From the Lab to the Bedside, UC Brain Tumor Center Makes Strides in Effort to Tame Glioblastoma

From left: Xiaoyang Qi, PhD, Rekha Chaudhary, MD, and El Mustapha Bahassi, PhD.

Families who confront glioblastoma multiforme, an aggressive brain cancer, shoulder a particularly harsh burden of disease. The cancer, as the word “multiforme” suggests, comes in many forms. Its heterogeneous nature and diffuse form make it difficult to treat.

But patients and families can take some solace in knowing that research scientists and clinicians around the world are making progress in their effort to find what Dr. Ronald Warnick, Medical Director of the UC Brain Tumor Center, calls “the holy grail” – the cure for glioblastoma multiforme. From the laboratory bench to the patient’s bedside, medical scientists are exploring every molecular nook and cranny of the difficult cancer while prodding and poking it with experimental therapies and technologies.

Much of that work is taking place right here at the UC Brain Tumor Center, which is part of the UC Gardner Neuroscience Institute and the UC Cancer Institute. Here, more than a dozen medical scientists are conducting laboratory, translational and clinical research. For patients in the Greater Cincinnati community who have been diagnosed with glioblastoma, the ramifications are profound: They have access to clinical trials that are beginning to produce hopeful results.

Rindopepimut in the news

A handful of patients at the UC Brain Tumor Center participated in a Phase 2 study of rindopepimut, a drug that stimulates the body to use its own immune system in the fight against glioblastoma. This group of patients had experienced a recurrence of their glioblastoma and also had a specific type of genetic mutation, referred to as EGFRvIII. This mutation, or “oncogene,” is found in about 30 percent of patients with glioblastoma.

Last month, in an interim analysis of the Phase 2 trial (known as ReACT), researchers reported that 125 study participants who took rindopepimut along with bevacizumab (Avastin) had improved survival compared to those who were treated with other drugs and chemotherapy. The data was presented by David Reardon, MD, of the Dana-Farber Cancer Center and Harvard Medical School, at a platform presentation at the Society for Neuro-Oncology’s annual scientific meeting in Miami.

“There has been very little data from all the clinical research in the recurrent glioblastoma setting that has shown promise,” says Rekha Chaudhary, MD, a neuro-oncologist at the UC Brain Tumor Center and Principal Investigator of the Cincinnati portion of the trial. “This data gives the whole brain tumor community –patients, caregivers, scientists and medical professionals — the one word we are all searching for: hope.”

Rindopepimut is an investigational drug developed by Celldex Therapeutics; Avastin is an FDA-approved drug marketed by Roche. The study results showed that rindopepimut was most effective in patients who had not previously taken Avastin.

A separate Phase 3 trial (ACT IV) in patients newly diagnosed with glioblastoma is ongoing at multiple centers around the world, including the UC Brain Tumor Center. In this study, patients with the EGFRvIII mutation are treated with rindopepimut along with temozolomide, a commonly used chemotherapy drug.

An additional half-dozen clinical trials exploring treatments for glioblastoma are also underway at the UC Brain Tumor Center.

Positive results for tumor treating fields (TTF) therapy

In other news of interest, investigators at the recent Society for Neuro-Oncology meeting in Miami released the initial results from a large randomized Phase 3 trial, which used the Novo TTF-100A tumor treating fields therapy in addition to temozolomide in patients newly diagnosed with glioblastoma. Tumor treating fields therapy involves the delivery of a low-intensity electric field with electrodes placed directly on the skin in the region surrounding the tumor. The electric field disrupts cell division and leads to subsequent cell death (apoptosis).

The researchers found that the 2-year survival in this study of 200 participants was 1.5 times greater for those who received the Novo-TTF device than for those who received temozolomide alone. The study results were so promising that the study was discontinued midway through, and the tumor treating fields therapy was offered to study participants who were receiving temozolomide alone.

