Life-or-death verdicts in cancer often result from the ways microscopic kinks and folds in proteins fit together within a tumor cell. While in college, Trever Bivona, MD, PhD, was fascinated by the idea that a single protein’s twists could determine the trajectory of the disease.
Making the connections between molecules in the lab and their actions in a patient’s cancer led him to pursue both doctoral and medical training. Now a practicing oncologist and researcher at UC San Francisco, Bivona’s studies are driven by a simple question: Which protein mutations are relevant to actually improving treatments?
To Bivona, the answer lies on a two-way street – taking mysteries from patients’ cells into the lab, where advanced genomic technologies have made molecular data easier than ever to obtain, and asking basic science questions that could lead to clinical improvements.
“Even in the time I’ve been in clinical practice, there’s been a huge increase in the amount of information translated into the clinic,” says Bivona, an associate professor of Hematology and Oncology and member of the UCSF Helen Diller Family Comprehensive Cancer Center. “But we’re not doing enough to help our patients yet.”
Filling Signaling Gaps
In a recent Nature Medicine paper, Bivona’s lab homed in on a form of malignant lung cancer that stems from a gene fusion, where the EML4 and ALK genes get squished together in a tumor-triggering conformation. The ALK gene is a critical target to treat these cancers – block it with inhibitors, and the tumor shrinks.
“Treatments that target ALK are better than standard chemotherapy, but it’s a temporary benefit,” Bivona says. “Within about a year, the tumors grow back even more virulent in almost every patient.”
Researchers began the study to identify ALK’s molecular accomplices within tumor cells. Looking for connections, the team used cell lines derived from patients’ tumors and individually examined several signaling molecules potentially triggered by the ALK mutation. These included pathways such as JAK-STAT, PI3K, and RAS-MAPK, all of which are known to be generally important in different cancers.
Much to their surprise, blocking the RAS-MAPK pathway was just as good as blocking the oncogene itself. “Modulating many other typically cancer-linked pathways did not have the same effect,” Bivona says. “This was a specific role of this particular pathway in this particular cancer context.”
The study demonstrates that it’s crucial to understand which signaling routes are most important in specific cancer types, Bivona says.
Armed with their cell line data, the group is now focused on a new clinical possibility: Could targeting the RAS-MAPK pathway in addition to ALK lead to better treatments, or at least longer remission times, in patients? It’s a question Bivona hopes to address with a clinical trial scheduled to launch later this year.
Building Better Bridges
Working with patients has served as a personal motivator when experiments fail or research hypotheses don’t pan out. When faced with research setbacks, he’s learned to double down – perhaps due to his clinical training.
“Oncology’s hard – so many patients die. If I were to give up after every failure. I’d go home after every patient,” he says. “But I’ve learned to use failure as motivation to do better.”
His impatience with the pace of discovery is paying off. In 2012, Bivona was awarded one of 51 prestigious National Institutes of Health (NIH) Director’s New Innovator awards for high-risk, high-reward research. The research accolades have continued: In December 2015, he was inducted as a member of the American Society for Clinical Investigation.
This week, Bivona’s research received further funding support from UCSF’s inaugural Marcus Program in Precision Medicine Innovation grants. As part of these projects, Bivona and his colleagues aim to transform cancer-driving mutations into targets that can be treated with drugs or other therapies.
But the research breakthroughs are only a stepping stone – albeit a crucial one – towards more tailored cancer treatments, Bivona says. The truest metrics of success lie in the clinic. “The answer will be in the clinical trial and ultimately we’ll be judged on whether we help patients or not.”
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