Peter Walter
The discovery of a basic life-and-death response within our bodies’ cells might prove to be the basis for a new cancer-fighting strategy. That’s the premise behind a new $4 million award from the Howard Hughes Medical Institute (HHMI) to an all-star team of researchers headed by Peter Walter, PhD, an HHMI investigator at UCSF.
Walter’s study of ways to use chemistry to identify and make possible magic-bullet molecules to target this life-or-death cellular response in cancer cells is one of eight projects funded by the HHMI from among 62 proposals submitted.
Participation in the research is not limited to HHMI investigators or even to UCSF experts. According to an HHMI statement, “The Collaborative Innovation Awards represent a shift for HHMI because they represent the first time the Institute will provide direct funding for specific research projects. They are intended to encourage both HHMI investigators and scientists outside HHMI to undertake projects that are new and so large in scope that they require a team of collaborators with a range of expertise.”
The research team includes UCSF researchers Frank McCormick, PhD, director of the UCSF Helen Diller Family Comprehensive Cancer Center; Jim Wells, PhD, director of the Small Molecule Discovery Center, which aims to find molecules that modify biological processes that are important in health and disease; Kevan Shokat, PhD, one the world’s foremost experts on the class of enzymes that are the focus both of this study and of recent pharmaceutical industry efforts to develop new cancer drugs; and Marc Shuman, MD, clinical director of the California Institute for Quantitative Biosciences and a physician-scientist focused on translating basic research into clinical application.
The team also includes Sebastián Bernales, PhD, from the Fundación Ciencia para la Vida, in Santiago, Chile, who will screen the researchers’ molecules for potential usefulness.
Walter discovered a key network of biochemical pathways within cells that sometimes trigger cellular suicide. This orchestrated chain of events helps cells cope when they have trouble keeping up with the body’s demands on them to make the many proteins used in signaling between cells. Walter identified key enzymes within the biochemical pathways that go into action when the cell can’t maintain the assembly line that folds these proteins into proper shape.
If all goes well, the enzymes responsible for this “unfolded protein response” help the cell recover and deliver properly folded proteins. If not, the cell may be goaded into killing itself for the greater good.
Now there is evidence that some cancer cells may develop abnormalities within the unfolded protein response that help them meet their supercharged needs for proteins to keep up with their out-of-control growth. The best evidence for this is in multiple myeloma, a cancer of the immune cells of the blood. But it might also play a role in breast cancer and other cancers, Walter says.
There are actually three branches in the unfolded protein response pathway, Walter says. “The different branches turn on and off at different times. Some are more protective, helping cells to reestablish quality control in protein folding and bringing the system back into a state of happiness. If this cannot be achieved, other parts of the pathway play a more important role in triggering cell death.”
One possible treatment strategy is to tip the balance, favoring cellular suicide in cancer cells but not in normal cells. The researchers may also explore other strategies geared toward taking away the growth advantage of cancer cells.
The HHMI-funded researchers are not in the business of drug development, but they want to be able to make a convincing case for further exploring any new treatment strategies. “What we are trying to do is establish proof of principle,” Walter says.
