Experimental Drug Shrinks Ovarian Tumors in Mouse Model

An experimental drug crafted to mimic the activity of the antiangiogenic protein thrombospondin-1 (TSP-1) dramatically reduced the size of ovarian tumors in a mouse model of the human disease.

TSP-1 is an antiangiogenic protein that inhibits the proliferation and migration of endothelial cells by interactions with the CD36 protein expressed on their surface of these cells. Inhibitory peptides and fragments of TSP-1 bind to CD36, leading to the expression of the FAS ligand (FasL), which activates its specific, ubiquitous receptor, Fas. This leads to the activation of caspases and apoptosis of the cell. Since tumors overexpressing TSP-1 typically grow slower, exhibit less angiogenesis, and have fewer metastases, TSP-1 is an attractive target for cancer treatment. Since TSP-1 is an extremely large molecule, not very abundant, and exerts multiple actions, its clinical usefulness is questionable. However, small-molecules based on a CD36-binding peptide sequence from TSP-1 are being tested.

One of these experimental drugs is the peptide ABT-898, which was used recently by investigators at the University of Guelph (Canada) to treat mice carrying human ovarian tumors. These mice were from a novel population of normally healthy animals that developed ovarian tumors two months after receiving injections of human ovarian cancer cells.

Results reported in the October 2011 issue of the journal Molecular Cancer Therapeutics revealed that ABT-898 induced tumor regression and reduced the morbidity of treated animals compared with controls. Analysis of tumors from ABT-898–treated animals showed reduced abnormal tumor vasculature, decreased expression of the proangiogenic compound VEGF (vascular endothelial growth factor), and reduced tumor tissue hypoxia. ABT-898 treatment initiated at late-stage disease also significantly prolonged disease-free survival compared with control animals.

“We are extremely excited about this,” said senior author Dr. Jim Petrik, professor of biomedical sciences at the University of Guleph. “It has the potential, particularly in ovarian cancer, to have a significant impact.”

“This new treatment enhances the ability to deliver chemotherapy drugs inside of the tumor where they need to go. So in combination with chemotherapy, it has fantastic potential,” said Dr. Petrik. “This is crucial. Women tend to succumb to ovarian cancer because the inefficient delivery of chemotherapy drugs allows the cells to build up resistance and they no longer respond to treatment.”

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University of Guelph