A new way to beat one of the most hard to pin down target proteins in cancer cells has been beaten by scientists by turning the protein's own molecular machinations against it.
Researchers at Dana-Farber/Boston Children's Cancer and Blood Disorders Center used a specially crafted compound to 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 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. Researchers now hope that the approach 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 - essentially serving as brightener/dimmer switches for gene activity. Lead author Edmond Chipumuro said that as per recent studies, when transcription factors like MYC were mutated or overabundant, they could have a cancerous effect. They cause a global rise in gene expression, making genes throughout the cell more active.
Although very rare in children older than 10, neuroblastoma has been by far the most common cancer in infants. It accounts for about 7 percent of all cancers in children, and 15 percent of all pediatric cancer deaths.
Chemical biologists led by Dana-Farber's Nathanael Gray, PhD, designed and custom-made a compound called THZ1 that forms a particularly strong bond with CDK7, which is one of the many proteins used in the assembly of a super-enhancer, 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.
Study's senior author, Rani George explained because normal cells didn't acquire super-enhancers on these master regulators, the agent had a profound impact on neuroblastoma tissue but not on normal tissue.
The study is published online in the journal Cell.