Germany's Xerion Pharmaceuticals has discovered a protein that seems to be intrinsically involved in the spread of cancers and could be a new target for drug therapies. The finding is also a validation of the firm's Xstream drug screening technology.
Researchers at the privately held company, along with collaborators at Tufts University School of Medicine and the National Cancer Institute in the US, have identified an extracellular form of heat shock protein (hsp) 90 and its role in cancer invasion.
Invasion is a key step in tumour progression that eventually leads to metastasis or the development of secondary tumours when a cancer cell penetrates through the extracellular matrix - sometimes into the blood or lymph circulation - and lodges elsewhere.
To date there are no effective and safe treatments against metastases due to the lack of reliable validated drug targets. For example, companies including the UK's British Biotech have tried to block enzymes called matrix metallproteases that allow malignant cells to break away from tumours, but without success.
Hsp90 recently has already gained significant attention as an important target for cancer therapeutics and hsp90 inhibitors are currently in Phase I and II clinical trials. However, since hsp90 is also a key protein for normal cell function, there is some concern about treatment-related toxicity, especially if hsp90 inhibitors are unable to distinguish normal and cancer cells.
In the latest study, researchers used functional screens on the extracellular membrane proteome of a highly invasive human tumour cell line, in a bid to identify cellular factors that are involved in tumour spread.
The screens made use of the Xstream technology that uses thousands of antibodies to try to simulate the activity of a diseased cell in a healthy cell. It is then possible to work out which cellular component is targetted by an antibody that 'switches on' the disease characteristic - in this case the ability to spread locally. The same antibody can be used to isolate the cell component using a process called immunoprecipitation, and it can then be identified using mass spectrometry.
Using this system, the Xerion researchers demonstrated a direct physical and functional interaction between hsp90 and matrix metalloprotease (MMP) 2, a primary enzyme in the tumour invasion process. This opens the possibility for developing antibodies against hsp90 for the treatment of cancer.
"This work highlights the relevance of validating function at the protein level. Genetic approaches would have missed the discovery of the novel mechanism of hsp90 action", said Daniel Jay, of Tufts University, who is the senior author of the paper. The results of the study appear in the June issue of Nature Cell Biology.