A particularly slippery transcription factor, MYCN, is thought to stimulate tumor cell growth and proliferation through amplification of gene transcription. MYCN and like proteins are slippery in the sense that they are all but “undruggable”—would-be drugs fail to latch onto them, and so they go their merry way, stirring otherwise tame stretches of DNA to frenzies of activity.
The MYCN-induced frenzy, it turns out, is self-reinforcing. One of the genes that becomes hyperactive is the gene for MYCN itself. Surplus MYCN spurs the production of more MYCN, which results in an even greater surplus and more cancerous growth. In this case, the growth perpetuates an aggressive form of neuroblastoma, a pediatric cancer that begins in embryonic nerve cells and generally occurs in infants and young children.
To thwart MYCN-induced neuroblastoma, researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center decided to take an indirect approach. Rather than direct a drug against MYCN, the researchers went after one of the oncoprotein’s supporting players.
Transcription factors such as MYCN work by summoning certain co-factor proteins to attach themselves to specific sections of DNA. The co-factors work like miniature pep squads, spurring nearby genes into activity. When MYCN is amplified, as in many cancer cells, it performs its work indiscriminately: Too many gene-activating proteins congregate at many long stretches of DNA. These stretches are known as “superenhancers” because they turbocharge the activity of neighboring genes.
One of the many proteins used in the assembly of a superenhancer is CDK7. This is the protein that researchers sought to block.
The researchers, led by Rani George, M.D., Ph.D., report that this approach produced encouraging results: In laboratory samples of neuroblastoma cancer cells and in mice with an aggressive form of neuroblastoma, cancer cells were killed and the animals’ tumors retreated, and normal cells suffered little or no harm.
These results appeared November 6 in the journal Cell, in an article entitled, “CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer.”
“Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification,” wrote the authors. “The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of superenhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma.”
The researchers devised and deployed on a compound called THZ1, which forms a particularly strong bond with CDK7, rendering the protein essentially nonfunctional.
“Because normal cells don’t acquire superenhancers on these master regulators, the agent had a profound impact on neuroblastoma tissue but not on normal tissue,” says Dr. George. “We’ve shown that it is possible to stifle MYCN itself as well as the effects of MYCN amplification.” Work is now underway to develop THZ1 into a drug that can be tested in human patients.