Fighting cancer: Innovative strategy takes aim at tumors’ drug resistance

A Clemson University professor said the cancer research he and his team are conducting could be a step toward managing tumors with drug combinations, turning them from potential death sentences to chronic yet treatable conditions.

Marc Birtwistle, a professor of chemical and biomolecular engineering, said the team is working on a new strategy for fighting cancer that focuses on how cells shifting from one state to another complicates efforts to conquer the disease.

The research will center on glioblastoma, an incurable brain cancer, but the problem the project targets is widespread across all human cancers, he said. Any new treatments derived from the research would take several years to develop, Birtwistle said.

The five-year project is funded with $2.6 million from the National Cancer Institute and the Physical Sciences in Oncology Network. Partners on the project include Professor James M. Gallo, Assistant Professor Yeh-Hsing Lao and Associate Professor Ashlee Ford Versypt, all of the University of Buffalo; and Assistant Professor Sai Ma of the Icahn School of Medicine at Mount Sinai.

One of the difficulties in treating cancer now is that drugs often become less effective over time, requiring new treatments. Previous research has shown that the way cells switch between different states plays a key role in drug resistance.

In the new project, researchers aim to create therapies that keep cancer cells in drug-sensitive states, making it harder for them to become resistant.

It could ultimately lead to drug combinations that contain the different states that tumor cells could take, Birtwistle said. The approach could work similarly to how drug combinations manage HIV, though cancer is more complex, he said.

Researchers are calling their proposed treatment Cell State-Network-Directed Therapy.

"You would have to take these drugs every day, but you could live an otherwise healthy, great life," Birtwistle said.

In a lab, researchers will grow glioblastoma cells derived from three different patients. Researchers will then use advanced tools, including state-of-the-art tumor-on-chip systems, to study how cells change states.

First they will study cells without the drugs to better understand how cell-state networks behave. Then researchers will conduct the same experiments in the presence of dozens of different drugs that cross the blood-brain barrier and are likely to be active in the transitions of cell-state networks, looking for drugs that kill cells or keep them from growing.

Researchers will feed that information into computer models to predict how the cells will respond to combinations of different drugs, then test those drugs one at a time and in combinations.

They will test the most promising drug combinations in 3D models that mimic real tumors. Researchers will analyze the results, refine their approach and work toward developing treatments that prevent cancer cells from becoming resistant.

The work is aimed at helping narrow down the number of possible drug combinations to treat cancer. The Food and Drug Administration has approved about 350 different anticancer drugs, and that doesn't include the drugs that are sometimes repurposed for combating cancer, Birtwistle said.

All told there about 7 million different drug combinations, he said. It is too many to conduct clinical trials on them all in a reasonable amount of time and why Birtwistle's expertise in computational modeling will be key. The computational models will help the team narrow down which drug combinations look most promising.

David Bruce, chair of the Department of Chemical and Biomolecular Engineering, congratulated Birtwistle and his team on securing the funding for the research.

"Marc's hard work and innovative approach make him the ideal leader for this research," Bruce said. "This grant not only positions his team to improve outcomes for cancer patients but also strengthens the department's reputation for conducting impactful, cutting-edge research."