumbar MRI findings 21 years after posterior or posterolateral fusion for isthmic spondylolisthesis in children and adolescents.

Surgical treatment of chronic otitis media with temporomandibular joint involvement