Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor

Morimoto, Alyssa; Tan, Nguyen Duy; West, Kristina; McArthur, Grant A.; Toner, Guy C.; Manning, William C.; Smolich, Beverly D.; Cherrington, Julie M.

doi:10.1038/sj.onc.1207268

Cited by 45 publications

(23 citation statements)

References 43 publications

(42 reference statements)

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“…Aberrant expression of cadherin-6 is associated with a poor prognosis. Interestingly, CDH11, that is expressed in the follicular histotype of differentiated thyroid carcinomas, has been reported to be modulated by sunitinib but does not appear to be a target in MTC (16). During sunitinib treatment, metalloprotease gene expression was up-, MMP26, or downregulated, MMP16.…”

Section: Discussionmentioning

confidence: 95%

“…Differential expressed genes compared with each time point-matched references were retained for fold change over 1.75 and value of P < 10 À3 as previously published (16). Molecular and cellular functions of genes were investigated using the Ingenuity software and considered as most regulated according to lowest P value.…”

Section: Pan Genomic Expression Profile Analysis During Sunitinib Trementioning

confidence: 99%

“…Sunitinib has been effective in some patients with advanced MTC (12)(13)(14)(15). Although its effects at the TKR target level are well documented in GIST (gastrointestinal stromal tumor) and renal cell carcinoma models, the molecular mechanisms of action remain poorly understood in MTC (16,17). Furthermore, in parallel to the development of molecular targeted therapies, identification of surrogate biomarkers that can early determine those patients who are most likely to achieve clinical benefits will be useful for clinical management of such therapies (18,19).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, sunitinib inhibits CT production at both the gene and protein expression levels. Using an original approach based on in vitro kinetic microarray studies (16), we identified during sunitinib treatment major changes in tissue invasion and metastasis gene expression. Among downregulated genes, some encode secreted proteins that were found to be highly expressed in the serum of metastatic MTC patients and thus may constitute putative biomarkers for sunitinib response.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Soluble Candidate Biomarkers of Therapeutic Response to Sunitinib in Medullary Thyroid Carcinoma in Preclinical Models

Broutin¹,

Ameur²,

Lacroix³

et al. 2011

Clinical Cancer Research

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Purpose: Medullary thyroid carcinoma (MTC), an aggressive rare tumor due to activating mutations in the proto-oncogene RET, requires new therapeutic strategies. Sunitinib, a potent inhibitor of RET, VEGF receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor (PDGFR)α/β, has been reported as clinically effective in some patients with advanced MTC. In this study, we examine molecular mechanisms of action of sunitinib and identify candidate soluble biomarkers of response. Experimental Design: Both in vitro and in vivo assays, using the human TT RETC634W MTC cell line, were done to assess the activity of sunitinib. Kinetic microarray studies were used to analyze molecular pathways modified by sunitinib and to identify candidate biomarkers that were subsequently investigated in the serum of patients. Results: Sunitinib displayed antiproliferative and antiangiogenic activities and inhibited RET autophosphorylation and activation of downstream signaling pathways. We showed that sunitinib treatment induced major changes in the expression of genes involved in tissue invasion and metastasis including vimentin (VIM), urokinase plasminogen (PLAU), tenascin-C (TN-C), SPARC, and CD44. Analyzing downregulated genes, we identified those encoding secreted proteins and, among them, interleukin (IL)-8 was found to be modulated in the serum of xenografted mice under sunitinib treatment. Furthermore, we demonstrated that metastatic MTC patients presented increased serum levels of IL-8 and TGF-β2. Conclusions: Experimental models confirm the clinical efficacy of sunitinib observed in a few studies. Molecular pathways revealed by genomic signatures underline the impact of sunitinib on tissue invasion. Selected soluble candidate biomarkers could be of value for monitoring sunitinib response in metastatic MTC patients. Clin Cancer Res; 17(7); 2044–54. ©2011 AACR.

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Section: Discussionmentioning

confidence: 95%

Section: Pan Genomic Expression Profile Analysis During Sunitinib Trementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Soluble Candidate Biomarkers of Therapeutic Response to Sunitinib in Medullary Thyroid Carcinoma in Preclinical Models

Broutin¹,

Ameur²,

Lacroix³

et al. 2011

Clinical Cancer Research

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“…Biological and pharmacological effects of sunitinib Sunitinib exhibited dose-and time-dependent antitumor activity in mice, potently repressing the growth of a broad variety of human tumor xenografts Murray et al 2003;Abrams et al 2003b;Morimoto et al 2004;Yee et al 2004]. In vivo, sunitinib caused bone marrow depletion and effects in the pancreas in rats and monkeys, as well as adrenal toxicity in rat (microhemorrhages).…”

Section: Sunitinibmentioning

confidence: 99%

Sunitinib in advanced pancreatic neuroendocrine tumors: latest evidence and clinical potential

et al. 2011

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Based on preclinical data available in the RIP1-Tag2 transgenic mouse model, sunitinib is an inhibitor of angiogenesis in pancreatic neuroendocrine tumors blocking vascular endothelial growth factor receptors and platelet-derived growth factor receptors in endothelial cells and pericytes, respectively. Evidence of objective response in phase I trials justified the initiation of a large phase II/III program using sunitinib in patients with advanced/ metastatic well-differentiated pancreatic neuroendocrine tumors. In the phase II study, sunitinib showed potent antitumor activity and a safe toxicity profile. In a recent double-blind placebo-controlled randomized phase III trial, sunitinib doubled the progression-free survival of patients, induced objective responses, and reduced the risk of death of patients with advanced/metastatic well-differentiated tumors. These data allowed the approval of sunitinib in several countries including Europe and the United States of America. These recent data provide hope for patients with well-differentiated pancreatic neuroendocrine tumors and will change standards of care in this disease.

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Molecular Pathology as a Way to Find the Right Dose for a Drug

Rojo

Rovira

Serrano

et al. 2008

Molecular Pathology in Drug Discovery and Development

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Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor

Cited by 45 publications

References 43 publications

Identification of Soluble Candidate Biomarkers of Therapeutic Response to Sunitinib in Medullary Thyroid Carcinoma in Preclinical Models

Identification of Soluble Candidate Biomarkers of Therapeutic Response to Sunitinib in Medullary Thyroid Carcinoma in Preclinical Models

Sunitinib in advanced pancreatic neuroendocrine tumors: latest evidence and clinical potential

Molecular Pathology as a Way to Find the Right Dose for a Drug

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