New strategy sees therapy ‘stiffening’ cancer cells and limiting mobility.
Existing cancer therapies are geared toward killing tumour cells, but Johns Hopkins researchers propose a different strategy, subtly hardening cancer cells to prevent them from invading new areas of the body. They devised a way of screening compounds for the desired effect and have identified a compound that shows promise in fighting pancreatic cancer. The study is published the Proceedings of the National Academy of Sciences.
The team state that this novel approach to cancer therapy could fight the disease with less potential for side effects and drug resistance than many current drugs. With the new screening system devised by the team helping to identify drugs for many other diseases, as well.
The roots of the project go back to 1997, when the team investigated whether better understanding how a cell divides into two would shed light on how cells change shape in general. Since changes in cell shape figure into conditions from cancer to chronic obstructive pulmonary disease to degenerative nerve diseases, compounds that affect cells shape could turn out to stall disease progress.
In 2008 the laboratory began working on a screen for molecules that tweak cell shape. Most drug screens look for an effect on a specific biochemical pathway that has been linked to disease; by contrast, the team’s novel screen is based on the end result for a whole cell, in this case the amoeba Dictyostelium, which closely resembles a number of mammalian cell types.
After treating the cells with a molecule, the team looked for out-of-the-ordinary numbers of cells with two or more nuclei. Since Dictyostelium normally have two nuclei only when they are in the process of dividing into two daughter cells, a high proportion of cells with more than one nucleus would indicate that the molecule had thrown a wrench in the process of cell division, likely by tweaking the mechanics of the cell skeleton.
A screen of thousands of molecules turned up 25 with the effect the team was looking for. Further studies revealed that one of them, 4-HAP, affected myosin II, a building block of the cell skeleton. The current study identified changes in the amount of myosin II in pancreatic cancer cells as they spread from the original tumour into other areas of the body, a crucial step in progression of the disease.
The team tested 4-HAP on lab-grown pancreatic cancer cells and found that it affected the myosin in their skeletons in a way that made them harder. The team summise that being relatively soft lets invading cancer cells slip through the body and colonize new areas.
The team is now testing 4-HAP in mice. The drug is already in use in some countries as a treatment for jaundice, so if it shows success against pancreatic cancer, it could potentially make it to market relatively quickly. But even if that doesn’t happen, the study demonstrates that the new drug screen has great potential.
Source: Johns Hopkins Medicine