Inhibition of KIT RNAi mediated with adenovirus in gastrointestinal stromal tumor xenograft

Wang, Tianbao; Huang, Wen‐Sheng; Lin, Wen‐Cheng; Hanping, Shi; Dong, Wenfeng

doi:10.3748/wjg.v16.i40.5122

Cited by 7 publications

(6 citation statements)

References 26 publications

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“…Of these cell line-derived xenografts GIST48 and GIST430 are described as being resistant to imatinib, although both have shown mild to moderate responses to imatinib in some published in vivo experiments [ 20 , 27 ]. Only a few research groups, including our own, have been able to establish GIST xenografts based on patient-derived biopsies [ 20 - 23 , 30 - 32 ]. Of these, only the model established by Revheim and colleagues is characterized by a secondary KIT exon 17 mutation [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization and assessment of the sensitivity and resistance of a newly established human gastrointestinal stromal tumour xenograft model to treatment with tyrosine kinase inhibitors

et al. 2014

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BackgroundAcquired resistance to tyrosine kinase inhibitors (TKIs) in gastrointestinal stromal tumours (GISTs) is most commonly caused by secondary KIT or PDGFRA mutations. In this study we characterize a newly established GIST xenograft model, UZLX-GIST9, and evaluate the in vivo response of the model to standard TKIs (imatinib, sunitinib, and regorafenib).MethodsTumour fragments from a metastatic lesion of a GIST patient clinically progressing after treatment with imatinib, sunitinib and regorafenib were engrafted in a nude, immunodeficient mouse. Upon sequential passaging from mouse to mouse, tumour fragments were collected for histopathological and molecular characterization. The sensitivity of the model to treatment with TKIs was evaluated in 28 mice [passage 2 (n = 8), passage 4 (n = 20), 41 tumours]. Mice were grouped as follows: control (untreated), imatinib (50 mg/kg/BID), imatinib (100 mg/kg/BID), sunitinib (40 mg/kg/QD), and regorafenib (30 mg/kg/QD). After three weeks of oral treatment, tumours were collected for subsequent analysis. The efficacy of treatment was assessed by tumour volume, histopathology and Western immunoblotting.ResultsUZLX-GIST9 maintains the same typical morphological features and immunohistochemical characteristics as the original patient biopsy and expresses CD117 and DOG1. The KIT mutational profile (p.P577del + W557LfsX5+ D820G) remains the same as the original tissue sample originating from an intraspinal metastatic site. Three week treatment with different TKIs showed that the model is resistant to imatinib. Sunitinib induces tumour growth delay and regorafenib reduces the tumour burden by 30% as compared to control animals. While none of the TKIs had a significant effect on cell proliferation or cell survival, a remarkable increase of necrosis and significant reduction of microvessel density was observed under sunitinib and regorafenib. Western immunoblotting showed a mild reduction in KIT and AKT activation only in regorafenib treated tumours.ConclusionsWe established a novel human GIST xenograft, UZLX-GIST9, harbouring KIT exon 11 and 17 mutations and maintaining the pheno-and genotype of the original tumour. UZLX-GIST9 shows different levels of response to standard TKIs. This model will help to study TKI resistance and to explore novel treatment approaches for patients with TKI-resistant GIST.

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Section: Discussionmentioning

confidence: 99%

Characterization and assessment of the sensitivity and resistance of a newly established human gastrointestinal stromal tumour xenograft model to treatment with tyrosine kinase inhibitors

et al. 2014

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“…The combination of the advantages of Ad as a gene delivery vector and RNAi technology potentiates the power of the approach for gene therapies, especially for cancer gene therapy. Ad‐mediated RNAi technology has been evaluated for treatment of various types of human cancers, such as hepatocellular carcinoma, lung cancer, colon cancer and gastrointestinal stromal tumor , and offers a promising option for cancer gene therapy in the future.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus‐mediated RNA interference targeting FOXM1 transcription factor suppresses cell proliferation and tumor growth of nasopharyngeal carcinoma

Chen

Yang

et al. 2012

The Journal of Gene Medicine

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“…To better approximate the genetic heterogeneity of human cancer, PDXs are now emerging as an alternative to cell lines. Like many tumors, GISTs can be SQ implanted into the flanks of mice [ 21 - 23 , 37 , 38 ]. However, for the aforementioned reasons, most SQ models are unable to recapitulate human tumor biology and therefore have less clinical relevance [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, no cell lines exist which contain either PDGFR α mutation/deletions/insertions or BRAF V600E mutations that also cause GIST. Regarding mouse models of GIST, subcutaneous (SQ) xenografts have been utilized as the prototype in nude mice [ 21 - 23 ]. However, because tumor growth or responses to drug treatment observed in SQ xenograft models are often different from those observed in an orthotopic environment, two groups have developed transgenic mouse models of GIST.…”

Section: Introductionmentioning

confidence: 99%

Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor

et al. 2014

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BackgroundGastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease.MethodsFresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed.ResultsHerein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473±695-mm3 (median 199-mm3, range 12.6-2682.5-mm3) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors.ConclusionsWe report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST.

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Inhibition of KIT RNAi mediated with adenovirus in gastrointestinal stromal tumor xenograft

Abstract: AdEGFP-U6-KIT is successfully constructed, and KIT RNAi mediated with Admax vector system can effectively inhibit the expression of the KIT gene and the growth of GIST in nude mice.

Cited by 7 publications

References 26 publications

Characterization and assessment of the sensitivity and resistance of a newly established human gastrointestinal stromal tumour xenograft model to treatment with tyrosine kinase inhibitors

Characterization and assessment of the sensitivity and resistance of a newly established human gastrointestinal stromal tumour xenograft model to treatment with tyrosine kinase inhibitors

Adenovirus‐mediated RNA interference targeting FOXM1 transcription factor suppresses cell proliferation and tumor growth of nasopharyngeal carcinoma

Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor

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