Pinpointing cancer's origins
Cancer is one of the most pressing health matters of our time. It is a disease that attacks the very building blocks of life, leading to uncontrolled cell division and disabling programmed cell death. Almost everyone has known at least one person who has had to cope with cancer; it remains one of the leading causes of death in Europe.
All living organisms are assembled according to instructions found in their genes. These genes produce proteins, which work together in a sequential manner to transmit a signal, either from one cell to another or within a cell. The sets of proteins and the genes that make them are commonly referred to as a ‘signalling pathway’, which determines responses to these signals, for example decisions whether a cell divides or not and when it dies. But when a signalling pathway becomes overactive or active in the wrong tissue, it can cause cancer.
“Imagine the information flow in our cells as one big public transportation network,” explains Professor Michael Boutros from the German Cancer Research Centre and Heidelberg University. “When one part gets blocked, the whole system is affected – and depending on where the blockage is, the effect may be bigger or smaller. So in order to understand carcinogenesis and design better and individual treatments, we have to understand how signalling molecules fit in the overall system. And we need a better understanding of the whole system rather than only individual components.”
New therapeutic approaches in cancer treatment have begun targeting signalling pathway components, such as the drug Herceptin (primarily used to treat breast cancer), which targets a growth factor receptor to reduce uncontrolled cell growth. However, the full potential of signalling molecules as therapy targets has yet to be explored.
This was the main goal of CancerPathways, a three-and-a-half-year EU-funded research project, which Boutros coordinated. “Many signalling pathways interweave so you cannot just target one with drugs without affecting others. Our hope was that by unearthing the players in carcinogenesis, we would also identify novel targets for therapy.” CancerPathways was launched in 2008 and received just under €3 million in EU funding.
Its main ‘research tool’ seems a bit unusual at first, as it came in the form of Drosophila – also known as fruit flies. On the surface human beings and fruit flies have few similarities. Underneath, however, they share approximately 70 percent of the genes known to be involved in human diseases. This surprising level of similarity in how humans and simpler organisms (such as the fruit fly) are put together, has allowed scientists to use flies as so-called ‘model organisms’ to work out how genes work in humans. In fact, over 90 percent of the signalling pathways that play an important role in cancer were first discovered through the study of flies.
"We tested both fruit flies and fruit fly cells grown in the lab with a method called RNA interference (RNAi),” Boutros explains. RNAi was only recently discovered, with first reports published in 1998. The mechanism involves putting a tiny chunk of genetic code into an organism or cells, to cancel out a specific gene. This effectively switches that gene off, thus enabling the systematic analysis of every single gene, including its signalling molecules and pathways. “Our research built the groundwork for future cancer therapies,” Boutros says. “We generated a nearly genome-wide RNAi library of Drosophila flies – containing about 11 000 different fly lines – which can be used for future research by the entire science community. We also identified several novel candidate genes and demonstrated their function in cancer signalling pathways.”
Over the past few years cancer diagnostics have become more precise, according to Boutros. The next decade will see cancer therapies becoming increasingly individualised. Drugs will be tailored to damage signalling components on a case-by-case basis. Boutros says: “CancerPathways’ work is an important contribution to making that possible”. The project’s success stemmed from the combined efforts of its eight European partners. “No single country would have had a science community with all the expertise needed for this kind of research, which requires both depth and breadth,” he explained. “It is this combination of expertise from different nations that makes European research unique.”
Officially the CancerPathways project ended in October 2011, however its work continues. After identifying small molecular compounds and exploring their potential for developing new anti-cancer drugs, the partners are currently evaluating these small molecules as well as new gene targets.