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Rare Type of Soft-Tissue Cancer May Be Cured by Suppressing Tumor Growth Protein

By BiotechDaily International staff writers
Posted on 13 Jan 2014
A rare, lethal type of soft-tissue sarcoma may be entirely eradicated merely by suppressing a key protein involved in its growth.

In the study published online December 26, 2013, in the journal Cell Reports, scientists report on the discovery that suppressing the action of a protein called BRD4 caused cancer cells to die in a lab mouse model of malignant peripheral nerve sheath tumors (MPNSTs).

“This study identifies a potential new therapeutic target to combat MPNST, an incurable type of cancer that is typically fatal,” said Dr. Lu Le, assistant professor of dermatology at the University of Texas (UT) Southwestern (Dallas, USA), and senior author of the study. “The findings also provide important insight into what causes these tumors to develop.”

MPNSTs are very aggressive sarcomas that form around nerves. These tumors can develop sporadically, but approximately 50% of cases are in patients with a genetic disorder called neurofibromatosis type 1 (NF1) that affects 1 in 3,500 people. About 10% of NF1 patients will develop MPNST, which usually evolves from a benign but often large and disfiguring tumor called a plexiform neurofibroma.

Up to now, the preferred treatment for MPNST has been surgical removal, but that frequently is difficult or impossible due to the tumor’s location around nerves. Radiation and chemotherapy are other alternatives, but their effectiveness is limited. The five-year survival rate for MPNST patients is about 50%.

By studying alterations in cells as they evolved into cancerous MPNSTs, researchers in Dr. Le’s laboratory were able to determine that BRD4, a bromodomain protein that binds to DNA to regulate gene activation, is expressed at an unusually high level in MPNST cancer cells. This action caused another protein called BCL-2 to keep cancer cells from dying. Alternately, when researchers inhibited BRD4 either genetically in the mice or pharmacologically by administering a compound called JQ1, the tumors shrank.

“These treatments suppressed tumor growth and caused the cancer cells to undergo apoptosis, or cell death. This is why BRD4 inhibition is exquisitely effective against MPNSTs and may represent a paradigm shift in therapy for these patients,” Dr. Le said.

The same class of drug used in the experiments is currently being evaluated in phase 1 and 2 trials for treatment of leukemia and a subtype of lung cancer. UT Southwestern in the meantime is working with a pharmaceutical company to develop a similar BRD4-inhibiting drug to initiate a clinical trial for MPNST patients.

New agents are urgently needed to treat MPNST and provide hope to NF1 patients at highest risk for this cancer, according to Dr. Le, who also serves as codirector of UT Southwestern’s Comprehensive Neurofibromatosis Clinic.

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University of Texas Southwestern



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