Why you should care
Because cancer drugs are helping, but this could make them work even better.
Bioengineer Jennifer Cochran has always needed to keep her hands occupied. While watching TV as a kid, she remembers having to do needlepoint or sew — “anything I could be creative with,” she says. “I was a multitasker from an early age … I could never sit still.”
Not much has changed, except that now her multitasking involves overseeing Stanford University’s bioengineering department, her own laboratory and a biotech startup. And instead of turning to arts and crafts for a creative outlet, Cochran designs proteins — ones that could give a big boost to existing cancer drugs.
Cochran has engineered protein “missiles” that guide drugs to tumor cells.
Many cancer drugs, like those used in chemotherapy, flood the body — including healthy cells — triggering nausea and other unpleasant side effects. One solution has been to tether them to proteins called antibodies, which act like missiles, guiding the drugs directly to tumor cells. But antibodies are too large to penetrate dense tumors, as well as the layer of cells guarding the brain, preventing them from effectively reaching brain tumors. Cochran has engineered protein “missiles” that guide drugs to tumor cells, but are small enough to squeeze through these tight spots. They could make immunotherapy drugs, which harness the immune system to attack cancer, work better — and even be used to treat patients who don’t respond well to these drugs alone.
Cochran “is certainly one of the leaders” in engineering proteins for clinical applications, says Stefan Lutz, chair of Emory University’s chemistry department. “Her approaches are very innovative.” Jeffrey Hubbell, a professor of molecular engineering at the University of Chicago, adds that “her repertoire is very broad,” and unlike many engineers who rely on biologists to help tackle clinical problems, “she’s doing it all by herself.”
That said, although Cochran’s engineered proteins have yielded promising results in mouse studies, their effects in humans remain to be seen. “We don’t know how things will work out,” Lutz says. After all, biological systems “are highly complex.”
Cochran has short ginger hair and a cherubic face. Growing up in Newark, Delaware, she dreamed of being a musician, performing in a cappella groups and garage bands. But then she took a chemistry class at a community college, and “fell in love” — pursuing a biochemistry degree at the University of Delaware and a Ph.D. in biological chemistry from MIT. Fascinated by proteins, she stayed at MIT to conduct postdoctoral research on protein engineering.
When Cochran joined Stanford’s faculty in 2005, researchers had started to focus on knottins, a class of small, compact proteins stitched together like knots. Because they can survive harsh conditions (even boiling acid, in some cases), they seemed well-suited for one of the harshest environments of all: the human body. “What if we could use them as a scaffold to design new drugs and diagnostics?” Cochran thought. Specifically, she wondered whether she could engineer them to target tumor cells.
Knottins and other proteins that exist in nature have developed specialized functions over a billion years of evolution. Cochran wanted to engineer a type of knottin from the seeds of the squirting cucumber to have a new function — targeting integrins, proteins expressed on the surface of tumor cells in a broad array of cancer types — but without the billion-year wait. To that end, she and her lab used a technique that hit fast-forward on this process: Called directed evolution, it involved generating millions of variants of the starting knottin protein and rapidly screening them to pinpoint the ones that could tightly bind to integrins.
Cochran and her team then came up with two ways to tether a chemotherapy drug to an engineered knottin to target the delivery of the drug to tumors. The first uses an antibody fragment as the tether, while the second uses a chemical link. The researchers tried these approaches in mice and in cells growing in a dish. Both approaches have blocked the proliferation of brain, ovarian, breast and pancreatic cancer cells, including those that had developed resistance to the chemotherapy drug alone.
In 2015, Cochran and her postdoc adviser, Karl Dane Wittrup, launched a startup, Nodus Therapeutics, to develop engineered knottins for immunotherapy applications. Many immunotherapy drugs work by targeting immune checkpoints, proteins on some types of immune cells that regulate the immune response. Tumor cells can evade immune attack by exploiting these checkpoints. For instance, some tumor cells express the protein PD-L1 on their surface. When PD-L1 binds to PD-1, an immune checkpoint on disease-fighting white blood cells called T cells, it deactivates those T cells, preventing them from triggering an immune attack against cancer cells.
Antibodies that block PD-L1 and PD-1, preventing their binding and unleashing the immune system to attack tumors, have already been approved for many types of cancer, but they work only in a subset of patients. Engineered knottins may boost their efficacy, and possibly make them work in patients who don’t respond well to anti-PD-1 drugs, by amplifying the immune response. Cochran saw that treating mice with a knottin tethered to an antibody fragment, and paired with an anti-PD-1 drug, triggered a cascade of effects that ratcheted up the deployment of immune cells, including T cells, to the tumor site. The activated T cells then killed the tumor cells. Sure enough, the combination therapy resulted in a higher survival rate than anti-PD-1 antibodies alone, and in some cases eradicated disease. What’s more, when Cochran exposed the cured mice to tumor cells, they didn’t develop cancer, indicating their immune systems had “remembered” to attack the tumor cells.
Cochran hopes to launch clinical trials of this combination therapy early next year. She has also tested engineered knottins with other drugs that target immune checkpoints in mice, with similarly encouraging results.
“These products are, in a sense, my babies,” Cochran says. “Being able to help shepherd them to be developed for patients has been a passion.” Sure, it keeps her hands busy — and she wouldn’t have it any other way.