Chemotherapy drug paclitaxel can target and reduce the migrating cancer cells that are responsible for the development of tumor metastases, according to a study by a research team at the University of California, Riverside. The findings of the study are published in the Journal of Medicinal Chemistry. Until now, paclitaxel has only been used to target rapidly dividing cancer cells. The team was successful in getting the drug to piggyback on 123B9, an agent they devised to target an oncogene called EphA2 (ephrin type-A receptor 2). EphA2 spreads cancer by allowing malignant cells to migrate from the primary tumor into circulation and eventually to adhere to other tissues.
‘Binding of 123B9 can cause the oncogene to reduce the number of circulating cancer cells and produce less metastatic cells.’
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"Once this novel tumor-homing agent binds to the EphA2 receptor, the oncogene functions as a cancer-specific molecular Trojan horse for paclitaxel, carrying the drug inside the cancel cell, killing the cell, and thwarting metastasis," said Maurizio Pellecchia, a professor of biomedical sciences at UCR's School of Medicine who led the research. "Without the targeting agent, paclitaxel cannot hitch a ride on EphA2." Tumor metastasis is a leading cause of patient morbidity and mortality, and no treatments are currently available that specifically target metastasis formation. Cancer cells depend on a number of oncogenes, like EphA2, to form metastasis, the medical term for cancer spreading from the primary site to other regions in the body, accomplished when cancer cells break away from the primary site, travel through the blood or lymph system, and form new tumors elsewhere in the body.
Pellecchia and his colleagues found that when 123B9 binds to the extracellular region of the EphA2 receptor expressed in cancer cells, it causes the oncogene to internalize and degrade inside the cell, thus preventing cancer cells from entering circulation and metastasizing.
"Because this binding causes EphA2 internalization, we also sought to conjugate 123B9 with paclitaxel and thus direct the drug to migrating cancer cells," said Pellecchia, who holds the Daniel Hays Chair in Cancer Research at UCR.
Recent collaborative work between UCR and Cedars-Sinai Medical Center in Los Angeles demonstrated that in animal models of human breast cancer, mice treated with 123B9 that was conjugated with paclitaxel had significantly fewer circulating cancer cells in the blood compared to mice that were not treated or even treated with paclitaxel alone.
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Pellecchia said the road to a therapeutic for human trials is still long and includes the iterative design and synthesis of more potent and selective agents.
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He noted that while these studies solidify UCR's partnership with Cedars-Sinai Medical Center, the research team moving forward is expanding. Already, it includes UCR's Jikui Song, an assistant professor of biochemistry, and Dr. Samar Nahas, an assistant clinical professor of gynecology and oncology in the School of Medicine.
Source-Eurekalert