Highlights •IFN-γ and 4D5 act directly on erbB2-positive breast cancer cells •IFN-γ, but not IFN-α or β, cooperates with 4D5 directly on erbB2+ breast cancer cells •IFN-γ and 4D5 alters KLF4 levels and degrades Snail by the GSK3-β/proteasome pathway •Sequential combination treatment with mAb and IFN-γ sensitizes for tumor eradication. Credit: http://dx.doi.org/10.1016/j.celrep.2015.08.044
This therapy, when translated for use in people humans, would be beneficial in reducing toxicity because the amount of antibody could be decreased by 2/3 and the amount of chemotherapy by at least 1/2, they say. This in turn, “reduces the cost of treatment so that individuals previously not able to afford targeted therapy will be able to do so.
“This line of research is important to future therapy for Her2-positive breast cancers because it defines a way to make the current treatment better and to use less amount of cancer drugs such as Herceptin by an ordered combination use with before interferon-gamma, which is also a clinically used drug,” said assist. Prof Hongtao Zhang, PhD. Anti-erbB2/neu monoclonal antibodies (mAbs) alone are only effective in 30% of breast cancer patients carrying the amplified target and cost about $100,000 a year. Currently, this antibody treatment must be combined with chemotherapy to increase the proportion of patients it helps.
The major take-away from this study is that Rx with herceptin or lapatanib followed by IFN-gamma dramatically improves tumor eradication in the mice. This one-two punch, which is a continuation of the pioneered antibody based Her-2 targeted therapy from this lab, renders the tumors highly sensitive to chemotherapy, which is needed to make the targeted therapy work.
All of the therapeutic agents used in this preclinical study are approved and we expect to try ordered therapy plus interferon in clinical trials soon,” Greene said.
Interferon-gamma is a small protein called a cytokine normally produced by T cells as part of the immune response. Interferon-gamma is a well-known cytokine to immunologists but is not used by oncologists so much because of other side effects. Interferon-gamma works by rendering the tumor cells much more susceptible to Her-2 inhibitors so that tumor cells can be killed more effectively. In addition, this combination therapy also augments host tumor immunity, which can be a good advantage for this therapy.
In a series of experiments in breast cancer cell lines and transgenic mice that develop breast cancer as adults, the team found that interferon-gamma on its own had no effect on tumors. Treatment of the tumors with anti-erbB2/neu mAbs followed by interferon-gamma led to a considerable inhibition of tumor growth and reduction of tumor size in the mice when the therapy is combined with a typical chemotherapeutic agent. http://www.uphs.upenn.edu/news/News_Releases/2015/10/zhang/
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