Stopping Cancer in Its Tracks

Cancer-causing genetic defects are harmful in multiple ways. They can help cancer cells grow and divide. They can interfere with tumor suppressor genes, which fix DNA errors and stop abnormal cells from turning into cancer. 

But imagine you could turn that around. Research by Huntsman Cancer Institute (HCI) investigators Mary Beckerle, PhD, Stephen Lessnick, MD, PhD, and Sunil Sharma, MD, indicates the researchers may have found a way to reverse the biology of the cancer-causing protein that drives Ewing sarcoma.

A highly aggressive bone and soft tissue cancer that affects children and young adults, “Ewing sarcoma is very challenging to treat because it has typically metastasized, or spread, by the time it is diagnosed,” says Beckerle. “We desperately need improved strategies for treatment of this disease.”

In nearly every case, Ewing sarcoma is driven by a change in DNA that results in the production of a dysfunctional protein called EWS/FLI. This protein has been shown to turn off tumor suppressor genes—the genes that help prevent cancerous cells from forming or spreading. Because scientists have been unable to directly inhibit EWS/FLI, the HCI team focused on a key master regulator of its activity—an enzyme called LSD1.

LSD1 allows EWS/FLI to function. By blocking LSD1, tumor suppressors might be activated, allowing them to protect cells from becoming cancerous. This possibility led HCI researchers to search for drugs that could interfere with the function of LSD1. They identified a candidate, HCI2509. (See the Possible New Ewing Sarcoma Treatment story in our 2012 Top Science Report.)

“When we treat patient-derived Ewing sarcoma cells with HCI2509, we find that it completely turns off the function of EWS/FLI,” says Lessnick. “It was kind of a shock to identify an agent that works so effectively to turn it off.”

In the latest study, published in the journal Clinical Cancer Research, the Beckerle LabLessnick Lab, and Sharma Lab members specifically show that HCI2509 led to increased activity of genes involved in stopping or killing abnormal cells. In addition, it led to decreased activity of genes involved in cell division and growth.

The investigators also found that HCI2509 alters the shape of cultured Ewing sarcoma cancer cells so they are no longer small and round, but flat and spread out like normal cells. The team hypothesizes that this change could slow the metastatic spread of Ewing sarcoma.

“HCI2509 may in fact be the first real targeted agent for Ewing sarcoma,” says Lessnick. “It gives us hope that we’re on the right track.”

“Our intent is to advance this therapy into the clinic as soon as possible,” adds Sharma. With a $1.7 million grant award from CureSearch for Children’s Cancer, the group will begin testing the compound in clinical trials, expected to occur within the next two years.

The LSD1 enzyme is associated with other cancers, including neuroblastoma, bladder, lung, liver, and colorectal. This suggests that if an effective drug is identified, it could have broad potential for cancer treatments.