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28March 2014

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New combination therapy against lung and colon cancer

Researchers of the Netherlands Cancer Institute (NKI) have developed a new combination therapy against lung- en colon cancer. The details are published this week in the journal Cell Reports.

The therapy is a another example of personalized medicine. In personalized medicine, physicians and scientists no longer focus on the location of a tumor, but on the specific genetic mutations that caused cells to become cancerous. Around 20 percent of the patients with lung cancer and 30 percent of the patients with colon cancer have tumors with a mutation in the KRAS gene. This mutation affects several protein pathways in the cell, causing rapid proliferation. 

Alternative pathways
KRAS mutations are hard to target with drugs. But there are drugs available that affect the proteins which become deregulated due to a KRAS mutation. Unfortunately, the individual effect of these drugs is often weak. Molecular geneticist prof. dr. René Bernards and his research group at the NKI started a search for a combination therapy in which the drugs do have a strong effect when given together.  Bernards likes to explain this tactic by using the analogy of a road map. On road maps, you can see that there are often several ways by which you can get from one point to another. Bernards: "Route A might be the easiest or fastest route. But if route A is blocked, you will take route B. Tumors behave in the same way: they prefer certain survival pathways. But if you block this preferred pathway, using drugs, they will switch to a different one. The trick is to not just block the preferred pathway, but also alternative ones."

After thorough research the team discovered that both lung and colon tumors with a KRAS mutation can effectively be treated with the combination of a MEK inhibitor, like selumetinib, and a drug that inhibits the proteins EGFR and ERBB2, like afatinib or dacomitinib. This combination also proved to be effective in mouse models. The discoveries of Bernards en his team are published today in the journal Cell Reports.  

Clinical Trial
The Netherlands Cancer Institute is both a research institution and a specialized cancer hospital. This enables quick translation of research outcomes to the clinic. Prof. dr. Bernards works in close collaboration with medical oncologist prof. dr. Jan Schellens. Schellens will start a clinical trial with the new combination therapy this April. He has high expectations of it. Schellens: "The individual drugs that make up this combination therapy have already been thoroughly tested. We know about their efficacy and their safety. The safety of the combination of these drugs does still have to be determined. But we believe this new therapy to be an even stronger concept than the successful combination therapy for patients with colon cancer and a BRAF mutation, which we recently developed. When I look at the strength of the biological data professor Bernards gathered, I certainly expect that this therapy will work in human patients."