James E. Bradner, MD
In the quest to arrest the growth and spread of tumors, there have
been many attempts to get cancer genes to ignore their internal
instruction manual. In a new study, a team led by Dana-Farber Cancer
Institute scientists has created the first molecule able to prevent
cancer genes from "hearing" those instructions, stifling the cancer
process at its root.
The study, published online by the journal Nature,
demonstrates that proteins issuing stop and start commands to a cancer
gene — known as epigenetic "reader" proteins — can be targeted for
future cancer therapies. The research is particularly relevant to a
rare but devastating cancer of children and young adults known as NUT
midline carcinoma (NMC) — a disease so obstinate that no potential
therapy for it has ever reached the stage of being tested in a clinical
"In recent years, it has become clear that being able to control gene
activity in cancer — manipulating which genes are 'on' or 'off' — can
be a high-impact approach to the disease," says the study's senior
author, James Bradner, MD, of Dana-Farber. "If you can switch off a cancer cell's growth genes, the cell will die. Alternatively, switching on a tissue gene can cause a cancer cell to become a more normal tissue cell."
In this study, Bradner's lab synthesized a molecule that has both
effects: by blocking a specific abnormal protein in NUT midline
carcinoma cells, it stops them from dividing so prolifically and makes
them 'forget' they're cancer cells and start appearing more like normal
The assembled molecule affects the cell's multi-layered apparatus for
controlling gene activity, a set of structures collectively known as
the epigenome. Vast portions of each gene play a regulatory role,
dictating whether the gene is active, busily sending orders for new
proteins, or inactive, and temporarily at rest. The gene's DNA is
packaged in a substance called chromatin, which is the slate on which
instructions to begin or cease activity are inscribed.
The instructions themselves take the form of "bookmarks," substances
placed on the chromatin by so-called epigenetic "writer" proteins.
Another group of epigenetic proteins, known as "erasers," are able to
remove the bookmarks. Both types of proteins have successfully been
disabled by scientists, using molecules made in the lab or taken from
nature. Their success has sparked intense interest in the development
of anti-cancer therapies that work by blocking such proteins.
A third variety of epigenetic proteins — potentially the most
appealing as therapeutic targets, because they switch genes on or off by
"reading" the bookmarks — has received scant scientific attention.
Bradner and his colleagues turned to this little-explored corner of
biology by focusing on NMC cells.
The disease is caused by a chromosomal "translocation," in which two
genes from different chromosomes become connected and give rise to an
abnormal, fused protein known as BRD4-NUT. A review of the scientific
literature suggested that some members of the benzodiazepine family of
drugs, which includes Valium, Xanax and Ativan, are active against
"bromodomain" proteins such as BRD4. With that as a clue, Bradner and
his Dana-Farber colleague Jun Qi, PhD, created an array of molecules to
see if any inhibited a "reader" protein of the BRD4-NUT gene. One did,
quite convincingly — a hybrid molecule, which researchers named JQ1, for
The investigators worked with researchers in the U.S. and overseas to
learn more about the properties of JQ1 and how it works in cells.
Stefan Knapp, PhD, of Oxford University in England, provided
crystal-clear images of the molecule bound to a protein; Olaf Wiest,
PhD, of the University of Notre Dame, showed that the molecule is less
flexible in the presence of a protein, explaining why it so effectively
blocks the protein; and Andrew Kung, MD, PhD, of Dana-Farber, engineered
animal models in which the molecule could be tested against NMC tumors.
The animal studies were especially encouraging. Investigators
transplanted NMC cells from patients into laboratory mice, which were
then given the JQ1 molecule.
"The activity of the molecule was remarkable," says Bradner, who is
also an associate member of the Chemical Biology Program at the Broad
Institute of Harvard and MIT. "All the mice that received JQ1 lived;
all that did not, died."
For now, JQ1's main utility is as a probe for better understanding
the biology underlying NUT midline carcinoma. Bradner, Qi and their
colleagues are tweaking the molecule to maximize its effectiveness as a
BRD4-NUT stopper. Eventually, it, or a similar molecule, could be the
basis for the first effective therapy against NMC.
"The disease tends to arise in the chest, head, or neck, along the
vertical centerline of the body, with aggressive tumor growth and
metastasis," Bradner explains. "Patients may have a brief response to
chemotherapy, but they eventually succumb to the spread of the disease."
Unlike most cancers, NMC's tissue of origin isn't known. It is a
disease defined entirely by its genetic signature — the presence of the
translocated gene BRD4-NUT. Prior to its genetic
identification by Christopher French, MD, of Brigham and Women's
Hospital and a study co-author, NMC wasn't recognized as a distinct
"This research further illustrates the promise of personalized
medicine," Bradner remarks, "which is the ability to deliver selected
molecules to cancer-causing proteins to stop the cancer process while
producing a minimum of residual side effects. The development of JQ1 or
similar molecule into a drug may produce the first therapy specifically
designed for patients with NMC."
In addition to Qi, the study's other lead authors are Panagis
Filippakopoulos and Sarah Picaud, of Oxford University, England. The
paper's co-authors include William Smith, Elizabeth Morse, Michael
McKeown, Yuchuan Wang, PhD, Amanda Christie, and Nathan West, of
Dana-Farber; Oleg Fedorov, Tracey Keates, Ildiko Felletar, Martin
Philpott, Shonagh Munro, Tom Heightman, and Nicholas La Thangue, of
Oxford University; and Tyler Hickman, Michael Cameron, and Brian
Schwartz, PhD, of Brigham and Women's Hospital.
The study was supported in part by the Chemistry-Biochemistry-Biology
Interface Program at the University of Notre Dame, Dana-Farber/Harvard
Cancer Center, the National Institute of General Medical Sciences, the
National Institutes of Health, the Burroughs Welcome Fund, and the
Leukemia & Lymphoma Society.