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"Discovering new targeted treatments for metastatic Ewing sarcoma."
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.
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.
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 thinks that if they can target LSD1, they may be able to regulate how Ewing sarcoma spreads. They are currently testing different drugs that inhibit LSD1 in the hopes that one of them will effectively stop the spread of Ewing sarcoma.
In the past year, they have developed 2 novel inhibitors of LSD1 function. These compounds are proprietary to Beckerle's lab. Initial tests showed that the compounds increased cell adhesion and reduced the cancer's growth and spread in the lab. After the first compound did not dissolve properly to treat the tumors, the team has created a new and more effective compound with better solubility that has been effective at treating the tumor cells in advanced models.
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.
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