Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530

Green, Tim P.; Fennell, Michael; Whittaker, Robin; Curwen, Jon; Jacobs, Vivien N.; Allen, Jack; Logié, Armelle; Hargreaves, Judith; Hickinson, D. Mark; Wilkinson, Robert W.; Elvin, Paul; Boyer, Brigitte; Carragher, Neil O.; Plé, Patrick; Bermingham, Alun; Holdgate, Geoffrey A.; Ward, Walter H.J.; Hennequin, Laurent; Davies, Barry R.; Costello, Gerard

doi:10.1016/j.molonc.2009.01.002

Cited by 198 publications

(199 citation statements)

References 51 publications

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“…Results similar to those from the above studies were reported in colon cancer, head and neck cancer, and lymphoma cell lines [70 -72]. Data showing the efficacy of saracatinib in reducing metastatic disease were seen in a murine metastatic model of bladder cancer in which there was a significantly lower number of tumor colonies that could be grown from mesenteric lymph node extracts in treated than in untreated mice [73]. Several phase I clinical trials of saracatinib have been conducted and an MTD of 175 mg daily has been established for advanced solid tumor malignancies.…”

Section: Dasatinibsupporting

confidence: 84%

Current Status of Src Inhibitors in Solid Tumor Malignancies

2011

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Summary. Src is believed to play an important role in cancer, and several agents targeting Src are in clinical development.Design. We reviewed Src structure and function and preclinical data supporting its role in the development of cancer via a PubMed search. We conducted an extensive review of Src inhibitors by searching abstracts from major oncology meeting databases in the last 3 years and by comprehensively reviewing ongoing clinical trials on ClinicalTrials.gov.Results. In this manuscript, we briefly review Src structure and function, mechanisms involving Src that lead to the development of cancer, and Src inhibitors and key preclinical data establishing a rationale for clinical application. We then focus on clinical data supporting their use in solid tumor malignancies, a newer arena than their more well-established hematologic applications. Particularly highlighted are clinical trials investigating new biomarkers as well as ongoing studies assessing Src inhibitor activity in biomarker-selected patient populations. We also review newer investigational Src-targeting agents.Conclusions. Src inhibitors have shown little activity in monotherapy trials in unselected solid tumor patient populations. Combination studies and biomarker-driven clinical trials are under way. The Oncologist 2011;16:566 -578

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Section: Dasatinibsupporting

confidence: 84%

Current Status of Src Inhibitors in Solid Tumor Malignancies

2011

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“…Overall, these finding and our present study suggest a series of coordinated signaling transduction events involving MDA-9/syntenin that ultimately leads to the acquisition of a motile phenotype by melanoma cells. Indeed, blocking MDA-9/syntenin in response to rFVIIa and FX, or interfering with TF (48), Rho proteins (49), NF-B-regulated genes such as MMP-2 (50), or more importantly inhibition of the Src/paxillin signaling pathway (45,51) has been shown to inhibit tumor growth and metastasis in preclinical studies and clinical trials.…”

Section: Discussionmentioning

confidence: 99%

MDA-9/Syntenin Is Essential for Factor VIIa-induced Signaling, Migration, and Metastasis in Melanoma Cells

Aissaoui

Prévost

Boucharaba

et al. 2015

Journal of Biological Chemistry

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Background: MDA-9/syntenin and tissue factor (TF) are overexpressed in most types of human cancer. Results: Induction of MDA-9/syntenin in melanoma involves the binding of FVIIa and FX to TF on the cell surface, which initiates a signaling circuit essential for cell motility and metastasis of melanoma. Conclusion: MDA-9/syntenin is an important TF-regulated gene. Significance: Targeting TF-mediated MDA-9/syntenin may represent a novel therapeutic strategy for eliminating cancer.

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“…Chang and colleagues (28) reported median doses ranging from 1 to 16 mmol/L for saracatinib-mediated growth inhibition in a panel of prostate cancer cell lines. In another study (29), the antiproliferative effect of saracatinib on cell lines from different tumor types was achieved with very variable median doses (from 0.2-14 mmol/L). Our analysis on BTC cell-cycle progression showed that saracatinib is very specific in blocking cells in the G 0 -G 1 phase, but not in apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of Src Inhibitor Saracatinib (AZD-0530) in Preclinical Models of Biliary Tract Carcinomas

Cavalloni

Peraldo-Neia

Sarotto

et al. 2012

Molecular Cancer Therapeutics

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Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is, therefore, an urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the nonreceptor tyrosine kinase Src, observing promising antitumor effects of its small-molecule inhibitor saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from patients with BTC. Upon saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28, and TGBC1-TKB. The effect of saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinibmodulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G 0 -G 1 phase, and inhibited cell migration. At high concentrations (median dose from 2.26-6.99 mmol/L), saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. Here, we provide a demonstration that the targeted inhibition of Src kinase by saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of saracatinib-based clinical applications.

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Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530

Cited by 198 publications

References 51 publications

Current Status of Src Inhibitors in Solid Tumor Malignancies

Current Status of Src Inhibitors in Solid Tumor Malignancies

MDA-9/Syntenin Is Essential for Factor VIIa-induced Signaling, Migration, and Metastasis in Melanoma Cells

Antitumor Activity of Src Inhibitor Saracatinib (AZD-0530) in Preclinical Models of Biliary Tract Carcinomas

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