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Targeting RNA Helicase DDX3 to Treat Recurrent High Grade Sarcoma

The Johns Hopkins University School of Medicine
David Loeb, MD, PhD
Grant Type: 
Reach Grants
Year Awarded: 
Type of Childhood Cancer: 
Ewing Sarcoma
Project Description: 

Current treatments for patients with relapsed sarcomas are ineffective. The best chemotherapy regimens shrink tumors only 40% of the time, without prolonging survival. Effective treatments for these patients are a critical unmet medical need, and new molecularly targeted therapies represent the most promising approach to this difficult problem.

One class of enzymes that is very important to the function of cancer cells is termed RNA helicases. RNA helicases control which proteins are expressed in cancer cells. One such enzyme, DDX3, is especially important in sarcoma biology. We found that sarcomas have very high levels of DDX3, and that reducing or eliminating DDX3 kills sarcoma cells in the lab and slows the growth of sarcomas in laboratory mice.

Project Goal
We propose that DDX3 plays a critical role in the survival and growth of sarcomas, and that inhibiting DDX3 with a new compound that we have developed, designated RK-33, will be an effective treatment for patients with relapsed sarcoma.  We will test this hypothesis through three specific aims: 
1) We will identify which proteins in sarcoma cells are controlled by DDX3
2) We will determine whether certain sarcoma-associated mutations affect how much DDX3 is present in a sarcoma, and
3) We will initiate a dose-finding clinical trial of RK-33 in patients with relapsed sarcoma.

This work will clarify the role of DDX3 in sarcomas, provide insight into how DDX3 is regulated, and begin the process of bringing a novel, targeted drug into clinical use for a group of patients with a dismal prognosis.