A Novel Epigenetic Strategy to Treat
Ewing Sarcoma




 
  • Mary Beckerle, PhD
  • Ralph E. and Willia T. Main Presidential Professor
    CEO and Director, Huntsman Cancer Institute
    The University of Utah
 

Ewing sarcoma is the second most common bone cancer in children and is a challenging cancer to treat because it has typically metastasized, or spread, by the time it is diagnosed. Further, once cancer has spread, many patients relapse after their initial chemotherapy and surgery. It is widely known that Ewing sarcoma occurs because of a chromosomal abnormality that causes an atypical protein, known as EWS/FLI, to be present (also called expressed), and that when EWS/FLI is expressed, literally thousands of genes mutate, or change from their normal state.

Now, a team at the University of Utah's Huntsman Cancer Institute led by Mary Beckerle PhD and including Steve Lessnick MD PhD, Sunil Sharma MD, and Alana Welm PhD has received a $1.73 million grant from CureSearch to test a novel targeted treatment for Ewing sarcoma that hopefully will disrupt the cancer's growth and spread.

In previous research, the team determined that EWS/FLI causes disruption of the internal cellular skeleton, which compromises the ability of the cells to adhere (stick) and remain in their normal environment. A cell that cannot remain in its normal environment is more likely to travel to another area of the body, facilitating the spread of the tumor. EWS/FLI also causes uncontrolled cell growth. Therefore, being able to stop, or block, EWS/FLI from changing a cell's adhesion might stop the spread of cancer.

Because it is difficult to directly inhibit EWS/FLI, Dr. Beckerle and her team are focused on a key regulator of EWS/FLI function, an enzyme called lysine specific demethylase (LSD1). Inhibitors of LSD1 thus represent a promising a new treatment approach for Ewing sarcoma. In their preliminary work, they used a computational chemistry approach to develop a molecule to inhibit (stop) LSD1. This agent displays potent anti-tumor activity when human Ewing sarcoma is implanted in mice. The LSD1 inhibitor reverses the effects of EWS/FLI and restores spreading and adhesion of the Ewing sarcoma cells, effects that the team proposes would prohibit the tumor cells from escaping and traveling to other areas of the body.

Now, they will expand their discovery with the goal of moving this approach into the clinic as a targeted therapy for Ewing sarcoma. They will evaluate the treatment effects of LSD1 inhibition--–alone or in combination with other medications in the form of preclinical trials. To do this, they will use a mouse model of metastatic Ewing sarcoma that mirrors the cancer in humans. At the same time, they will develop biomarkers and imaging tests to monitor responses to treatment and perform studies to assess the safety and toxicity of the new treatment, while determining appropriate dosing and timing which will serve as a guide when testing moves from the laboratory into patients.

To pursue these goals, a multidisciplinary scientific team at Huntsman Cancer Institute at the University of Utah has been assembled. Team members include: Dr. Mary Beckerle, a cell biologist who is a specialist in cell adhesion and motility and who serves as the Principal Investigator on the project; Dr. Steve Lessnick, pediatric oncologist with a long standing program in Ewing sarcoma research; Dr. Sunil Sharma, an oncologist with drug development and early phase clinical trial expertise in both the pharmaceutical and academic settings; Dr. Alana Welm a specialist in bone metastasis and development of predictive preclinical models; As well as collaborators, Drs. Lor Randall and Kevin Jones, surgical oncologists; Dr. Mary Bronner, pathologist; Dr. John Hoffman, molecular imaging specialist.

< Acceleration Initiative Grantees 

 

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