Controlling gene expression to halt cancer growth

NUT midline carcinoma (NMC) is a cancer without a cure, and one that affects all age groups. NMC is a rapid-growth disease with an average survival time of four and a half months after diagnosis, making the development of clinical trials for potential therapies or cures for this cancer difficult, to say the least.

But difficult doesn't mean impossible, and Olaf Wiest, professor of chemistry and biochemistry at the University of Notre Dame, is one of a group of collaborators studying the effects of a specific molecule (JQ1) on the trigger that controls the growth of this form of cancer.

Most people are familiar with genetics and the role they play in our height, hair color, and even predisposition to various diseases. "But there is this whole other world called epigenetics that controls which genes are expressed and which aren't," says Wiest.

This epigenetic world is made up of three classes of proteins: writers, erasers and readers, collectively the "instruction manual" that tells a gene when to activate and when to cease activation. Writers will create the instruction for the gene while erasers will remove instructions. Readers control the group and issue the start and stop commands for genes to use their instructions.

"The reason NMC is so aggressive is because these cancer cells divide very fast," says Wiest. This rapid-growth is caused by the protein BRD4, an epigenetic reader that interacts with another protein called a histone. Their interaction changes the instructions for the gene and keeps the growth trigger permanently activated.

"The solution is that you have to block that protein," Wiest says. "Which is something that is traditionally very difficult in protein-to-protein interactions because the binding between them is not very strong. Normally when you're talking to somebody in chemistry and say you're going to target a protein to protein interaction, they say 'you're nuts.'"

NUT midline carcinoma (NMC) is a rare and life-threatening type of cancer. It typically, but not always, affects the body’s "midline," including the nose, mouth, sinuses, trachea, upper airways, chest, and thymus. NMC occurs in both children and adults. NMC is often resistant to treatment; currently the average survival from diagnosis is less than one year. NMC is named for and defined by a DNA mutation of the NUT gene. In all NMCs, NUT is fused to another gene, most commonly BRD4, forming the BRD4-NUT fusion oncogene. Described by our group in 2004, NMC is a newly recognized disease, and awareness within the medical community remains limited. NMC is under-diagnosed and its true frequency in the population is not known. An optimal approach to treating this cancer has not yet been developed. We have formed the International NUT Midline Carcinoma Registry to increase awareness of this disease and to learn more about what causes it and how to treat it.

"Of course the way to prove them wrong is to go on and do it," he concludes.