The UCI professor’s lab uses novel techniques to destroy cancer cells by targeting their metabolism.
Each year, millions of people die from cancers of all types and many millions more are diagnosed. For decades, researchers have worked tirelessly to find ways to slow or stop the growth of cancer with varying success, depending on the type of cancer. And because there are so many forms of cancer, there is no one-size-fits-all approach.
Unless of course one could target a universal aspect of cancer cells. Aimee Edinger, UC Irvine (UCI) professor of developmental and cell biology in the School of Biological Sciences, is doing just that by targeting a process that occurs in every living organism: metabolism.
CALIFORNIA TO PENN AND BACK AGAIN
Before Edinger was unlocking the secrets of metabolism for cancer therapies, her interest was in medicine, which led her to UC Davis for undergraduate studies where she began a trajectory toward veterinary school.
It was there, as a pre-vet student, that Edinger was first exposed to research, becoming involved in a project that explored the physiological effects of altitude on horses and another that looked into the biological mechanisms that allow mammals to generate heat while they hibernate.
Then, after learning that the National Institutes of Health-sponsored medical scientist training program at the University of Pennsylvania (Penn) also supports veterinarians, Edinger went on to Penn to earn a doctorate of veterinary medicine and a Ph.D. in microbiology.
As a thesis student at Penn, Edinger worked to develop human immunodeficiency virus (HIV) vaccines, later conducting postdoctoral work on cancer metabolism, which is now the primary focus of the Edinger Lab at UCI.
The Edinger Lab, however, views cancer metabolism through a different lens than the average researcher.
“What distinguishes what we do from a lot of what other people in this space do, is we’re really cell biologists, and a lot of people who work on cancer metabolism are biochemists,” said Edinger. “So when you study cancer metabolism as a biochemist, you’re looking at enzyme activity – the chemical reactions that change metabolites into the building blocks of cells. We study how membranes and vesicles and organelles move around the cell and how this intracellular traffic affects metabolite availability.”
Part of the lab’s success, according to Edinger, comes from combining their cell biology expertise with that of scientific collaborators from different disciplines, an approach that has laid the groundwork to develop novel approaches to cancer therapy.
Such approaches include looking at ways to stop macropinocytosis – the indiscriminate engulfment of material in the tumor microenvironment by cancer cells as a means of nutrient scavenging – and using interesting molecules called sphingolipids to target multiple nutrient uptake pathways simultaneously.
RIDDLE OF THE SPHINGOLIPIDS
In their search for new cancer therapies, Edinger and team learned important lessons from yeast cells.
“Yeast are kind of like cancer cells in that they are trying to grow as fast as they can in a manner that is every cell for itself,” said Edinger.
The tricks yeast use to survive in the wild focused their attention on sphingolipids, molecules named after the sphinx because of their enigmatic nature. These molecules slow down nutrient uptake into yeast cells to induce a state similar to hibernation when cells are under stress. The hope was to evoke the same hibernation response in normal human cells. While a state of hibernation can protect normal cells from stress, cancer cells cannot simply turn down their revved up metabolism. Unable to cope with the reduced nutrient levels by slowing their growth and reducing nutrient demand, cancer cells starve to death.
“As Napoleon once said, ‘an army marches on its stomach.’ So if you want to stop cancer in its tracks, you take away its fuel. Attack the supply wagons. It’s just kind of common sense,” said Edinger.
To translate this effect from yeast cells to cancer cells, the Edinger Lab collaborated with Stephen Hanessian – synthetic and medicinal chemist and UCI Distinguished Professor of Chemistry, Pharmaceutical Sciences and Pharmacology – and his medicinal chemistry group to develop a drug-like compound named SH-BC-893 to mimic the naturally occurring molecules and starve perpetually ravenous cancer cells to death.
This new compound turned out to deliver a one-two punch. It not only prevents nutrients from entering cells, but also disables the cancer cell’s ability to generate nutrients from macromolecules via digestion. This combination of preventing cancer cells from accessing extracellular or intracellular nutrient sources has proved to be effective in petri dishes and in mice and does not negatively affect organ function.
In 2017, Edinger and team were awarded funds through the UCI Beall Applied Innovation Proof of Product (POP) Grants program to further their research with the drug-like compound. The funds allowed them to answer vital questions about the compound as well as retain critical lab staff.
“The most expensive thing in research is personnel, and it’s even more expensive to lose people with deep knowledge of the project,” said Edinger. “My postdoc, at that point, had been in my lab for six years and had been working on this project from the very beginning. To lose her to another lab or company would have been catastrophic.”
Edinger and her collaborators felt their cancer therapy had promise, so they decided to translate the findings into a startup.
SIEGE PHARMACEUTICALS
Edinger and Hanessian started Siege Pharmaceuticals to take SH-BC-893 from the lab to the public, where they hope to make a difference for cancer patients.
Siege Pharmaceuticals, though still in its infancy, has hit a number of milestones, such as securing Series A funding from an investor they met through Applied Innovation.
The startup also applied for a Small Business Innovation Research (SBIR) grant, receiving valuable feedback from consultants at the Small Business Development Center @ UCI Beall Applied Innovation, who helped the team transition from writing grants with academic goals to writing grants that had more business-oriented goals.
“[It] really helped us prioritize what is going to move the needle as a company,” said Edinger. “Understanding the next best step and the key milestones to hit in order to get to that next step is crucial.”
Siege Pharmaceuticals is currently leasing wet lab space through University Lab Partners – an Applied Innovation ecosystem partner, located at the Cove @ UCI – where they continue their work of moving SH-BC-893 closer to clinical trials and Food and Drug Administration approval.
EXTRACELLULAR ACTIVITIES
When Edinger is not busy spending time with family, teaching, researching novel approaches to cancer therapies and working on Siege Pharmaceuticals, she also serves as the equity advisor for the School of Biological Sciences. It’s through this appointment that Edinger raises awareness of best practices for promoting faculty diversity and inclusion, and shares insights on how to be more mindful on and off campus.
“Just because people are biased doesn’t mean they’re the enemy. Implicit biases – those that are subconscious – aren’t our fault. Everyone has implicit biases, myself included. Understanding the problem is always the first step,” said Edinger. “The nonprofit Project Implicit has free online tests that can help us identify our biases and take steps to counteract them.”
Learn more about the Edinger Lab.
Photos: Daniel Xu and Amy Vong