Protein that Fuels Ovarian Cancer Identified and Inactivated by Researchers

A protein has been identified that stimulates blood vessel growth, accelerating ovarian cancer. However, its production can be suppressed by a tiny piece of RNA wrapped in a fatty nanoparticle.

The study, led by scientists from the University of Texas M.D. Anderson Cancer Center (Houston, TX, USA), was reported in the February 26, 2008, issue of the Journal of the [U.S.] National Cancer Institute.

"The protein interleukin-8 [IL-8] is a potential therapeutic target in ovarian cancer,” said senior author Anil Sood, M.D., a professor in the M.D. Anderson departments of gynecologic oncology and cancer biology.

The study demonstrated that high IL-8 expression in tumors is associated with advanced tumor stage and earlier death for ovarian cancer patients. Laboratory experiments and research in a mouse model show that short interfering RNA (siRNA) can decrease IL-8 expression, reducing tumor size by attacking its blood supply.

"This comprehensive analysis--with human data, animal data, and lab experiments to highlight the molecular mechanisms involved--helps us develop the new targets needed for a more effective approach against ovarian cancer,” Dr. Sood said.

Interleukin-8 is overexpressed in many types of cancer and has previously been shown to promote tumor growth, new blood vessel growth known as angiogenesis, and metastasis, the spread of cancer to other organs. "In the long run, this research will have applications in other cancers as well,” Dr. Sood said.

Ovarian cancer is often detected in later stages. Initial treatment includes surgery and taxane- or platinum-based chemotherapy regimens that keep the cancer in check for a time in most patients. Recurrence is common and often lethal. To examine IL-8's role in ovarian cancer, the researchers analyzed tumors from 102 patients diagnosed and treated between 1988 and 2006 at M.D. Anderson and the University of Iowa (Iowa City, USA). Of those, 43 had tumors with high levels of IL-8 and 59 had low levels. The median survival of those with high IL-8 tumors was 1.62 years, compared with 3.79 years for those with low expression of the protein.

All 43 tumors with high expression of IL-8 were of high grade and 42 of 43 were advanced, either stage III or IV tumors. By comparison, 10 of 59 tumors with low IL-8 expression were early stage tumors and 6 were of low grade.

Genes transcribe single strands of RNA that in turn are "read” by ribosomes to produce proteins. siRNAs are short, double-stranded bits of RNA capable of blocking that process. The investigators confirmed in a lab experiment that a specific siRNA silences IL-8 and then tested it against two lines of ovarian cancer in a mouse model. They are constructing an arsenal of siRNAs capable of silencing genes that produce cancer-promoting proteins. The researchers packaged siRNA that inhibits IL-8 into a small ball of fat known as a liposome, a combination they developed to overcome a problem-- siRNA is difficult to deliver to tumors.

Tumors shrank by a median of 32% and 52% in the two cancer lines among mice that received injections of the IL-8 siRNA liposome compared to those receiving control siRNA or empty liposomes. Mice that received both the IL-8 siRNA plus the taxane-based chemotherapy drug docetaxel had median tumor weight reduction of 90% and 98% in the two cell lines. Mice with control siRNA plus docetaxel saw reductions of 67% and 84%.

Finally, the investigators tested the approach in mice with an ovarian cancer cell line known to be resistant to taxane-based drugs such as docetaxel. IL-8 siRNA alone reduced the size of these tumors by 47%, and when combined with docetaxel reduced tumor size by 77%, suggesting that the combination re-sensitizes a resistant tumor to taxanes. The researchers assessed the impact of IL-8 siRNA on tumor blood supply by measuring the density of blood vessels in the tumor. The IL-8 siRNA alone reduced blood vessel density by 34% and 39% in two cancer lines.

"These are encouraging results. We want to move one of our siRNA agents into the clinic to test its potential for therapy,” Dr. Sood said, "and then in the longer term, we'll consider moving additional siRNA agents into the clinical arena.”

The IL-8 siRNA liposome is the third developed by the MD Anderson researchers. Two others target the oncoproteins FAK and EphA2. The EphA2 siRNA liposome is closest to phase I clinical trial, with required toxicology studies nearly complete. A clinical trial could begin within one year.

Techniques used to inject siRNA in high volumes for research purposes are impractical for human therapy. Drs. Sood and Lopez-Berestein developed the liposomal approach to ensure that the siRNA reaches the cell intact so it can silence the targeted gene. Their research has shown that the liposome penetrates deeply into cells to deliver its siRNA.


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M.D. Anderson Cancer Center