CAMBRIDGE, Mass.—In a recent study, researchers at theMassachusetts Institute of Technology (MIT) and Brigham and Women's Hospitalfocused on another pivotal way to fight cancer: HER3, a receptor and a protein thatspreads the signals that cause cancer cells to continually and abnormally growand replicate. By shutting off this protein, the researchers found that cell division in cancerous cellscould be slowed or stopped completely.
Related receptors, such as EGFR and HER2, are well-known andalready used in cancer treatment, and early-stage trials have started to lookat antibodies that directly target HER3. The receptor is often involved inovarian and pancreatic cancer, which MIT Professor Linda Griffith, who led theresearch team with Harvard Stem Cell Institute and Brigham and Women'scardiologist Richard Lee, says is one factor that has researchers so interestedin the receptor.
The study originated in a regenerative-medicine project byco-first author Luis Alvarez, who received his Ph.D. from MIT. Alvarezdeveloped a series of paired proteins in his search to promote bone re-growth,ones that researchers thought might have the ability promote interactionsbetween HER3 and EGFR, both of which are growth receptors. When the researchersnoticed that the proteins seemed to shut off cell growth and migration, theyused the proteins on cancer cells, which caused the cells to stop growing and,in some cases, die.
"It was not something we were expecting to see — you don'texpect to shut off a receptor with something that normally activates it — butin retrospect it seemed obvious to try this approach for HER3," Griffith, theSchool of Engineering Professor of Innovative Teaching in MIT's Department ofBiological Engineering and director of the Center for Gynepathology Research,said in a press release. "We pursued it only because we had people in the labworking with cancer cells, and we thought, 'Since it had these effects in stemcells, let's just try this in tumor cells, and see if something interestinghappens.'"
Cancer cell division and replication is rife with problems.Whereas normal cells will stop division if they detect DNA damage, or willundergo apoptosis, or cell death, cancer cells continue to divide andreplicate, a condition known as hyperplasia. When these cells replicate,creating daughter cells with damaged or abnormal DNA, which will also grow anddivide more often than normal, it is known as dysplasia. Additionally, cancercells do not exhibit contact inhibition, as the CancerQuest website explains,which leads to the formation of tumors. Cancer cells reproduce without thenormal external signals, which CancerQuest, an education program at EmoryUniversity, likens to "a car moving without having pressure applied to the gaspedal." The cells, aided by HER3, can reproduce without the usual need forexternal signaling.
The MIT protein works by disrupting HER3's connection with HER2,which cripples HER3 since it has to pair with another receptor, usuallyHER2, to send out growth signals to the rest of the cell. The protein is afused pair of neuregulin molecules, and while single molecules usuallystimulate the HER3 receptor, paired neuregulin molecules bind two adjacent HER3receptors, which blocks them from binding with the HER2 receptors as needed.
In six different kinds of cancer cells in which HER3 isoverexpressed, the protein worked to shut off growth in each one, even in atype resistant to drugs targeting the EGFR receptor.
The next step for the protein is to develop a version moresuited to being tested in living animals, a task the MIT and Brigham andWomen's team is already working on. Testing will be undertaken under theleadership of Steven Jay, co-first author of the paper and a joint MIT/Brighamand Women's postdoc. MIT postdoc Elma Kurtagic and graduate student Seymour dePicciotto are also first authors of the paper, which was published online May26, 2011 in The Journal of Biological Chemistry.
SOURCE: MIT press release
