Fat-packed siRNA reduces ovarian tumours

Source: MD Anderson Cancer Centre

US researchers have used a short interfering RNA (siRNA) packaged in a liposome to turn off interleukin-8 (IL-8) expression in ovarian cancers in a mouse model.

The researchers, from the University of Texas MD Anderson Cancer Center, reported their findings in the Journal of the National Cancer Institute.

Interleukin-8 is overexpressed in many types of cancer and has previously been shown to promote tumour growth, angiogenesis and metastasis. The new paper demonstrates that high IL-8 expression in tumours is associated with advanced tumour stage and earlier death for ovarian cancer patients.

They analysed tumours from 102 patients diagnosed and treated between 1988 and 2006 at MD Anderson and the University of Iowa. Of those, 43 had tumours with high levels of IL-8 and 59 had low levels. The median survival of those with high IL-8 tumours was 1.62 years, compared with 3.79 years for those with low expression of the protein.

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

In experiments in mouse models, the researchers show that siRNA can cut IL-8 expression, reducing tumour size by attacking its blood supply.

Senior authors Dr Anil Sood and Dr Gabriel Lopez-Berestein and colleagues are building an arsenal of siRNAs capable of silencing genes that produce cancer-promoting proteins. They packaged siRNA that stymies IL-8 into a small ball of fat known as a liposome, a combination they developed to overcome a major problem - siRNA is hard to deliver to tumours.

Tumours shrank by a median of 32 per cent and 52 per cent 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 got both the IL-8 siRNA plus the taxane-based chemotherapy drug docetaxel had median tumour weight reduction of 90 per cent and 98 per cent in the two cell lines. Mice with control siRNA plus docetaxel saw reductions of 67 and 84 per cent.

Finally, they 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 tumours by 47 per cent, and when combined with docetaxel reduced tumour size by 77 per cent, suggesting that the combination re-sensitises a resistant tumour to taxanes.

The team gauged the impact of IL-8 siRNA on tumour blood supply by measuring the density of blood vessels in the tumour. The IL-8 siRNA alone reduced blood vessel density by 34 per cent and 39 per cent in two cancer lines.

"These are encouraging results," Sood said. "We want to move one of our siRNA agents into the clinic to test its potential for therapy 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 Sood's and Lopez-Berestein's team. 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 a year.

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.