UAB researcher obtains grant to study protein linked to brain cancer

A University of Alabama at Birmingham researcher has received a significant Research Scholar Grant from the American Cancer Society to further understanding of glioblastoma multiforme, the most common and deadly cancer originating in the brain.

Christopher Willey, M.D., Ph.D., associate professor in the Department of Radiation Oncology, has been awarded a $792,000 grant to study a protein called MARCKS that he believes is important for regulating how GBMs grow, spread and resist treatment.

Glioblastoma multiforme is the most common malignancy that starts in the brain. It is extremely deadly; the typical patient will live only about 14 months after diagnosis despite receiving standard-of-care therapy including surgery, chemotherapy and radiation treatments.

“There is a lot we do not know about GBM and why it is so resistant to treatments,” said Willey, a scientist in the experimental therapeutics and neuro-oncology programs at the UAB Comprehensive Cancer Center. “Further, there is a lot about MARCKS that we don’t understand. MARCKS seems to have a Jekyll and Hyde relationship to cancer. In some cancer types, higher MARCKS levels are associated with bad outcomes, while in others, like GBM, it may be associated with better outcomes.”

Willey began studying MARCKS several years ago while investigating how radiation works in targeting tumor blood vessels. After coming to UAB, he and a graduate student found that, when MARCKS levels were low, GBM cancer cells did not migrate very well, but did, however, multiply much faster and become resistant to radiation. Conversely, if they increased MARCKS levels, the cancer cells grew slowly and, in some cases, stopped growing altogether. Based on studies in cell cultures, in human tumors implanted in mice and in patient clinical data, they found that if certain GBM tumors, or proneural subtype, had high levels of MARCKS, the patients lived much longer than expected, more than five years on average.

The ACS grant allows Willey and his research team to delve into the mechanism by which MARCKS impacts GBM growth and treatment response.

“Over the next four years, we believe our research will identify the most important part of the MARCKS protein in terms of GBM biology, and will determine how GBM tumor cells regulate MARCKS levels and functions. Our ultimate hope is to one day treat GBM patients with MARCKS targeting therapies, and also identify additional targets for drug development based on our studies.”

“We believe that MARCKS is interacting with molecules at the inner surface of the cell to suppress some of the bad signals that drive the aggressiveness of GBM cells,” Willey said. “We are also trying to determine what part of the protein is most important for these processes to help us home in on where we should target MARCKS for drug discovery purposes.”

There are no MARCKS-targeted agents on the market, except for one in a clinical trial as a lung disease therapy.

“We have partnered with the company that makes this therapy in order to test whether it can effectively treat GBM tumors in mice,” Willey said. “We have also designed some additional agents that may be effective in treating GBM.

“Over the next four years, we believe our research will identify the most important part of the MARCKS protein in terms of GBM biology, and will determine how GBM tumor cells regulate MARCKS levels and functions. Our ultimate hope is to one day treat GBM patients with MARCKS targeting therapies, and also identify additional targets for drug development based on our studies.”

BioMarck Pharmaceuticals will provide therapeutics for this project.