Researchers Take New Approach to Stop ‘Most Wanted’ Cancer Protein
November 07, 2014
finds tumors shrink with little or no harm to normal cells
BOSTON — Researchers at Dana-Farber/Boston
Children’s Cancer and Blood Disorders Center have found a way to defeat one
of the most tantalizing yet elusive target proteins in cancer cells — employing
a strategy that turns the protein’s own molecular machinations against it.
In a study published online by the journal Cell, the scientists 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. 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 – essentially serving 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,” says the lead
author of the new study, Edmond Chipumuro, PhD, of Dana-Farber Cancer Institute. “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,
neuroblastoma is 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
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
about 50 percent of all cases of aggressive neuroblastoma.
One of the genes that becomes hyperactive through this
process is MYCN itself — 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.
Transcription factors like 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 “super-enhancers” because they
turbocharge the activity of neighboring genes.
One of the many proteins used in the assembly of a
super-enhancer is CDK7. This is the protein that researchers sought to block in
the current study.
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, 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
“Because normal cells don’t acquire super-enhancers on
these master regulators, the agent had a profound impact on neuroblastoma
tissue but not on normal tissue,” says the study’s senior author, Rani
George, MD, PhD, of Dana-Farber/Boston Children’s. “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.
The co-authors of the study are Eugenio Marco, PhD,
Camilla Christensen, PhD, Tinghu Zhang, PhD, Clark Hatheway, Bandana Sharma,
PhD, Caleb Yeung, Abigail Altabef, Kwok-Kin Wong, MD, PhD, Guo-Cheng Yuan, PhD,
and Nathanael Gray, PhD, of Dana-Farber; Nicholas Kwiatkowski, PhD, Brian
Abraham, PhD, and Richard Young, PhD, of the Whitehead Institute for Biomedical
Research at the Massachusetts Institute of Technology; and Antonio
Perez-Atayde, PhD, of Boston Children’s Hospital.
The study was supported by grants from the National
Institutes of Health, American Cancer Society, U.S. Department of Defense, and
Friends for Life Neuroblastoma Foundation.