Researchers at the Brain Tumor Center at the University of Cincinnati Neuroscience Institute are zeroing in on noninvasive biomarkers that may soon help guide doctors’ treatment of the malignant brain tumor glioblastoma multiforme. The novel translational research, led by El Mustapha Bahassi, PhD, Research Assistant Professor of Medicine, in collaboration with Peter Stambrook, PhD, Professor in the Department of Molecular Genetics, Biochemistry and Microbiology, focuses on DNA that breaks off from the tumor and cycles through the bloodstream.

The research, begun as a pilot study that also involved the UC Cancer Institute, was funded by UC and small foundation grants from the Mayfield Education & Research Foundation, the Shemenski Foundation and the LCS/Sahlfeld Foundation. The research kicked into a higher gear last week with the awarding of a $100,000 grant from the Center for Clinical and Translational Science Training (CCTST) and an additional $35,000 gift from the Shemenski Foundation.

During the pilot study, Dr. Bahassi and his team¹ sequenced the genomes of glioblastoma tumors that were surgically removed from 10 study participants. In a major innovation, the Cincinnati team then sought to identify genetic abnormalities in individual tumors and to follow those abnormalities through the bloodstream by taking simple blood tests.

The researchers established preliminary evidence that by sequencing an individual’s tumor and tracking the tumor’s DNA through the blood, they could enable doctors to address three significant challenges posed by the aggressive cancer. Specifically, they could help doctors:

• Determine the sub-type of glioblastoma and the patient’s prognosis;
• Determine whether the tumor had recurred; and
• Determine whether indeterminate markings on MRI scans following treatment were a sign of necrosis or tumor recurrence.

In the future, Dr. Bahassi hopes that determination of the glioblastoma sub-type will also enable doctors to provide patients with individualized treatments rather than the current one-size-fits-all constellation of therapies that are currently available.

“Brain tumors in general, and glioblastoma in particular, are diseases of the genes,” Dr. Bahassi said. “We have come to appreciate that every tumor is different; every patient is different; and therefore, the cookie-cutter method of treatment is not working, and we need to find another way to do it. There is a need for personalized treatments or individualized therapies. The way we will accomplish this is through whole-genome sequencing of the tumor. We will find out everything about a tumor and then tailor the treatment to that tumor.”

The research is of critical importance, because approximately 10,000 people are diagnosed with glioblastoma annually in the United States alone. Glioblastoma presents special problems for doctors because it is not solid and cannot be removed in one clean piece. The tumor is diffuse and infiltrative, and individual cells tend to survive surgery, radiation and traditional chemotherapy. As a result, the tumor often grows back near the site of the initial mass.

In sequencing the ten glioblastoma tumors in the pilot study, at a cost of $2,300 per tumor, the team identified genomic defects that lead to glioblastoma, including:

• Duplications on chromosome 7, meaning that the patient has more copies of the chromosome than he needs. This is the home of the EGFR receptor, which can lead to amplified cell division and cancer.
• Deletions on chromosome 9, meaning that the patient has fewer copies than normal. This is the home of CDK2NA, a protein that acts as a tumor suppressor.
• Deletions on chromosome 10, the home of PTEN, a protein that prevents cells from growing too rapidly.

The team further classified the 10 tumors studied into three subtypes, including a classic subtype in which three defects (EGFR, PTEN and CDK2NA) were all present. Those patients had particularly poor prognoses.

“So not only did this study allow us to classify patients based on their genomic signatures, it also allowed us to have a prognosis of how well they would do,” Dr. Bahassi said. “Now if we can use these genomic defects as pathways to develop targets to treat those patients, then we will have accomplished our ultimate task.”

The researchers will sequence and track tumor DNA in an additional 20 patients during the next several months. Their work will be facilitated by the ability of Dr. Bahassi’s lab to perform its own data analysis of the genome sequencing. Only a few sites nationally have this capability.

In this secondary study researchers will also seek to confirm the therapeutic value of tracking tumor DNA in the bloodstream to determine recurrence.

“As a physician, I don’t have a crystal ball when I’m treating a patient with glioblastoma,” said Ronald Warnick, MD, Medical Director of the UC Brain Tumor Center and Professor of Neurosurgery and Radiation Oncology. “Following treatment, I cannot tell whether I am seeing a recurrent tumor on a brain scan or necrosis. The only foolproof way to be sure is to perform surgery. In the future, however, we hope to confirm that we can monitor our patients’ status and determine recurrence through a simple, noninvasive blood test.”

Dr. Warnick said that small foundation grants play a critical role in the type of pioneering research that Dr. Bahassi is leading. “You need seed money to do this type of work, to get the preliminary data that allows you to then apply for a grant from the National Institutes of Health,” he said. “There is a gap between a great idea, a smart person in the lab, and the acquisition of enough information that you can be successful in your application for a large federal grant. These small foundation grants serve as the catalyst.”

The team’s success in tracking tumor DNA that circulates through the bloodstream also holds promise for other tumors. “I would like to use this technology to address other questions, to detect other abnormalities, such as brain metastasis,” Dr. Bahassi said.

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¹ Researchers John M. Furgason and Emily Cross; Neurosurgeons Ronald Warnick, MD, Christopher McPherson, MD, and Tracy Ansay, MD; Pathologist Ady Kendler, MD, and Clinical Trials Specialists Ruth Steele, Suzanne Sifri and Alison Kastl.

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The Shemenski Foundation honors the life of John Shemenski, who died of a brain tumor in 2008, by spreading the hope, courage and determination needed to beat brain cancer. The Foundation donated $24,000 to the UC Brain Tumor Center in 2012 and another $35,000 earlier this month. In the provided photo, from left, Kelly Heaps, Jeff Rieder, Dr. Ronald Warnick, Kathy Beechem, Jeff Eggleston, Lisa Suwalski, Andrea Zahumensky and Kira Knight.

– Cindy Starr