Expression of Proteins Linked to Poor Outcome in Women with Ovarian Cancer

Scientists have established the presence of certain proteins in ovarian cancer tissues and have linked these proteins to poor survival rates in women with advanced stages of the disease. The study, led by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, appears in Cancer online, April 19, 2010.

The proteins in question belong to the nuclear factor kappa Beta (NF-kB) family. NF-kB controls many processes within the cell including cell survival and proliferation, inflammation, immune responses, and cellular responses to stress.

“This study sheds light on the distinctive genetic features of the NF-kB pathway and may provide targets for the development of novel therapies for ovarian cancer,” said lead investigator, Christina M. Annunziata, M.D., Ph.D., associate clinical investigator, Medical Oncology Branch.

Abnormalities in NF-kB signaling have been found in several types of cancer, including ovarian cancer, but the mechanism and importance of such alterations in ovarian cancer was not defined. To address these knowledge gaps, the research team investigated the expression of NF-kB-related proteins in the cells of tumor tissue obtained at surgery from 33 previously untreated women who were newly diagnosed with advanced epithelial ovarian cancer. The patients had similar stage (all late stage), grade, and type of disease. All patients were treated with a three-drug regimen of standard chemotherapy agents in an NCI clinical trial that was conducted at the NIH Clinical Research Center.

To assess NF-kB family members and associated proteins in ovarian tumor cells, the scientists used immunohistochemistry, a method that uses antibodies—a type of protein that the body’s immune system produces when it detects harmful substances—to identify specific molecules in tissue specimens. Subsequently, they looked for associations between the percentage of tumor cells in individual proteins and patient outcomes.

The data revealed that the presence of one NF-kB family member—p50—in more than one-quarter of the cells was associated with poor survival. Low-frequency or nonexpression of a target gene, matrix metallopeptidase 9 (MMP9), was also associated with poor prognosis. Further, the team identified two NF-kB family members—p65 and RelB—and a protein called IKKa that plays a role in promoting inflammation, that were frequently expressed in the same cells, providing more evidence that NF-kB is active in some ovarian cancers. It is possible that the NF-kB activity in these cancers could increase their growth and/or resistance to treatment.

“This work continues to define and characterize the biological relevance of NF-kB activity in ovarian cancer by translating research findings with ovarian cancer cells in the laboratory to ovarian cancer in women at the time of initial diagnosis,” said Annunziata.

In related work, published online in Cancer Research, April 27, 2010, the team investigated the biological relevance of NF-kB in ovarian cancer using a small molecule inhibitor of IKKB. They found that the gene signature regulated by IKKB in cell lines was related to poor outcome in independently collected sets of primary ovarian cancers, suggesting that IKKB activity contributes to an aggressive phenotype of this disease.

In the Cancer Research study, Annunziata found that over-activation of the cellular activities of IKKB is consistent with the poor prognostic associated in patients with ovarian cancer. The diversity of functions controlled by IKKB in ovarian cancer may have implications for treatment of this malignancy.

While small molecule inhibitors of IKKB are under preclinical development, they may not exhibit a strong anti-cancer effect as a single agent in most forms of ovarian cancer. Therefore, IKKB inhibitor therapy, in combination with chemotherapy, should be focused to patients whose tumors express a molecular profile suggestive of dependence on IKKB activity, say the scientists.

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