New line of attack on a dreaded disease

Few diseases are as feared, or as deadly, as glioblastoma multiforme (GBM), the most aggressive and most common form of brain cancer, which accounts for about 60 percent of all brain tumors diagnosed in the United States each year. Over the past five years, improvements in radiotherapy and surgical techniques, and the advent of drugs that block blood vessel formation in tumors have significantly increased survival time in patients with GBM. But despite these advances, on average these patients live less than one year after diagnosis.

One promising avenue for transforming the prognosis faced by GBM patients is genomic research, which can identify aberrant genes present in GBM tumors and determine how such genes vary from patient to patient. Recent genetic sequencing research on GBM has already paid dividends: four new classifications of GBM based on genomic data are guiding the development of more precisely targeted therapies, as well as personalized approaches to treatment based on the genetic makeup of a given patient’s tumor.

Last year’s launch of the Yale Center for Genomic Analysis (YCGA) placed the School of Medicine at the forefront of genomic sequencing research. Now, with a $12 million, multi-year gift from Turkish financier Mehmet Kutman, M.B.A., to launch a new Yale Program in Brain Tumor Research, researchers at Yale School of Medicine will be bringing the power of the latest genomic techniques to better understand brain tumors, with a particular focus on GBM and related illnesses.

“Mehmet Kutman’s generous support for Yale’s genomic research will spur the effort to find new treatments for patients whose lives are threatened by these brain cancers,” says Yale President Richard C. Levin.

The new program will be directed by Murat Günel, M.D., Nixdorff-German Professor of Neurosurgery at Yale and an accomplished researcher on genetic causes of brain disorders, who was the recipient of Kutman’s donation. “This gift brings unprecedented opportunities for us to extend our expertise in genomic sequencing to one of the deadliest diseases, and hopefully, to make a difference for patients,” says Günel, also professor of neurobiology and genetics and co-director of the Yale Neurogenetics Program.

“Mr. Kutman’s selection of Dr. Günel to perform these studies is a testimony to Murat’s international reputation in neuroscience. He is a gifted clinician and investigator who can use these resources to focus on the genetic basis for glioblastoma,” says Joseph M. Piepmeier, M.D., Nixdorff-German Professor of Neurosurgery and director of surgical neuro-oncology at the School of Medicine. “Under Dr. Günel’s leadership, the Yale Program on Neurogenetics is now positioned to discover effective treatment for this fatal disease.”

The gift, which was announced at a February 17 signing ceremony at Yale’s Woodbridge Hall, was made by Kutman in honor of a close friend and fellow board member at Istanbul-based Global Investment Holdings, a merchant bank with diverse interests in Turkish seaports, real estate, energy generation and distribution, and financial institutions. Kutman’s colleague is currently being treated for GBM.

“I have a great deal of confidence in both Dr. Günel and Yale School of Medicine,” says Kutman. “We hope very much to break ground in genomics- related GBM research in the near future.”

Based on this agreement, some 400 samples of brain tumors from Turkish hospitals will be delivered to Yale, a valuable research resource that will supplement the many pathological specimens already on hand at the medical school.

“In spite of much research and the application of the latest in technology, the prognosis for survival of patients with GBM is unacceptably short,” says Robert J. Alpern, M.D., Dean and Ensign Professor of Medicine. “Basic research leading to an understanding of the biology of these tumors is essential. The generous gift of Mr. Kutman will permit Murat Günel to use state-of-the-art genomics to study the molecular mechanisms responsible, thus paving the way for new treatments.”

Günel says that sequencing of GBM tumors so far, while quite productive, is incomplete. “As we work to contribute to a complete catalog of the mutations present in brain tumors, we will be able to understand individual tumors and come up with better therapies,” he says.

School of Medicine researchers at the YCGA led by Günel’s longtime mentor and colleague Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics and Howard Hughes Medical Institute investigator, have pioneered a speedy and inexpensive genomic technique known as exome sequencing, in which only those parts of the genome containing protein-coding genes are sequenced.

This approach will be valuable for studying a variety of brain tumors, says Günel, because the genomic research on other brain tumors completed by scientists so far suggests that some genes may have a major effect, and that even a single gene mutation could play a role in a large percentage of tumors. However, Günel says, it will be important to compare data from exome scans with those of the entire genome, because non-coding genomic regions are believed to play an important role in tumor formation in the brain.

Though the Yale Program in Brain Tumor Research has just been established, research on the genetic roots of GBM is already up and running at the School of Medicine, says Günel. “We’re sequencing brain tumors right now,” he says. “There’s no time. A cure cannot wait.”