Understanding epigenetics to develop new therapies
By Hilary Graham
Some might call it fate. Three scientists who started their careers in different parts of the world and come from different scientific disciplines now work together at
MD Anderson to develop new treatments for patients.
Philip Jones, Ph.D., a medicinal chemist originally from England, and
Jannik Andersen, Ph.D., a biologist originally from Denmark, are both drug discovery scientists who spent time at the pharmaceutical giant, Merck and Co., while Michelle Barton, Ph.D., a professor in Biochemistry and Molecular Biology, is originally from Illinois and has spent the past 13 years at MD Anderson.
identify drug candidates that selectively
kill cancer cells. Via a cross-departmental
collaboration, Yanai Zhan (left) and
Xi (Thomas) Shi (center), members of
Jannik Andersen’s biology team, discuss
such findings with Srikanth Appikonda, Ph.D.,
postdoctoral fellow in Michelle Barton’s lab
and an expert on TRIM24 biochemistry.
Photo: Wyatt McSpadden
When Jones and Andersen moved from Boston to join the Institute for Applied Cancer Science (IACS) in 2011, they were excited to meet Barton, whose research had linked a novel epigenetic protein to breast cancer. This work, which was published in the prestigious journal Nature, included an analysis by Mien-Chie Hung, Ph.D., vice president for Basic Research and co-leader of the Breast and Ovarian Moon Shot.
The study characterized the mode of action of a novel bromodomain-containing protein, called TRIM24, and showed that overexpression of this protein correlates with a poor prognosis for breast cancer patients.
The histone code
When genomic DNA is packed into the nucleus of a cell, it’s first wrapped around a core of histone proteins, which condenses the DNA into chromatin structures — like thread wrapped around a spool. Several families of enzymes then act in concert to add or remove small chemical marks that modify the histones. These marks have evolved into a sophisticated language known as the “histone code.”
In contrast to DNA mutations, these marks are reversible (i.e. they can be written and erased), and the study of these marks is known as epigenetics. These modifications act as “zip codes” to recruit specific enzymes to the DNA, thereby controlling gene expression and, in the case of cancer, promoting aberrant cell growth. TRIM24 is one such protein that binds to these chemical marks and helps to read the histone code.
Promising new drugs that prevent the binding of specific epigenetic reader proteins to histones are already in early clinical development. Barton’s data suggests that inhibiting TRIM24 with a small molecule drug might benefit breast cancer patients.
Formation of a drug discovery team
Based on the above discovery, Jones and Andersen quickly established a collaboration with Barton and her research group to jump-start a drug discovery program on TRIM24 and other cancer-relevant “reader” proteins. First, they assembled a cross-functional team of scientists from within IACS who have the shared goal of identifying a small molecule that can bind to TRIM24 and inhibit its function in cancer cells, which may ultimately benefit patients as a therapeutic drug.
The project team comprises scientists from multiple disciplines, who work together to design a single molecule with all the characteristics necessary for a new drug to be effective in the clinic.
Working together toward a common goal
To initiate any small-molecule drug discovery program, a suitable screening assay (test) must be established to evaluate small molecules that may bind to and inhibit the protein. This requires an understanding of the underlying biology of the target protein and its role in the disease process.
Fortunately, through some elegant scientific experiments, Barton’s group had already defined the specific histone mark that was recognized by TRIM24. These insights allowed the in vitro pharmacology group at IACS to quickly establish relevant binding assays. Such tests are conducted rapidly and reproducibly using extensive laboratory robotics.
Medicinal chemists at IACS then began to design and synthesize novel small molecules that bind to pockets on the protein’s surface. Close collaborations with structural biologists John Ladbury, Ph.D., and Guillaume Poncet-Montange, Ph.D., professor and instructor in Biochemistry and Molecular Biology, respectively, allow the medicinal chemists to get a snapshot of how their small molecules interact with the protein, thereby helping them rationally design the next iteration
(see “Revealing structural insights”).
Typically the chemistry team makes 25-50 new molecules each week, which are then tested in the screening assays. When the biological data is returned to the chemists, they seek to understand which features of the molecule improve activity and immediately make more potent versions.
In addition to potency, the medicinal chemistry team must install all the qualities necessary for the compound to be effective absorbed and properly distributed in the body and delivered to cancer cells. They also need to avoid its premature elimination from the body by metabolism and excretion. Finally, the team ensures the drug will be safe and well tolerated in humans. To date, the team has generated thousands of related small molecules that are progressively becoming more drug-like.
In parallel, Andersen and his team developed sophisticated novel assays to measure the activity of TRIM24 in cancer cells — showing how this protein enters the nucleus of cancer cells and binds to histones. The small molecules made by the IACS team block this interaction. Currently the project team is working with Barton’s group to further understand how and in what specific setting this inhibition can effectively kill cancer cells.
Beyond TRIM24, IACS is also aggressively focusing on other epigenetic proteins that “write” and “erase” the histone marks. These fully integrated projects align cancer biologists and drug discovery scientists at IACS with the world-class clinicians at MD Anderson, working toward the common goal of delivering new effective therapeutics that benefit cancer patients.
Collaboration and discovery
Beyond the drug discovery effort at IACS, a number of MD Anderson researchers and clinicians are making seminal contributions to the fundamental understanding of the biology of epigenetic regulators, as well as leading clinical trials of newly developed experimental epigenetic therapies.