A Phase II Trial of Saracatinib, an Inhibitor of src Kinases, in Previously-Treated Advanced Non–Small-Cell Lung Cancer: The Princess Margaret Hospital Phase II Consortium

Laurie, Scott A.; Goss, Glenwood D.; Shepherd, Frances A.; Reaume, M. Neil; Nicholas, Garth; Philip, Lindsay; Wang, Lisa; Schwock, Joerg; Hirsh, Vera; Oza, Amit M.; Tsao, Ming‐Sound; Wright, John J.; Leighl, Natasha B.

doi:10.1016/j.cllc.2013.08.001

Cited by 30 publications

(30 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As in our trial, other solid tumor studies have been published also showing the lack of benefit of this agent as monotherapy in gastric and gastroesophageal junction cancer, recurrent or metastatic head and neck squamous cell cancer, castration-resistant prostate cancer, metastatic melanoma, hormone receptor negative breast cancer, extensive stage small cell lung cancer, and pancreatic cancer [21][22][23][24][25][26][27]. A phase II trial in 37 patients with previously-treated advanced nonsmall-cell lung cancer, however, showed some signal of benefit, with 2 of 31 evaluable patients having partial responses lasting 3.7 and 14.6 months, and 6 patients being progression free at 16 weeks (primary endpoint) [28]. Saracatinib has not been studied in combination with other therapeutic agents in colorectal cancer but has not improved outcomes in combination studies with gemcitabine in pancreatic cancer [29] or with paclitaxel in platinum-resistant ovarian, fallopian and primary peritoneal cancer [30].…”

Section: Discussionmentioning

confidence: 99%

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In a phase II clinical trial, Laurie et al suggested that saracatinib, an orally available inhibitor of SFKs, may benefit a subset of NSCLC patients, which is currently molecularly undetermined; thus, further use of saracatinib in populations preselected for target mutations and smoking status should be considered (129). For instance, saracatinib could be functional as a combinatory therapy with EGFR TKIs, erlotinib or gefinitib, in patients who are smokers or former smokers and harboring activating EGFR mutations.…”

Section: Therapeutic Perspectivesmentioning

confidence: 96%

Lung Injury and Lung Cancer Caused by Cigarette Smoke-Induced Oxidative Stress: Molecular Mechanisms and Therapeutic Opportunities Involving the Ceramide-Generating Machinery and Epidermal Growth Factor Receptor

Goldkorn

Filosto

Chung

2014

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Chronic obstructive pulmonary disease (COPD) and lung cancer are frequently caused by tobacco smoking. However, these diseases present opposite phenotypes involving redox signaling at the cellular level. While COPD is characterized by excessive airway epithelial cell death and lung injury, lung cancer is caused by uncontrolled epithelial cell proliferation. Notably, epidemiological studies have demonstrated that lung cancer incidence is significantly higher in patients who have preexisting emphysema/lung injury. However, the molecular link and common cell signaling events underlying lung injury diseases and lung cancer are poorly understood. This review focuses on studies of molecular mechanism(s) underlying smoking-related lung injury (COPD) and lung cancer. Specifically, the role of the ceramide-generating machinery during cigarette smoke-induced oxidative stress leading to both apoptosis and proliferation of lung epithelial cells is emphasized. Over recent years, it has been established that ceramide is a sphingolipid playing a major role in lung epithelia structure/function leading to lung injury in chronic pulmonary diseases. However, new and unexpected findings draw attention to its potential role in lung development, cell proliferation, and tumorigenesis. To address this dichotomy in detail, evidence is presented regarding several protein targets, including Src, p38 mitogen-activated protein kinase, and neutral sphingomyelinase 2, the major sphingomyelinase that controls ceramide generation during oxidative stress. Furthermore, their roles are presented not only in apoptosis and lung injury but also in enhancing cell proliferation, lung cancer development, and resistance to epidermal growth factor receptor-targeted therapy for treating lung cancer.

show abstract

“…It has been well demonstrated that AZD0530 effectively inhibits Src kinases in cancer cells (Chang et al, 2008;Morrow et al, 2010;Laurie et al, 2014). To determine the optimal dose required to inhibit Src kinase activation induced by TGF-b1, the dose effect of AZD0530 on Src activation was examined in human lung fibroblasts (Fig.…”

Section: Tgf-b1 Induces Src Kinase Activation In Humanmentioning

confidence: 99%

Therapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis

Meng

Che

Han

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Myofibroblasts are effector cells in fibrotic disorders that synthesize and remodel the extracellular matrix (ECM). This study investigated the role of the Src kinase pathway in myofibroblast activation in vitro and fibrogenesis in vivo. The profibrotic cytokine, transforming growth factor b1 (TGF-b1), induced rapid activation of Src kinase, which led to myofibroblast differentiation of human lung fibroblasts. The Src kinase inhibitor AZD0530 (saracatinib) blocked TGF-b1-induced Src kinase activation in a dose-dependent manner. Inhibition of Src kinase significantly reduced a-smooth muscle actin (a-SMA) expression, a marker of myofibroblast differentiation, in TGFb1-treated lung fibroblasts. In addition, the induced expression of collagen and fibronectin and three-dimensional collagen gel contraction were also significantly inhibited in AZD0530-treated fibroblasts. The therapeutic efficiency of Src kinase inhibition in vivo was tested in the bleomycin murine lung fibrosis model. Src kinase activation and collagen accumulation were significantly reduced in the lungs of AZD0530-treated mice when compared with controls. Furthermore, the total fibrotic area and expression of a-SMA and ECM proteins were significantly decreased in lungs of AZD0530-treated mice. These results indicate that Src kinase promotes myofibroblast differentiation and activation of lung fibroblasts. Additionally, these studies provide proof-ofconcept for targeting the noncanonical TGF-b signaling pathway involving Src kinase as an effective therapeutic strategy for lung fibrosis.

show abstract

A Phase II Trial of Saracatinib, an Inhibitor of src Kinases, in Previously-Treated Advanced Non–Small-Cell Lung Cancer: The Princess Margaret Hospital Phase II Consortium

Cited by 30 publications

References 20 publications

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

Lung Injury and Lung Cancer Caused by Cigarette Smoke-Induced Oxidative Stress: Molecular Mechanisms and Therapeutic Opportunities Involving the Ceramide-Generating Machinery and Epidermal Growth Factor Receptor

Therapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis

Contact Info

Product

Resources

About