“Discovering new targeted treatments for metastatic Ewing sarcoma.”
What This Project Does
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 they hope will disrupt the growth and spread of the cancer.
Ewing sarcoma occurs because of a chromosomal abnormality that causes an atypical protein, known as EWS/FLI, to be expressed. When EWS/FLI is present, it causes literally thousands of genes mutate. In previous research, Dr. Beckerle’s team determined that EWS/FLI also disrupts 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. Therefore, being able to stop EWS/FLI from changing a cell’s “stickiness” might help 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.
Potential Impact on Children
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. Treatment for Ewing sarcoma involves surgery and chemotherapy, but many children will relapse with metastatic disease. Those who do relapse have poor survival rates. Dr. Beckerle and her team want to change the outcome for children with metastatic Ewing sarcoma. If their work is successful, they will develop a new treatment that stops Ewing sarcoma from spreading and changes the odds for these high-risk children.
18 Month Research Update
Dr. Beckerle at the Huntsman Cancer Institute has worked on Ewing sarcoma for several years. They have demonstrated that EWS/FLI, a protein that has long been known to be present in Ewing sarcoma, is regulated by an enzyme called LSD1. Dr. Beckerle’s team hopes that by targeting LSD1, they may be able to prevent the spread of Ewing sarcoma.
In the past 18 months, Dr Beckerle’s team has tested more than 47 compounds leading to the discovery of 2 novel inhibitors of LSD1. The team is now in completing preclinical testing on these two inhibitors. The initial tests are very promising. Using advanced preclinical models, they showed that the drugs make the cancer cells more “sticky” and prevent spread of the tumor.
In an effort to scale up production of the compounds, for eventual use in patients, they found that the compounds did not dissolve. Dr Beckerle’s team went through several rounds of troubleshooting to discover what was causing this problem. After much testing, the team found a new purification method which preserves the drug’s ability to dissolve. Dr Beckerle is hopeful that, after overcoming this technical challenge, they will soon be able to test the compounds in a clinical trial in the near future. To prepare for this step, the team is developing biomarker and imaging tests. These tests will allow the researchers to monitor how effectively the drugs block LSD1 function in their preclinical models, and eventually, in patients.
This program is supported in part by generous contributions from the Nick Currey Fund. For more information about the Nick Currey Fund, visit www.curesearch.org/Nick-Currey-Fund.