Xenical (orlistat) works as a treatment for obesity by virtue of its action as a pancreatic lipase inhibitor, blocking the absorption of dietary fat from the gastrointestinal tract. But its potential as a cancer treatment rests with its action on another enzyme known as fatty acid synthase.
Fatty acid synthase is elevated in prostate cancer cells and various other tumours, including those affecting the breast, colon, ovary, liver, lung and brain, but largely absent in healthy cells. Moreover, tumours which express the enzyme tend to be more malignant, so the suggestion is that inhibitors of the enzyme could provide highly-targeted therapy, with little impact on healthy tissue, in patients who need effective treatment the most.
"High levels of fatty acid synthase correlate with poor prognosis, so it is a great treatment target," commented Steven Kridel of the department of cancer biology at Wake Forest University in the US.
Xenical has proved a useful product for Roche in terms of earning potential, but failed to live up to its once-touted blockbuster status and has started to see its sales slide, with a 10 per cent decline in the first quarter of 2007 to CHF 163m ($98m). Now the drug has been adapted for over-the-counter use - often a marker that a brand is nearing the end of its commercial life - and reached the US market in this form last month. The OTC version is sold as Alli by GlaxoSmithKline.
So could a new use in cancer inject some renewed vigour into orlistat? Unfortunately, not, although the drug could become a template for the design of novel compounds that share its activity.
Orlistat itself cannot be used as a cancer treatment because, while it can kill cancer cells in the laboratory, in humans it is designed to work only in the digestive tract, according to the researchers, who have published their findings in the online edition of Nature Structural and Molecular Biology.
The goal now is to use data from X-ray crystallography studies - which map the three-dimensional interaction of orlistat with the target enzyme - to develop related compounds that have orlistat's activity profile but can be absorbed into the blood and reach tumour sites.
The team have undertaken a screening programme and narrowed the search down to around a dozen compounds that seem to have the right profile to be developed as pharmaceuticals.
And as fatty acid synthase is also found in fat cells, the compounds might also prove to have potential as obesity treatments, according to Todd Lowther, one of the researchers involved in the project.
"You might have the same drug for treating a cancer patient as an obese patient," said Lowther.
Pharmaceutical companies have already started bringing inhibitors of fatty acid synthase through the development pipeline. For example, US firm CytRx has compounds in early stage development and hopes to brig them forward as treatments for obesity and diabetes.
Meanwhile, another US company, FASgen, is developing a fatty acid synthase inhibitor for cancer applications in collaboration with Johns Hopkins University in the US, and is scheduled to take its lead compounds - dubbed FAS31 and FAS93 - into clinical trials later this year.
