IU researchers defining new target to kill glioblastoma

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Indiana University cancer researchers soon will be testing a new approach to treating glioblastoma that, if successful, will attack cells that are resistant to treatment, increasing life expectancy and reducing the amount of toxic chemotherapy needed during initial treatment of the unpredictable disease.

Indiana University researchers soon will be testing a new approach to treating glioblastoma that, if successful, will attack cells that are resistant to treatment, increasing life expectancy and reducing the amount of toxic chemotherapy needed during initial treatment of the unpredictable disease.

Karen E. Pollok, Ph.D., and Reza Saadatzadeh, Ph.D., are investigating glioblastoma cells in their lab with mice whose immune systems have been altered to tolerate foreign tissue. Pollok, an associate professor of pediatrics and adjunct professor of pharmacology and toxicology at IU School of Medicine, is a member of the IU Simon Cancer Center’s Tumor Microenvironment and Metastasis research program. Saadatzadeh is an associate research professor of pediatrics at IU School of Medicine.

In a unique approach to understanding this complicated brain cancer, Pollok and Saadatzadeh are working with fresh human glioblastoma tissue obtained during surgeries performed by Aaron Cohen-Gadol, M.D., M.Sc., professor of neurological surgery at IU School of Medicine and a member of the IU Simon Cancer Center, and colleagues. The tissue, implanted into the mouse brain, is monitored and analyzed to see how the cancer mutations adapt or die during treatment.

Glioblastoma is a complex disease because of the diversity of the cells within each tumor and the ability of those cells to evade death or repair damage caused by therapeutic treatment.

The disease is doubly difficult to treat because of the organ it attacks: the human brain. Treatment is complicated because glioblastoma is not contained in any form that can easily be removed surgically. It sends out tendrils from the primary location that wind through delicate brain tissue. Surgeons cannot remove these “vines” without damaging vital tissue.

Surgery is the first line of treatment for glioblastoma, but that is just the start, Pollok said. Radiation also is ordered for most patients but, like surgery, it cannot attack all of the tumor’s tendrils without damaging critical brain cells. Chemotherapy is next in the treatment lineup but no one drug is effective at killing the divergent and fluctuating glioblastoma cells.

“All of these therapies have some benefits, but none of these alone eliminate glioblastoma,” Pollok said. This is where her research starts, seeking a way to kill the cancer cells that have evaded treatment.

“The National Cancer Institute’s objectives include funding research that establishes models to simulate what is going on in the patient,” Saadatzadeh said. “We are studying the molecular mutations of human cancer inside the mouse. We want to design a therapy that will attack these mutations and kill the tumor.”

“If you are going to find a cure or stabilize this disease, it’s going to take a combination therapy approach,” Pollok said. “Glioblastoma is a very genetically complicated tumor.”

A glioblastoma tumor is composed of many cell types. On one edge of the tumor, a cell type that responds to a specific chemotherapy may exist, but nearby is a cell type that is resistant to that very treatment. Treatment with a specific drug may cause diseased cells to become resistant to the drug. The residual cells that don’t respond to various chemotherapy agents and those that become resistant to therapy are what makes glioblastoma so deadly.

Pollok’s goal is to kill the residual cells by interfering with what is called the DNA damage response — one of the key things that makes glioblastoma such a genetically complicated and adaptable disease. Her team is looking at three different approaches — or pathways — cancer cells use to overcome damage inflicted by drugs or radiation.

“We are working with three different drug groups that cause the DNA response to turn into cell death and not cell repair,” Pollok explained. “Our big challenge is to determine what combinations work best to attack residual disease and attack the DNA damage response to increase cell death, but to do it in a well-tolerated manner to minimize toxicity.”

The number of combinations available is mind-boggling. Pollok said she recently spent eight months working out the dosage for one of the combination therapies proposed for a next phase study in their mouse models of human glioblastoma. Before her research can move from mice into human clinical trials, she and her team will have screened more than 20 different combinations that have the potential to kill the glioblastoma cells. The challenge is to sort out which dose combinations kill the cancer cells but spare the normal cells in the body.

Pollok and Saadatzadeh are confident that combination therapy holds the key to stopping glioblastoma. They are confident their approach to studying the deadly cancer in mouse brains will speed the process of finding a cure. They are also realistic that glioblastoma is a challenging adversary. Patience, tenacity and optimism are required for them to succeed.  

“The biggest problem with glioblastoma is there is no cure,” Pollok said. She, Saadatzadeh and their colleagues are working to change that.