ӳ����ý

Researchers developed a new technique that uses different colored beads to detect abnormally active proteins in patient tumors. The technique helped them pinpoint a new potential drug target in brain cancer.
Image courtesy of Sigrid Hart, ӳ����ý Communications

Glioblastoma (GBM) is an aggressive type of brain tumor whose cells entwine brain tissue, making curative surgery nearly impossible. Radiation and chemotherapy offer little help in controlling the spread of the disease. Scientists at the ӳ����ý of MIT and Harvard and the Dana-Farber Cancer Institute are hunting for novel therapeutic approaches to treat these as well as myriad other tumors by dissecting the course of molecular events that lead to cancer. The researchers, led by ӳ����ý Cancer Program director Todd Golub, developed a new screening technique that enabled them to detect a key protein, a type of tyrosine kinase, whose activation underlies the growth and spread of GBM. Although first applied to brain cancer, the method holds promise for unearthing similar players in a wide range of cancers.

“Many of the molecular abnormalities that drive cancers are evident not at the DNA level, but at the protein level,” said Todd Golub, who is also the Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute and an investigator at the Howard Hughes Medical Institute. “We have developed a robust and inexpensive way to rapidly discover these changes in a key class of proteins across a variety of human cancers.”

Jinyan Du, a research fellow in Golub’s laboratory at Dana-Farber Cancer Institute and at the ӳ����ý, said that she and her colleagues chose to first apply this new method to GBM because of its lethality and the current lack of treatment options. “GBM is a unique example of a cancer where there is a locally invasive tumor, but it is very, very deadly,” she said. The researchers’ new understanding not only helps lay bare one of the molecular events that leads to tumor growth, involving a key protein called SRC, it may also open the door to a new approach to treatment.

SRC is a tyrosine kinase, a special type of protein that can be turned on or off like a light switch. Based on the central roles that these proteins are known to play in some cancers, Du and her colleagues were interested in detecting tyrosine kinases that were being switched on abnormally in GBM patients. To screen for these activated proteins, the researchers developed an innovative assay known as a “multiplex immunosandwich assay” based on the Luminex technology. On one side of the sandwich are 100 colored beads, each assigned a unique color and adorned with an antibody that captures a specific tyrosine kinase. On the other side is an “all-purpose” antibody that can detect the level of activation in any tyrosine kinase. The researchers combine these two halves together with tumor material from patients, allowing them to read which kinases are active. By applying this sandwich approach to GBM, the researchers could see that SRC was active in roughly 60% of patients.

Remarkably, when Du and her colleagues treated GBM cells in the laboratory with dasatinib, a drug that inhibits SRC activity, the growth of cancer cells decreased and the drug prevented cell migration. The researchers also used dasatinib to treat mice with glioblastoma and found that the drug significantly reduced tumor growth.

These promising results may ultimately spur clinical trials in humans, but first Du hopes to find clinically useful indicators of dasatinib response. This way, only patients who will respond to dasatinib — those with active SRC — will be prescribed the treatment.

Du explained that one of the reasons they were able to detect the new target was because their approach focuses on the level of active protein rather than the genetic mutations that may be causing it. “There are so many ways to end up with aberrant kinase activation. You won’t find all of them if you look only at the DNA sequence,” she said. “Using our approach, you can look at activated protein levels directly.”

Detecting the events that lead to SRC activation could help researchers develop additional treatment options, but for now, Du hopes that their discovery might offer one treatment method for at least some patients with an otherwise incurable disease. More broadly, by devising an experimental approach that can be readily applied to any type of cancer, she and her colleagues may have also laid the groundwork for therapeutic insights in other diseases.

Other ӳ����ý researchers contributing to this work include Paula Bernasconi, Rameen Beroukhim, Melissa Burns, Karl R. Clauser, DR Mani, Xiao P. Peng, Bina Julian, Haley Hieronymus, Rebecca L. Maglathlin, Timothy A Lewis, and Steven A Carr. Researchers at other institutes including Dana Farber Cancer Institute, Harvard Medical School, Howard Hughes Medical Institute, Brigham and Women’s Hospital, Memorial Sloan-Kettering Cancer Center, Massachusetts General Hospital, and the David Geffen School of Medicine also contributed to this research.