Drug Pair Conquers Highly Aggressive Childhood Cancer

ARMS accounts for more than 50% of all soft-tissue cancers in children, but even after extensive therapy the survival rate of patients with advanced disease is less than 20%.

In the current study, the investigators worked with a prototype drug (NVP-AEW541) that inhibited the insulin-like growth factor 1 receptor (Igf1r), a protein heavily overexpressed on ARMS cells. While the drug could inhibit cell growth and induce apoptosis in vitro, drug resistance in vivo was common and was associated with increased Igf1r overexpression. Igf1r overexpression was accompanied by an increase in another tumor surface enzyme, human epidermal growth factor receptor 2 (Her2). Her2 is also found on certain types of breast tumors, and the drug lapatinib has been approved for treating this form of breast cancer.

In their paper published in the March 29, 2011, online edition of the journal Molecular Cancer Therapeutics the investigators described results of experiments in which NBP-AEW541 was used in combination with lapatinib to treat mice with ARMS.

They reported that NVP-AEW541 reduced tumor growth in a third of the mice before the tumors became resistant to the drug. Lapatinib alone had no effect on the tumors, but the combination of the two drugs almost completely blocked tumor growth without development of resistance.

"Despite our best efforts, outcomes for metastatic alveolar rhabdomyosarcoma have not improved for decades. That is why our findings are significant. Our clinical partners now have a new method of mitigating resistance to the current treatment for childhood muscle cancer,” said first author Dr. Jinu Abraham, senior cancer biology research associate at the Oregon Health and Science University. "Fortunately, when we treated resistant rhabdomyosarcoma cells with a combination of the Igf1r inhibitor and the Her2 inhibitor lapatinib, there was a significant increase in tumor cell killing compared with either drug alone. Our study has shown that targeting both Igf1r and Her2 may be a very promising approach in preventing resistance to Igf1r-inhibiting drugs in rhabdomyosarcoma.”

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