How Colon Cancer Adapts — And How IU Is Fighting Back

IN HER LAB, Heather O’Hagan, PhD, is chasing one of colorectal cancer’s most frustrating traits: its ability to adapt. A molecular biologist, O’Hagan studies how cellular stress affects gene expression. Colon cancer is relatively easy to study — data is abundant, and cell types make experiments quick. That led her to assign a grad student a simple project: How does a protein called LSD1 behave under stress?

The results were stark. Instead of curbing the number of cells, the cells changed. “We just kept building on that,” O’Hagan said.

Five years later, O’Hagan has shown that LSD1 helps a rare form of colorectal cancer, one with a median survival of 18 months, evade treatment. How? By helping cancer cells change their identity.

In the face of harsh therapy, LSD1 draws together two other proteins to activate genes to help cells “change their lineage.” As a result, cancer cells resemble a specialized secretory cell commonly found in the lining of the colon, and they survive therapy.

In April, just two months after outlining that process, O’Hagan’s team published data showing how a drug combination, including a molecule targeted at LSD1, can slow colorectal cancer’s growth. But there’s a catch. The molecule has proven too toxic to patients when used in trials against other cancers.

“We’ll need to find a new one,” O’Hagan said.

O’Hagan is developing screening tests to find new options. Once several are identified, she’ll collaborate with drug discovery experts based at IU School of Medicine in Indianapolis. In the near-term, her findings can help oncologists devise more aggressive treatments.

“It gives us more insight into why this cancer is so bad,” she said. “It responds poorly to chemotherapy and everything else because it can adapt so easily.”

To help advance innovative colorectal cancer research and the development of new therapies at IU Simon Comprehensive Cancer Center, please contact Liz Standiford at estandi@iu.edu.