Oncology Intelligence

GIST Cancer
Historic & ongoing GIST clinical trials

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: childhood cancer, GIST, sarcoma
Although regorafenib was approved for use in patients who had progressive GIST despite imatinib and/or sunitinib on the basis of phase II and phase III data, it has not been examined in a systematic fashion in patients with other forms of sarcoma. Given the activity of sorafenib, sunitinib and pazopanib in soft tissue sarcomas, and evidence of activity of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like sarcoma, there is precedent to examine SMOKIs (small molecule oral kinase inhibitors) such as regorafenib in sarcomas other than GIST. It is also recognized that SMOKIs (small molecule oral kinase inhibitors)such as regorafenib, sorafenib, pazopanib, and sunitinib have overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most of these SMOKIs (small molecule oral kinase inhibitors) block vascular endothelial growth factor and platelet derived growth factors receptors (VEGFRs and PDGFRs), speaking to a common mechanism of action of several of these agents.
Tuesday, September 13, 2016 4:20 PM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: cKIT, GIST
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Gonullu, D.; Demiray, O.; Ilgun, S.;...
Background : Gastrointestinal Stromal Tumors (GISTacrnm1) are originated from mesenchymal cells and express the cKIT (CD117) protein; the most involved are gastrointestinal organs, and rarely extraintestinal retroperitoneum, mesentery and omentum....
Sunday, July 31, 2016 3:00 PM|Cancer|Cancer via|Comments|Labels: GIST
Gastrointestinal stromal tumors (GISTs) are considered to be potentially malignant mesenchymal tumors of the gastrointestinal tract. Clinically relevant GISTs are rare; however, subclinical GISTs (mini‐GISTs) (1‐2 cm) and pathologic GISTs (micro‐GISTs) (<1 cm) are frequently reported. Most mini‐GISTs and almost all micro‐GISTs of the stomach may exhibit benign clinical behavior, and only mini‐GISTs with high‐risk features may progress. For this review, a provisional algorithm was used to propose diagnostic and treatment strategies for patients with small GISTs. Because surgery is the only potentially curative treatment, in its application for small GISTs, the principles of sarcoma surgery should be maintained, and cost effectiveness should be considered. Indications fo...
Thursday, July 28, 2016 8:48 AM|Seifert, A. M., Zeng, S., Zhang, J. Q., Kim, T. S., Cohen, N. A., Beckman, M. J., Medina, B. D., Maltbaek, J. H., Loo, J. K., Crawley, M. H., Rossi, F., Besmer, P., Antonescu, C. R., DeMatteo, R. P.|Clinical Cancer Research Online First Articles|Labels: PD-1/PD-L1, GIST

Purpose: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumor (GIST), but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GIST. Experimental Design: We analyzed tumor and matched blood samples from 85 patients with GIST and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558/+ mice that develop GIST. Results: The inhibitory receptors PD-1, lymphocyte activation gene 3 (LAG-3), and T cell immunoglobulin mucin-3 (TIM-3) were upregulated on tumor-infiltrating T cells compared to T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFN--induced upregulation of PD-L1 via STAT1 inhibition. In KitV558/+ mice imatinib downregulated IFN--related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone, but enhanced the antitumor effects of imatinib by increasing T cell effector function in the presence of KIT and IDO inhibition. Conclusions: PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GIST. Collectively, our results provide the rationale to combine these agents in human GIST.

