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M.D. Anderson researchers find PEA-15 prolongs overall survival in human ovarian cancer
HOUSTON—In research ultimately aimed at developing small peptide molecules into novel therapeutics, a research team at M.D. Anderson Cancer Center has discovered that the previously noted antitumor effect of E1A is due to PEA-15. Phospho-enriched protein in astrocytes—or PEA-15—Is a 15-kDa phosphoprotein that slows cell proliferation by binding to, and sequestering, extracellular signal-regulated kinase (ERK) in the cytoplasm.
"PEA-15 offers us a new dimension for potentially targeting ERK," says senior author Dr. Naota Ueno. To date, he notes, no one has been able to develop a successful ERK inhibitor. PEA-15 involves location-based targeting that has its effect on ERK in the cytoplasm, before it moves to the nucleus and upregulates cancer-inducing proteins.
"We've shown with high levels of PEA-15, women with ovarian cancer are surviving longer," Ueno says. Levels of the protein in tumors also might affect how other drugs work against the disease, he adds.
Newly diagnosed cases of ovarian cancer were expected to exceed 22,000 in 2007, with more than 15,000 women expected to die of the disease. Because very few cases are detected at an early stage, the researchers note, understanding the molecular mechanism of tumor development is crucial if more effective treatments are to be developed.
The M.D. Anderson team lead by Ueno used tumor tissue samples from 395 women with primary epithelial ovarian cancer to determine if PEA-15 expression was linked to overall survival. Analysis revealed that women with high expression of PEA-15 had a median survival time of 50.2 months compared with 33.5 months for women with low levels of the protein in their tumors.
High expression of PEA-15 inhibits the growth of ovarian cancer cells by killing cells via autophagy rather than by apoptosis. In apoptosis, defective cells die from self-induced damage to their nuclei and DNA. Autophagy kills when a cell entraps parts of its cytoplasm in membranes and digests the contents, leaving a cavity. As this recurs, the cell becomes riddled with cavities and dies. The team also confirmed that PEA-15 knockdown increases proliferation of ovarian cancer cells.
Sixty-eight percent of the patients in the study had stage III disease, serous adenocarcinoma (77 percent) and tumors of nuclear grade 3 (91 percent). Average age was 60. Sixty-nine percent of the women showed moderate expression of PEA-15, 19 percent showed low expression and 12 percent were in the high expression group. Univariable analysis showed PEA-15 expression and well-known prognostic factors such as age, histopathologic diagnosis and disease state were significantly associated with longer survival.
"These findings provide a foundation for developing a PEA-15 targeted approach for ovarian cancer and for clarifying whether this protein is a novel biomarker that can predict patient outcomes," Ueno says. His associate, Dr. Chandra Bartholomeusz, notes that the M.D. Anderson team is also studying PEA-15 in breast cancer and says that preliminary results are very promising.
The research was funded by a National Cancer Institute grant to Ueno and a Susan G. Komen for the Cure postdoctoral fellowship to Bartholomeusz to study PEA-15 in breast cancer. DDN