Scientists at the University of Texas Southwestern Medical Center have discovered a key protein that is involved in the growth of a deadly and rare type of soft-tissue cancer. They found that by inhibiting the action of the key protein, known as BRD4, cancer cells in a mouse model of malignant peripheral nerve sheath tumors (MPNSTs) begin to die.
According to Dr. Lu Le, Assistant Professor of Dermatology at UT Southwestern and senior author of the study, “This study identifies a potential new therapeutic target to combat MPNST, an incurable type of cancer that is typically fatal. The findings also provide important insight into what causes these tumors to develop.”
MPNST can develop suddenly and approximately half of all cases involve patients with a genetic disease known as neurofibromatosis type 1 (NF1), an aggressive sarcoma that forms around nerves. It is reported to affect 1 in 3,500 people and about 10 percent of NF1 individuals will develop MPNST. These tumors start out as benign and develop into a large plexiform neurofibroma. Current treatment protocol for plexiform neurofibromas is surgical removal, which proves difficult due to the tumor’s location around nerves. Radiation and chemotherapy is another option, but limited in effectiveness. The five-year survival rate for MPNST patients is about 50 percent.
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Le and colleagues were able to study changes in these cells as they develop into cancerous MPNSTs. They were able to determine that BRD4, a bromodomain protein, is expressed in high amounts in the cancer cells. BRD4 binds to DNA to regulate gene activation. This in turn affects a protein known as BCL-2 to keep cancer cells from dying. Researchers were able to inhibit BRD4 by administering a compound known as JQ1 which caused the tumors to shrink. Additionally, this treatment caused the cancer cells to undergo programmed cell death (apoptosis).
The same class of drug is currently being evaluated in phase 1 and 2 trials for leukemia and a subtype of lung cancer. UT Southwestern has partnered with a pharmaceutical company to develop a similar BRD4-inhibiting drug and will begin a clinical trial for MPNST positive patients.
Le, who also serves as Co-director of UT Southwestern’s Comprehensive Neurofibromatosis Clinic, notes, new drugs are needed for MPNST and this provides hope to NF1 patients. The clinic offers neurofibromatosis individuals access to the latest clinical trials and therapies. The clinic is part of the Harold C. Simmons Comprehensive Cancer Center and is co-directed by Dr. Laura Klesse, Assistant Professor of Pediatrics. The clinic serves all three types of hereditary neurofibromatosis, including dominant NF1 type and NF2 and Schwannomatosis forms.