Scientists devise targeted therapy strategy for rare form of childhood cancer

By "distracting" cancer proteins from their usual activity, scientists at Dana-Farber Cancer Institute and Brigham and Women's Hospital have caused cells in a rare, lethal form of cancer to begin behaving like normal cells - one of the longest-standing, and most rarely achieved, goals of cancer research. The study's findings are published online by the journal Cancer Research and will appear later in a print issue.

When the approach was tested in a child with an advanced case of the malignancy, known as NUT midline carcinoma (NMC), it slowed the course of the disease for several months. That result, in a cancer for which there are no other effective treatments, is a powerful impetus for making the new therapy available to patients in clinical trials, the authors assert.

"NUT midline carcinoma arises people of all ages, but predominantly in children and young adults," explained the study's senior co-author, James Bradner, MD, of Dana-Farber. "It usually originates in the chest, sometimes in the head or neck, and is often mistaken for other types of cancer. Traditional therapy involves surgery, radiation, and chemotherapy, but even in combination these approaches don't work well: most patients live only about nine and a half months after diagnosis. As we've learned more about the molecular basis of the disease, we've begun to be able to devise therapies against it."

The cause of the disease was discovered by Christopher French, MD, a senior author of the study from Brigham and Women's Hospital. It results from a "translocation" in which two genes from different chromosomes stick together and give rise to an abnormal, fused protein called BRD4-NUT. While Bradner and his colleagues have subsequently developed and studied compounds that target BRD4-NUT directly, the newly published study involves a more oblique approach.

Researchers discovered that BRD4-NUT causes cells to become cancerous by attaching to DNA's packing material within the nucleus - a band of proteins known as histones, part of the machinery for switching genes on and off. BRD4-NUT essentially locks down the machinery's control panel, preventing changes that allow cells to develop into mature, stable, slow-growing adults, leaving them in a state of perpetual, hyperactive youth.

To interfere with BRD4-NUT's affinity for histones, French and Bradner tried a diversionary tactic. They treated NMC cells with a substance called an HDAC (histone deacetylase) inhibitor, which creates competing binding sites for BRD4-NUT throughout the nucleus. The hope was that, like a burglar who bypasses one house for the promise of a bigger prize in another, the HDAC inhibitor would lure BRD4-NUT away from certain locations in the genome.

In laboratory experiments, they found that NMC cells treated with an HDAC inhibitor turned into ordinary, non-dividing skin cells - a process known as "differentiation," which has been a central goal of cancer research for well over half a century. In studies with animals engrafted with NMC tissue, animals treated with HDAC inhibitors had slower-growing tumors and lived longer than those who were not treated.