“Just within the last month we have two new positive trials for patients with brain cancer,” says Richard Curry, MD, a neuro-oncologist at the UC Brain Tumor Center. “We are actively chipping away at these aggressive tumors and continue to move closer to the day when a cure becomes reality.”

In the laboratory

In laboratories on the UC Academic Health Center campus, seven research scientists are searching for glioblastoma’s molecular Achilles’ heel. Working collaboratively yet independently, and with the support of grants from local foundations, the federal government, and Walk Ahead for a Brain Tumor Cure, they are striving to find a way to halt the tumor’s growth and its ability to elude conventional therapies.

Bahassi and Stambrook Laboratories
El Mustapha Bahassi, PhD, Research Assistant Professor of Medicine, and Peter Stambrook, PhD, Professor of Molecular Genetics, Biochemistry and Microbiology, are studying biomarkers that may soon help guide doctors’ treatment of glioblastoma multiforme. Using simple blood tests, Dr. Bahassi and his team are studying DNA that breaks off from the tumor and flows through the bloodstream to identify genetic abnormalities in individual tumors.
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Desai Laboratory
Pankaj Desai, PhD, Professor of Pharmacokinetics and Drug Metabolism at the Winkle College of Pharmacy, and his team are exploring the potential of letrozole, a drug administered orally to treat breast cancer, to treat brain cancer.
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Driscoll Laboratory
James Driscoll, MD, PhD, Assistant Professor of Hematology-Oncology, and his team have tested hundreds of different small-molecule compounds for signs of effectiveness in the treatment of glioblastoma multiforme. They have developed a high-throughput, automated screen to rapidly test hundreds of compounds at the same time.
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Plas Laboratory
David Plas, PhD, Associate Professor of Cancer Biology, is focused on a protein known as S6Kinase1, or S6K1. The protein is in a pathway downstream of another protein, PTEN, a major tumor suppressor that is frequently mutated in brain cancer. The deficiency of PTEN occurs in all four molecular subtypes of glioblastoma. Dr. Plas and his laboratory team have assembled a panel of five pre-clinical compounds through collaboration with chemists from the pharmaceutical industry as well as leading academic chemists. Using these compounds, they are performing the first comprehensive analysis of S6K1 as a target for brain cancer therapy.
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Qi Laboratory
Xiaoyang Qi, Associate Professor of Hematology-Oncology, is internationally recognized for designing the nanovesicle SapC-DOPS, short for saposin-C dioleoylphosphatidylserine, while working at Cincinnati Children’s Hospital Medical Center in 2002. SapC-DOPS is a drug that has been shown in preclinical studies to cause several types of cancer cells – including brain cancer cells – to self-destruct, without causing harm to healthy cells or tissues. While the world awaits a Phase I trial involving SapC-DOPS technology, Dr. Qi continues to forge ahead in his lab. He has discovered that SapC-DOPS technology can be used to make brain cancer cells fluoresce and thereby become visible in brain scans. Finding the tumor at an earlier stage, Dr. Qi says, could enable doctors to treat it sooner and more effectively.

Learn more about SapC-DOPS nanovesicles for treatment of glioblastoma »
Learn more about SapC-DOPS nanovesicles for enhanced brain imaging »

Sasaki Laboratory
Atsuo Sasaki, PhD, Assistant Professor of Hematology-Oncology, was recently awarded a $1.67 million federal grant to test his novel hypothesis that glioblastoma can be inhibited by targeting  PI5P4Kβ, a key player in cancer that has recently emerged. In preliminary research funded by Walk Ahead for a Brain Tumor Cure and other sources, Dr. Sasaki and his laboratory team became the first known researchers to go after the “boiler room” of energy-guzzling glioblastoma cells. They hypothesize that they can stop the growth of glioblastoma cells by interfering with the PI5P4Kβ (phosphatidylinositol-5-phosphate 4-kinase-β) pathway. With the infusion of federal dollars, Dr. Sasaki is using both pharmacological and molecular approaches that target PI5P4Kβ in a cell culture and in animal tumor models.
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— Cindy Starr

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