A microscopy image of an ovarian adenocarcinoma. MIT researchers have found a new way to disrupt a protein often overexpressed in ovarian tumors, known as HER3. Image: Nikon Microscopy |
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 HER3.
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 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 re-growth, 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.'”
Targeting vulnerability
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.
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.
