New approach to stop most-wanted cancer protein

A specially crafted compound targeting the protein MYCN in cancer cells can disrupt the protein's ability to rev up its own production and that of other proteins involved in tumor cell growth.

The result, in laboratory samples of neuroblastoma cancer cells and in mice with an aggressive form of neuroblastoma, was death of the cancer cells and retreat of the animals' tumors, with little or no harm to normal cells. Neuroblastoma is a pediatric cancer that begins in embryonic nerve cells and generally occurs in infants and young children.

The study, published in Cell (2014; doi:10.1016/j.cell.2014.10.024), focused on a cell protein called MYCN, one of a family of proteins that are notorious not only for stimulating the growth and proliferation of cancer cells, but also for their ability to evade targeted drug therapies. Like other members of the MYC family, MYCN has proved very difficult for targeted agents to reach and latch onto, making it, for all intents and purposes, undruggable. Researchers are hopeful that the approach they used in this study of neuroblastoma may prove effective against some of the many other cancers also characterized by a surplus of MYC-family proteins in tumor cells.

MYCN and its kin are transcription factors, proteins that bind to DNA and influence the rate at which genetic information is used by the cell. These essentially serve as brightener/dimmer switches for gene activity.

"Recent studies have shown that when transcription factors like MYC are mutated or overabundant, they can have a cancerous effect. They cause a global rise in gene expression, making genes throughout the cell more active," said lead author Edmond Chipumuro, PhD, of Dana-Farber Cancer Institute in Boston, Massachusetts. "Because transcription factors have proven so difficult to block with targeted therapies, we wanted to see if an alternative approach that targets these defective transcriptional mechanisms would be effective."

Although very rare in children older than 10 years, neuroblastoma is by far the most common cancer in infants. It accounts for approximately 7% of all cancers in children, and 15% of all pediatric cancer deaths.

The type of neuroblastoma studied by the investigators is distinguished by a glut of MYCN protein in the tumor cells. Such MYCN-amplified disease accounts for approximately 50% of all cases of aggressive neuroblastoma.

This process causes MYCN itself to become hyperactive, producing a self-perpetuating loop in which surplus MYCN spurs the production of more MYCN, which results in an even greater surplus and more cancerous growth. One of the proteins that increases MYCN production is CDK7.

In this study, chemical biologists designed and custom-made a compound called THZ1 that forms a particularly strong bond with CDK7, rendering the protein essentially nonfunctional. When researchers treated laboratory samples of MYCN-amplified neuroblastoma cells with THZ1, the tumor cells died, but normal cells were unaffected. When they used the agent to treat mice with this type of neuroblastoma, the tumors shrank markedly, with no negative side effects for the animals.

Work is now underway to develop THZ1 into a drug that can be tested in human patients.

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