Peter Stambrook, PhD, Professor of Molecular Genetics, Biochemistry and Microbiology and winner of the 2013 Environmental Mutagenesis and Genomics Society Award for outstanding research contributions, collaborates with El Mustapha Bahassi, PhD, to identify noninvasive biomarkers that may soon help guide doctors’ treatment of the malignant brain tumor glioblastoma multiforme. The novel translational research focuses on DNA that is released in tiny amounts from the tumor into the blood stream, where it can be detected.
The research, begun as a pilot study funded by UC and small foundation grants from the Mayfield Education & Research Foundation, the Shemenski Foundation and the LCS/Sahlfeld Foundation, has kicked into a higher gear with the awarding of a $100,000 grant from the Center for Clinical and Translational Science Training (CCTST).
During the pilot study, the UC research team¹ sequenced the genomes of glioblastoma tumors that were surgically removed from 10 study participants. In a major innovation, the 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 significant challenges posed by the aggressive cancer, including whether the tumor had recurred.
“Doing whole genome sequencing of glioblastomas we identified changes in DNA that have occurred and are unique to the tumor,” Dr. Stambrook says. “We used what is called a polymerase chain reaction, or PCR, a very sensitive method to selectively identify DNA that is derived from tumors.
“We detected this tumor DNA within the patient’s blood plasma,” Dr. Stambrook continues. “Prior to the surgical removal of the brain tumor you can see it; after surgery it is gone; and if there is a recurrence, it comes back. So we have a minimally invasive method for asking whether or not a tumor has recurred. Hopefully, we can discover a recurrence before the patient complains of symptoms so that if it’s possible to treat the recurrence early, we can do so. Catching a glioblastoma recurrence early may make a difference. It may enable you to reduce its bulk and increase survival time.”
Dr. Stambrook’s history with the Brain Tumor Center dates back to 1992, when he and several colleagues, including Ronald Warnick, MD, John M. Tew, MD, Robert Brackenbury, PhD, Anil Menon, PhD, and Linda Parysek, PhD, were awarded a $2.25 million grant from the National Institutes of Health to establish one of eight brain tumor research centers in the United States. The grant funded basic science projects and the establishment of an institutional brain tumor tissue bank.
In the mid-1990s Dr. Stambrook collaborated with Dr. Warnick, the principal investigator, in a national trial that studied the effectiveness of gene therapy treatment for recurrent glioblastoma. Gene therapy utilizes DNA that has been packaged within a delivery vector, such as a virus, to treat disease.
“Dr. Warnick and I were co-authors on a paper describing what is called a ‘bystander effect’ using a gene therapy approach,” Dr. Stambrook says. “Cells that express the gene HSVtk are killed by the drug ganciclovir. We introduced HSVtk via a retrovirus into brain tumor cells in the lab, followed by treatment with ganciclovir. The ganciclover was toxic to tumor cells that had taken up the therapeutic HSVtk gene, but it was also toxic to neighboring tumor cells that had not taken it up.
“We then described the mechanism by which that happened: There was metabolic cooperation whereby small cytotoxic molecules passed between neighboring cells via gap junctions without actually exiting the cells.
“That research helped put the investigative arm of UC’s neuroscience program on the map,” Dr. Stambrook continues. “It wasn’t the only discovery that propelled us forward, but it really contributed.”
Glioblastoma remains the ultimate target in brain cancer research, “the holy grail” in the words of Dr. Warnick. In the future, Drs. Stambrook and Bahassi hope that determination of glioblastoma sub-types through genome sequencing will enable doctors to provide patients with individualized treatments rather than the current one-size-fits-all therapies that are currently available.
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.