Evolutionary approach to cancer treatment

The existence of cancer is based on a fundamental process that occurs in an organism: cell division. A tumor cell breaks the rules of cell division that other cells follow. Cancer can only grow this way if some of the tumor suppressor genes – such as the p53 gene – get mutated in the cancer cells. Then, some corrupt cells do not get fixed. Over time, one of these cells can grow and divide into thousands, then tens of thousands of cancer cells. Eventually there may even be billions of cells in a tumor.

Developmental biologist Timothy Weil of the University of Cambridge in the UK says, “It is like they are a different organism. The better that cell gets at dividing faster than its neighbours and gaining nutrients, the more likely it will survive and grow.”

Cancer cells are far from being all alike. Whenever a cancerous cell divides, it can pick up new mutations that affect its behaviour. In other words, they evolve.

Just like individual species – humans, other mammals, frogs, even bacteria – gain genetic variation over time, so do cancer cells. “Tumors evolve in a branched evolutionary manner, which means that no two cells in a tumor are the same”, says Charles Swanton of the Francis Crick Institute in the UK. As a result, the cells of a tumor are evolving to become more cancerous. The fact that tumors are constantly changing is one of the reasons why cancers are so hard to kill. It is for this reason that Swanton, and others in the field, take an evolutionary approach to tackling cancer.

The evolution that goes on in cancer can be pictured as a tree with many branches. At the base of the tree are the original mutations that triggered the tumor in the first place: mutations that should be shared by all of the cancer cells in the tumor. In theory, a therapy that targets one of those base mutations should destroy every one of them. However, these therapies do not work as well as we might hope. Even with them, resistance often appears over time.

“It occurs because there will be one or more cells in the tumor branches that has a resistance mutation that allows it to outwit the therapy,” Swanton says. This means, some of the branches of the cancer tree have evolved in a way that makes them less vulnerable to attack through the base mutation.

But what if a therapy targeted two of those basal mutations at the same time? Swanton and his colleagues investigated how many base mutations in the cancer “trunk” they would have to target simultaneously to ensure that they could successfully destroy all of the cancer cells. Three was the magic number. Their calculations suggest that targeting three base mutations at the same time will “chop the trunk down” and destroy every single cell in the tumor.

Cancer researcher Alberto Bardelli of the University of Turin in Italy has also been inspired by evolutionary theory for a potential solution to overcoming drug resistance.

He begins by giving patients a particular drug therapy and then monitoring them to see when a particular cancerous “clone” rises to dominance in the tumor because it has developed drug resistance.

Then Bardelli stops treating the cancer with the drug. This removes the evolutionary pressure that allowed the clone to become so successful. Without that pressure, other types of cancer cell in the tumor also have a chance to flourish. When some of those other clones have gained ground, it is time to administer the drugs again, as these new clones should not yet have developed resistance. Bardelli calls it “the war of clones”.

For now we do not know if this tactic will work or not. Bardelli’s team is starting a clinical trial in the summer of 2016.