Using a technique known as directed evolution, Stanford researchers have created an engineered protein that prevented the spread of cancer and thus halted disease progression in mice. These promising early results suggest that one day, this new therapy could be used as a safer, more effective alternative to chemotherapy. The study can be found in Nature Chemical Biology.
After tumors develop in the body, cancer cells can break away from this primary site and spread to other areas or organs, forming new, or secondary, tumors. This process, which is known as metastasis, is actually responsible for around 90% of human cancer deaths. There are numerous drugs available that are designed to stop this from happening, but unfortunately they are not very effective and many have serious side effects that limit their usefulness. Stanford scientists therefore wanted to find a new, safer way to inhibit metastasis, so they turned to proteins.
A few years ago, scientists discovered a receptor called Axl that is thought to play a critical role in metastasis. When Axl’s partner, a protein called Gas6, binds, a wave of signals are generated that ultimately allow the cancer cell to escape the original tumor site and spread to other body areas. The Stanford team therefore wondered whether preventing Axl and Gas6 from interacting could thwart metastasis, so they engineered a decoy version of Axl. This new protein was found to tightly bind to Gas6 in the lab, blocking it from latching on to the normal version of Axl present on cancer cells and therefore inhibiting the metastatic signals from being generated. The decoy Axl was so potent that it actually bound to Gas6 around 100 fold more effectively than natural Axl.
To create this engineered protein, the researchers adopted a technique known as directed evolution. Directed evolution mimics natural evolution in the test tube to rapidly mutate, or evolve, proteins towards a desired property or function. Darwinian evolution occurs very slowly in nature, but scientists can rapidly speed up the process using genetic manipulation. They started off by generating over 10 million slightly different DNA sequences for the Axl protein, each one coding for an altered version of the protein.
Next, they screened each of these mutants to see which ones were best at binding to Gas6. After selecting the best candidate, they made a few other final alterations to improve its longevity in the bloodstream and further increase its affinity for Gas6. The team then ended up with a protein that bound so tightly to Gas6 that the interaction was virtually irreversible.
The team then administered their designer protein to mice with aggressive breast and ovarian cancers in the lab and it was found to potently prevent metastasis and halt disease progression. Mice with breast cancer that received the treatment had 78% less metastases than those in the control group, and those with ovarian cancer had 80% fewer. Furthermore, the protein was found to be nontoxic to the animals.
Because these preliminary results are so promising, the researchers will now conduct further animal studies to ensure its safety and efficacy before applying for approval for human trials. They will also need to discover a way to scale up production as currently they can only produce the protein in small quantities.