Linda Griffith - Turning off cancer's growth signals
Biological engineers’ new approach to shutting down cell division could lead to new cancer drugs.
Anne Trafton, MIT News Office
June 8, 2011
One hallmark of cancer cells is uncontrollable
growth, provoked by inappropriate signals that
instruct the cells to keep dividing. Researchers at
MIT and Brigham and Women’s Hospital have now
identified a new way to shut off one of the proteins
that spreads those signals — a receptor known as
Drugs that interfere with HER3’s better-known
cousins, EGFR and HER2, have already proven
effective in treating many types of cancer, and
early-stage clinical trials are underway with
antibodies directed against HER3. HER3 is of great
interest to cancer biologists because it is commonly involved in two of the deadliest forms of the disease, ovarian
and pancreatic cancer, says MIT Professor Linda Griffith, who led the research team with Harvard Stem Cell
Institute and Brigham and Women’s cardiologist Richard Lee.
The study, published online May 26 in the Journal of Biological Chemistry, resulted from a serendipitous finding in
a regenerative-medicine project. Co-first author Luis Alvarez, who earned his PhD from MIT during a three-year
leave from the Army, was interested in regenerative medicine because he knew many soldiers who had been
wounded in Iraq and Afghanistan.
While looking for ways to promote bone regrowth, Alvarez developed a series of paired proteins that the
researchers thought might promote interactions between growth receptors such as HER3 and EGFR to control
growth and differentiation.
Alvarez’s proteins had some impact on regeneration, but the researchers also noticed that in some cases, they
appeared to shut off cell growth and migration. Alvarez and others in Griffith’s lab decided to see what would
happen if they treated cancer cells with the protein. To their surprise, they found that the cells stopping growing,
and in some cases died.
“It was not something we were expecting to see — you don’t expect to shut off a receptor with something that
normally activates it — but in retrospect it seemed obvious to try this approach for HER3,” says Griffith, the
School of Engineering Professor of Innovative Teaching in MIT’s Department of Biological Engineering and
director of the Center for Gynepathology Research. “We pursued it only because we had people in the lab
working with cancer cells, and we thought, ‘Since it had these effects in stem cells, let’s just try this in tumor cells,
and see if something interesting happens.’”
Around the same time, Griffith developed a personal interest in this family of cell receptors: She was diagnosed
with a form of breast cancer that often overexpresses the receptor EGFR.
EGFR has received much attention from biologists — the cancer drugs Erbitux, Iressa and Tarceva all target it —
but not all cancers that overexpress the EGFR respond to targeted therapies. The first highly successful targeted chemotherapy, Herceptin, goes after another member of the family, the HER2 receptor.
The new MIT protein targets a specific vulnerability of HER3: To convey its growth-stimulating signals to the rest
of the cell, HER3 must pair up with another receptor, usually HER2.
The new protein, which consists of a fused pair of neuregulin molecules, disrupts that pairing. Single molecules of
neuregulin normally stimulate the HER3 receptor, promoting cell growth and differentiation. However, when the
paired neuregulin is given to cells, it binds together two adjacent HER3 receptors, preventing them from
interacting with the HER2 receptors they need to send their signals.
The researchers tested the molecule in six different types of cancer cells that overexpress HER3, and found that
it effectively shut off growth in all of them, including a cell type that is resistant to drugs that target EGFR.
Mark Moasser, a professor of oncology at the University of California at San Francisco, described the new
technique as clever and elegant, adding that more experiments are needed to determine if it will be effective in
living organisms. “Based on the mechanism, it has potential, and it lays the groundwork for a lot of future work,”
says Moasser, who was not involved in this study.
The MIT and Brigham and Women’s team is now working on a new version of the molecule that would be more
suited to tests in living animals. They plan to undertake such testing soon under the leadership of Steven Jay, a
joint MIT/Brigham and Women’s postdoc and co-first author of the new paper. MIT postdoc Elma Kurtagic and
graduate student Seymour de Picciotto are also first authors of the paper.