Chemotherapy attacks cancer by killing cells that are rapidly dividing. But this leads to serious side effects, like intestinal upset and hair loss, because some normal cells also grow quickly.
So researchers like Jennifer Cochran, PhD, a professor and the chair of bioengineering at Stanford, are developing more targeted cancer therapies, dubbed “guided missiles.” She recently described her work to professor and radio show host Russ Altman, MD, PhD, on an episode of the radio show The Future of Everything.
“We, and others, have developed novel proteins that can selectively target cancer cells and then we can attach cargo to them — this is where the missile analogy comes in,” Cochran told Altman. “The cargo that we attach, things like chemotherapy, can then be selectively targeted to the tumor.” The idea is to precisely deliver to the tumor a more poisonous dose than you could deliver systemically, she said.
One way to do this is to bioengineer antibodies, which are molecules that recognize and help neutralize foreign substances like bacteria. However, Cochran’s lab took a slightly different approach. She explained to Altman:
As amazing as antibodies are, they can have some limitations in that they are very large in terms of molecular size so they have trouble wiggling into a tumor. So we’ve created smaller versions of tumor-targeting proteins that can hopefully penetrate into tumors better. And we’ve then chemically attached chemotherapy molecules to deliver a punch to the cancer cells.
In order to develop these proteins, her team is expediting protein evolution in a test tube — making favorable properties that would normally evolve over millions of years happen in just a few weeks. To do this, the team uses genetic manipulation to create millions of slightly different protein variants, tests them with high-throughput screening in just a few hours, identifies the ones most desirable for a certain task, and then determines these variants’ DNA sequences.
For example, they used this evolutionary process on a peptide, a small fragment of protein, from the seeds of a plant known as a squirting cucumber to turn the molecule into a favorable drug scaffold. “We ran the protein through this evolution process to create a tumor-targeting protein that we then hooked the chemotherapy agents on to,” said Cochran.
Cochran’s group is also investigating immunotherapy applications for her proteins. She is teaming up with Dane Wittrup, PhD, a professor in chemical engineering and biological engineering at Massachusetts Institute of Technology, who has developed new ways to use the immune system. By combining Cochran’s tumor-targeting technology with Wittrup’s insights into immunotherapy, they are able to give a “one-two punch” and activate multiple factors of the immune system to more effectively attack cancer, she said.
Her research team is also interested in applying their work to other diseases. As she told Altman:
We’ve been applying them for cancer, but you can use the same approach to deliver therapies to other types of disease tissue. We have really only just scratched the surface of what we can do. A big driver of this has been the interdisciplinary culture of collaborative research at Stanford. We’ve been working together with physicians, clinicians, scientists, engineers and physicists to tackle really challenging problems.
Cochran's bioengineered proteins are not yet available to patients. However, some tumor-targeting molecules are already approved by the U.S. Food and Drug Administration and many more are in the pipeline. “There are a number of molecules that are FDA approved and you might have heard commercials for them,” she told Altman. “But they only work for a subset of patients. So the question is: how do we make them work better for a larger subset of patients?”
Photo by Allocer