Wednesday, July 20, 2016 9:31 AM|Kim, W. K., Yun, S., Park, C. K., Bauer, S., Kim, J., LEE, M. G., Kim, H.|Clinical Cancer Research Online First Articles|Labels: cKIT, GIST

Purpose: Tumorigenesis of gastrointestinal stromal tumors (GIST) is driven by gain of function mutations in the KIT gene, which result in over-expression of activated mutant KIT proteins (MT-KIT). However, the mechanism of MT-KIT over-expression is poorly understood. Experimental Design: By protein expression analysis and immunofluorescent microscopic analysis, we determine the stability and localization of MT-KIT in four GIST cell lines with different mutations and HeLa cells transfected with mutant KIT model vectors. We also used 154 human GIST tissues to analyze the relationship between the expression of PKC- and MT-KITs, and correlations between PKC- over-expression and clinicopathological parameters. Results: We report that four different MT-KIT proteins are intrinsically less stable than wild type KIT due to proteasome-mediated degradation and abnormally localized to the endoplasmic reticulum (ER) or the Golgi complex. By screening a MT-KIT-stabilizing factor, we find that PKC- is strongly and exclusively expressed in GISTs and interacts with intracellular MT-KIT to promote its stabilization by increased retention in the Golgi complex. In addition, western blotting analysis using 50 GIST samples shows strong correlation between PKC- and MT-KIT expression (correlation coefficient = 0.682, P < 0.000001). Immunohistochemical analysis using 154 GISTs further demonstrates that PKC- over-expression significantly correlates with several clinicopathological parameters such as high tumor grade, frequent recurrence/metastasis, and poor patient survival. Conclusions: Our findings suggest that sustained MT-KIT over-expression through PKC--mediated stabilization in the Golgi contributes to GIST progression, and provides a rationale for anti-PKC- therapy in GISTs.

Thursday, July 14, 2016 10:05 PM|Wang, H.-C., Li, T.-Y., Chao, Y.-J., Hou, Y.-C., Hsueh, Y.-S., Hsu, K.-H., Shan, Y.-S.|Clinical Cancer Research recent issues|Labels: cKIT, GIST

Purpose: KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GIST), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis.

Experimental Design: A total of 170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacologic methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations.

Results: Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557–558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557–558 deletion (KIT 557–558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT 557–558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT 557–558–mediated cell migration. Moreover, KIT 557–558–induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT 557–558 was prevented. In addition, KIT exon 11 codons 557–558 deletion enhanced CXCL12-mediated GIST cell migration and invasion.

Conclusions: KIT exon 11 557–558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs. Clin Cancer Res; 22(14); 3477–87. ©2016 AACR.

Thursday, July 7, 2016 7:46 AM|Gasparotto, D., Rossi, S., Polano, M., Tamborini, E., Lorenzetto, E., Sbaraglia, M., Mondello, A., Massani, M., Lamon, S., Bracci, R., Mandolesi, A., Frate, E., Stanzial, F., Agaj, J., Mazzoleni, G., Pilotti, S., Gronchi, A., Dei Tos, A. P., Maestro, R.|Clinical Cancer Research Online First Articles|Labels: GIST

Purpose: The majority of Gastrointestinal Stromal Tumors (GISTs) are driven by KIT, PDGFRA or, less commonly, BRAF mutations, and SDH gene inactivation is involved in a limited fraction of gastric lesions. However, about 10% of GISTs are devoid of any of such alterations and are poorly responsive to standard treatments. This study aims to shed light on the molecular drivers of quadruple-negative GISTs. Experimental Design: Twenty-two sporadic quadruple-negative GISTs with no prior association with Neurofibromatosis Type 1 syndrome were molecularly profiled for a panel of genes belonging to tyrosine kinase pathways or previously implicated in GISTs. For comparison purposes, 24 GISTs carrying KIT, PDGFRA, or SDH gene mutations were also analyzed. Molecular findings were correlated to clinicopathological features. Results: Most quadruple-negative GISTs featured intestinal localization, with a female predilection. About 60% (13/22) of quadruple-negative tumors carried NF1 pathogenic mutations, often associated with biallelic inactivation. The analysis of normal tissues, available in 11 cases, indicated the constitutional nature of the NF1 mutation in 7/11 cases, unveiling an unrecognized Neurofibromatosis Type 1 syndromic condition. Multifocality and a multinodular pattern of growth were common findings in NF1-mutated quadruple-negative GISTs. Conclusions: NF1 gene mutations are frequent in quadruple-negative GISTs and are often constitutional, indicating that a significant fraction of patients with apparently sporadic quadruple-negative GISTs are affected by unrecognized Neurofibromatosis Type 1 syndrome. Hence, a diagnosis of quadruple-negative GIST, especially if multifocal or with a multinodular growth pattern and a non-gastric location, should alert the clinician to a possible Neurofibromatosis Type 1 syndromic condition.

