The Molecular Pathogenesis of Gastrointestinal Stromal Tumors

Tarn, Chi; Godwin, Andrew K.

doi:10.3816/ccc.2006.s.002

Cited by 20 publications

(7 citation statements)

References 118 publications

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“…Primary or secondary mutations in the kinase domain of KIT involving imatinib resistance include V654A, T670I, T823A, del557–55873, insAY502–593, and other sites of exon 9 (partial resistance), 13 and 17 in the kinase domain of KIT , and D842V in PDGFRA . Alteration of imatinib sensitivity can be fought by specific RTK inhibitors, and new paradigm of classification integrating the classic pathological criteria with the molecular changes will facilitate personalized prognosis and treatment 17,74…”

Section: Discussionmentioning

confidence: 99%

Genetic aberrations of gastrointestinal stromal tumors

Yang

Lazar

et al. 2008

Cancer

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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract and is associated with mutations of the KIT or PDGFRA gene. In addition, other genetic events are believed to be involved in GIST tumorigenesis. Cytogenetic aberrations associated with these tumors thus far described include loss of 1p, 13q, 14q, or 15q, loss of heterozygosity of 22q, numeric chromosomal imbalances, and nuclear/mitochondrial microsatellite instability. Molecular genetic aberrations include loss of heterozygosity of

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Section: Discussionmentioning

confidence: 99%

Genetic aberrations of gastrointestinal stromal tumors

Yang

Lazar

et al. 2008

Cancer

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“…All data were normalized to HPRT expression. For immunoblotting, whole cell extracts were prepared and the proteins evaluated as previously described (42). …”

Section: Methodsmentioning

confidence: 99%

Detection of Treatment-Induced Changes in Signaling Pathways in Gastrointestinal Stromal Tumors Using Transcriptomic Data

et al. 2009

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Cell signaling plays a central role in the etiology of cancer. Numerous therapeutics in use or under development target signaling proteins; however, off-target effects often limit assignment of positive clinical response to the intended target. As direct measurements of signaling protein activity are not generally feasible during treatment, there is a need for more powerful methods to determine if therapeutics inhibit their targets and when off-target effects occur. We have used the Bayesian Decomposition algorithm and data on transcriptional regulation to create a novel methodology, Differential Expression for Signaling Determination (DESIDE), for inferring signaling activity from microarray measurements. We applied DESIDE to deduce signaling activity in gastrointestinal stromal tumor cell lines treated with the targeted therapeutic imatinib mesylate (Gleevec). We detected the expected reduced activity in the KIT pathway, as well as unexpected changes in the p53 pathway. Pursuing these findings, we have determined that imatinib-induced DNA damage is responsible for the increased activity of p53, identifying a novel off-target activity for this drug. We then used DESIDE on data from resected, post-imatinib treatment tumor samples and identified a pattern in these tumors similar to that at late time points in the cell lines, and this pattern correlated with initial clinical response. The pattern showed increased activity of ETS domain-containing protein Elk-1 and signal transducers and activators of transcription 3 transcription factors, which are associated with the growth of side population cells. DESIDE infers the global reprogramming of signaling networks during treatment, permitting treatment modification that leverages ongoing drug development efforts, which is crucial for personalized medicine. [Cancer Res 2009;69(23):9125-32]

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“…From the experience with IM, the type of KIT or PDGFRA mutations greatly influenced how the patients responded to therapy [139]. Mutations in exon 11, the most common, have the highest IM response rates and prolonged disease control in clinical trials [40].…”

Section: Expert Opinionmentioning

confidence: 99%

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Alturkmani

Pessetto

Godwin

2015

Expert Opinion on Investigational Drugs

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Introduction Gastrointestinal stromal tumor (GIST) is the most common non-epithelial malignancy of the GI tract. With the discovery of KIT and later PDGFRA gain-of-function mutations as factors in the pathogenesis of the disease, GIST was the quintessential model for targeted therapy. Despite the successful clinical use of imatinib mesylate, a selective receptor tyrosine kinase (RTK) inhibitor that targets KIT, PDGFRA and BCR-ABL, we still do not have treatment for the long-term control of advanced GIST. Areas covered This review summarizes the drugs that are under investigation or have been assessed in trials for GIST treatment. The article focuses on their mechanisms of actions, the preclinical evidence of efficacy, and the clinical trials concerning safety and efficacy in humans. Expert opinion It is known that KIT and PDGFRA mutations in GIST patients influence the response to treatment. This observation should be taken into consideration when investigating new drugs. RECIST was developed to help uniformly report efficacy trials in oncology. Despite the usefulness of this system, many questions are being addressed about its validity in evaluating the true efficacy of drugs knowing that new targeted therapies do not affect the tumor size as much as they halt progression and prolong survival.

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The Molecular Pathogenesis of Gastrointestinal Stromal Tumors

Cited by 20 publications

References 118 publications

Genetic aberrations of gastrointestinal stromal tumors

Genetic aberrations of gastrointestinal stromal tumors

Detection of Treatment-Induced Changes in Signaling Pathways in Gastrointestinal Stromal Tumors Using Transcriptomic Data

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

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