IU Simon Cancer Center researchers perfecting one-two punch for challenging adversary: glioblastoma

Wednesday, August 30, 2017

Glioblastoma multiforme is a fickle foe. It has no hesitation about expanding its boundaries or modifying its structure to make itself resilient. It can host multiple cellular signatures within each tumor and is efficient at repairing therapeutic cellular damage. 

These are some of the reasons glioblastoma multiforme (GBM) is such a deadly cancer. It may be a resilient opponent, but two IU Simon Cancer Center researchers are committed to developing new combination therapies for GBM, using the variable and fluctuating genetic signatures of the tumor to guide those therapies.

Karen E. Pollok, Ph.D., and Aaron Cohen-Gadol, M.D., M.Sc., are collaborating using malignant human tissue that can be grown in the brains of specialized immunodeficient mice to pinpoint the mechanisms involved that allows GBM to survive therapeutic attacks. Dr. Cohen-Gadol, a professor of neurological surgery at IU School of Medicine and Goodman Campbell Brain and Spine, specializes in the treatment of GBM. Dr. Pollok is a highly recognized associate professor of pediatrics at IU School of Medicine with a research interest in therapeutic strategies to modulate DNA repair in cancer. Drs. Cohen-Gadol and Pollok are co-directors of the Signature Center Initiative for the Cure of Glioblastoma.

Using GBM tissue from neurosurgery, Dr. Pollok’s team implants human glioblastoma tumors in mouse brains. Using the fresh tissue allows Dr. Pollok to more closely simulate how the tumor changes at a molecular level in human patients when treated with chemotherapy or radiation.

GBM is a complex enemy. It sends malignant finger-like invasive extensions into the brain, making complete surgical removal virtually impossible. GBM cells migrate along capillaries that provide a ready source of nutrition from the blood. This allows the cancer cells to spread and grow rapidly. Each tumor is a conundrum – different genetic signatures can be found in different sections within each tumor. Genetic signatures are what therapeutic agents target to kill cells, but if each tumor has multiple genetic signatures, targeting becomes more complex and only partially effective.

Karen Pollock, Ph.D.
Dr. Pollok

As if that doesn’t complicate the process enough, Dr. Pollok said the GBM cells are particularly efficient at protecting themselves by activating a process called DNA damage response, which senses cellular damage and repairs it. DNA damage response is an effective tool at preventing cellular changes from foreign agents such as tobacco products or ultraviolet light; it also can block advantageous changes such as cell death from chemotherapeutic agents or radiation.

“You are really working with a genetically unstable situation,” Dr. Pollok said. “That’s where we are finding an approach that incorporates multiphase therapy useful.

“The cancer cells respond to chemotherapy and then the DNA damage response increases,” she added.  “There’s a window of time when we can use a drug to inhibit the DNA response. Our goal is to inhibit the pathways to decrease survival of the GBM cells and increase the effectiveness of the therapy while at the same time making sure that any toxicity to normal tissues is minimized.”

“Our goal is to inhibit the pathways to decrease survival of the GBM cells and increase the effectiveness of the therapy while at the same time making sure that any toxicity to normal tissues is minimized.”Karen Pollok, Ph.D.

Multiphase therapy employs standard chemotherapy (temozolomide) and additional targeted inhibitors to attack the GBM cells. Following each treatment, the tumor cells are tested to see how they have adapted, and then treated again with multiphase therapy before the DNA damage is corrected. This process is applied multiple times and, in mouse models, is proving effective.

Aaron Cohen-Gadol, M.D., M.Sc.
Dr. Cohen-Gadol

“We have some exciting new results in lengthening survival rates,” Dr. Cohen-Gadol said. “We are hopeful about moving to the clinical trial phase in the future, perhaps as soon as five years. But for now we are still trying to prove their efficacy thoroughly in the mouse model, adjusting the dose to get the optimal effect.”

Drs. Pollok and Cohen-Gadol are optimistic their focus may ultimately result in a new approach to treating GBM. By understanding what changes occur on the molecular level and using multiphase therapy to target those changes, the researchers believe they will make the elusive GBM tumors an easier target.