Monday, June 6, 2016 4:58 AM|FRIEDRICH, R. E., WUNDER, T., SCHUMACHER, U., BARTEL-FRIEDRICH, S., ZUSTIN, J.|Anticancer Research recent issues|Labels: GIST, HNN

Background: The calcium-activated chloride channel protein discovered on gastrointestinal stromal tumour 1 (DOG1) is expressed in a variety of normal and neoplastic tissues. DOG1 is a specific marker for gastrointestinal stromal tumour. In the head and neck region, DOG1 is a sensitive discriminator for acinar cell carcinoma. Only a few publications have presented data concerning the expression of DOG1 in head and neck squamous cell carcinoma (HNSCC). The expression of DOG1 in HNSCC appears to be associated with a poor prognosis. The aim of this study was to analyze the expression pattern of DOG1 in poorly differentiated carcinoma of the upper aerodigestive tract. Materials and Methods: A total of 84 specimens from 31 patients with carcinomas of the upper aerodigestive tract were immunohistochemically investigated for DOG1 expression. Inclusion criterion was poorly to undifferentiated carcinoma of the head and neck, but samples of the same resection site that exhibited moderate or well-differentiated squamous cell carcinoma were also enrolled. Immunoreactivity in carcinomas was estimated using a visual score (0: negative; 1: basally positive, 2: parabasally positive, 3: completely positive, 4: basally and parabasally positive). Results: Fifteen out of 84 specimens were immunoreactive to antibody to DOG1 (17.8%). DOG1 immunoreactivity was restricted to eight patients (25.8%). However, DOG1 expression was considerably heterogeneous in tumours, with three (9.6%) cases showing a positive reaction in all samples. Basal and parabasal staining patterns (five specimens each) dominated. Discussion: This study demonstrated expression of DOG1 to be restricted to some poorly differentiated carcinomas of the upper aerodigestive tract. Although the proportion of DOG1-positive carcinomas was moderate compared to results of previous studies on head and neck cancer tissues, DOG1 expression possibly indicates a subset of HNSCC. Further studies are necessary to investigate the heterogeneity and clinical relevance of DOG1 expression in HNSCC.

Tuesday, May 31, 2016 1:00 AM|Koji Fukuda, Kazuhiro Shimazu, Taichi Yoshida, Masahiro Inoue, Masatomo Miura, Hiroyuki Shibata|International Journal of Cancer Therapy and Oncology|Labels: GIST

Many molecular target agents are continuously administered at fixed dosages. Imatinib, which can control the growth of a gastrointestinal stromal tumor, is administrated at 400 mg/day. However, many patients cannot continue treatment because of adverse events, such as neutropenia. To obtain the best therapeutic response while maintaining quality of life, individualization should be considered. Study participants were gastrointestinal stromal tumor patients who required treatment with imatinib. Therapeutic drug monitoring was conducted using high-performance liquid chromatography. In our study, the trough (lowest) concentration that a drug reaches before the next dose is administered differed among patients. The grades of adverse events also differed individually. Moreover, the dosage that was necessary to shrink gastrointestinal stromal tumor differed in cases by cases. Dosage was modified according to the balance between blood concentration and therapeutic responses in order to minimize adverse events for individual patients, and to maximize the effect as the responses differed among patients. It was shown that based on therapeutic drug monitoring, individualization enabled the patients who may not normally continue the typical treatment to tolerate imatinib. According to the therapeutic drug monitoring, individualization of dosage of imatinib could improve the patients’ outcomes in both ends, therapeutic and adeverse responses.