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24 July 2008
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HER-2 and IGF-IR inhibitors synergize to combat breast cancer growth
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MedWire News: The combination of human epidermal growth factor (HER)-2 monoclonal antibody treatment and a novel insulin-like growth factor-I receptor (IGF-IR) antagonist act synergistically to combat breast cancer cell proliferation, Spanish researchers report.
The team hopes that this combined approach could help overcome resistance to HER-2 antibody treatment in breast cancer patients with HER-2 overexpressing tumors.
"Taken together, the biochemical and genomic data indicate that [this] combination may exert its action on breast cancer cells through a complex array of transcriptional and posttranscriptional modifications of proteins that control cell number," Atanasio Pandiella (University of Salamanca) and colleagues comment.
The development of monoclonal antibody therapy for breast cancer patients whose tumors overexpress the HER-2 oncogene has turned an aggressive and often fatal subtype of the disease into a highly treatable condition, the researchers note in the Annals of Oncology.
However, in spite of its effectiveness in some women, a substantial number of HER-2-positive patients do not respond to the antibody or relapse in a short period of time.
"This resistance has been attributed to various mechanisms, including phosphatase and tensin homolog inactivation, the presence of HER-2-truncated forms, or the activation of other tyrosine kinase receptors such as IGF-IR," Pandiella et al comment.
Noting recent research interest in IGF-IR, the researchers used Western blotting to test the expression of this marker in tumor samples from 22 breast cancer patients and a similar number of healthy breast specimens from cosmetic reductions. They found IGF-IR expression was significantly upregulated in most breast cancer samples relative to the controls.
Next, the researchers cultured breast cancer cells in vitro, treating them with various combinations of HER-2 monoclonal antibody and an IGF-IR antagonist (designated NVP-AEW541).
Analysis showed that the combination of these two agents together inhibited proliferation and increased apoptosis to a greater degree than what would be expected from the additive effect observed with both modalities alone.
Furthermore, biochemical analysis revealed that this combination had a similar synergistic effect in suppressing expression of known oncogenic markers pAkt and p27.
"In summary, our results support the clinical development of anti-IGF-IR agents in breast cancer, especially in combination with agents such as [HER-2 monoclonal antibodies]," Pandiella et al conclude.
Ann Oncol 2008; Advance online publication
http://annonc.oxfordjournals.org/
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