RAS proteins (the name comes from "rat sarcoma virus") function as molecular switches in processes important for normal cell proliferation, migration and survival. Normally, these switches are tightly controlled and become activated only in response to specific signals. However, in some diseases such as cancer, RAS proteins become permanently switched ‘on’ and this helps tumor cells grow and metastasize.
Locked out
Many of the most aggressive and treatment-resistant tumors have RAS mutations, such as pancreatic cancer, colon cancer and non-small cell lung cancer. “RAS genes are the most commonly mutated oncogenes in cancer. These mutations are responsible for more than a million deaths per year worldwide,” explains Dr. Alan Gerber, assistant professor in the Department of Neurosurgery at Cancer Center Amsterdam.
Although the role of mutated RAS in cancer has been known for more than 40 years, the development of effective therapies has remained elusive. Finding effective drugs against cancers with RAS mutations is often referred to as the 'Holy Grail'.
A lock and key problem
“In this study, we propose a new strategy to address oncogenic RAS by looking at it as a 'lock and a key' problem,” says Dr. Gerber. When RAS is permanently switched ‘on’ due to mutations, it is in a configuration that no longer accepts the ‘off’ key.
Dr. Alan Gerber and his team have an original and ambitious strategy to bioengineer the off key – called GAP – so that it fits the mutated RAS lock and can deactivate it. “Our idea is to unleash the power of natural selection by generating enhanced GAP proteins that inactivate mutant RAS and can kill cancer cells.”
Crafting the right key
A team of researchers with various expertise plans to generate over a million modified GAP proteins, each representing a slight alteration of the structure of the 'key'. These will be introduced to the mutated ‘on’ RAS protein in a cell culture system that will allow for the selection of cells that have lost RAS activity. This strategy will eliminate cells expressing inactive modified GAP proteins. Cells that survive will, in theory, have active GAP proteins keys that can engage with and turn off the mutant RAS.
Mini-key
If active GAP proteins are identified, the structure of the modified protein will be studied in detail to understand how it is working to turn off the RAS protein. With this understanding, smaller parts of the GAP protein can be made to be tested as drug candidates (peptide-based inhibitors).
“The aim here is to obtain a peptide drug which will have the same activity as the active part of the whole GAP protein by adopting the same structure,” says Dr. Gerber. “It is also important that it does not have activity against normal RAS in normal cells.”
Unique and essential research
While the project will not immediately deliver an active human therapy agent, it will be a much needed and mandatory first step to acquire the preliminary data. This is in-line with the KWF ‘unique high-risk call’ grant category under which this project has been funded.
Dr. Gerber: “The proposed research is an essential step to pave the way for the development of new anti-cancer drugs that behave like no other tested so far."
For more information, contact Dr. Alan Gerber.