Outside the Box
Five cancer-fighting experts go beyond scientific boundaries to take innovative cancer research and patient care in new directions.
by Alicia Di Rado and Lori Oliwenstein
What went wrong?
Cancer patients know that somehow, for causes they cannot pin down or explain,
something went awry in their bodies to cause the disease that has so changed
their lives.
While patients try to make some sense of it all, scientists ask the same
question, but for a very different reason. For investigators and physicians,
the answers to the enduring mystery—what makes cancer start and thrive—holds
the key to beating back malignancy.
A new corps of cancer-fighting experts at USC/Norris Comprehensive Cancer
Center is tackling the cancer whodunit with scientific zeal and an infectious
curiosity. These five new faculty members will build on the advances made
by researchers already at USC/Norris, while expanding innovative research
programs in new directions.
Cathie T. Chung, M.D., Ph.D., exclusively cares for patients, bringing the
latest discoveries to bear in the treatment of breast cancer. Basic scientists
Judd Rice, Ph.D., and Woojin An, Ph.D., perform the laboratory research that
makes medical advances possible. Allen Yang, M.D., Ph.D., and Ana Aparicio,
M.D., straddle both domains, balancing patient care in hematologic and genitourinary
cancers with basic research.
Cathie T. Chung, M.D., Ph.D. 
Soon, instead of a single, cell-blasting chemotherapy for all cancer patients,
a variety of molecular “smart bombs” will partner with chemotherapy
to disrupt the many mechanisms at the heart of each individual’s cancer.
Oncologists have already started to add some of these therapies to their
toolbox, says Cathie T. Chung, M.D., Ph.D., assistant professor of medicine
at the Keck School of Medicine and the newest breast cancer specialist at
the Harold E. and Henrietta C. Lee Breast and Ovarian Center at USC/Norris.
Chung is especially interested in biological therapies, treatment methods
that interfere with how cancer develops and grows. Probably the best-known
example of such therapies is Herceptin.
Herceptin targets only aggressive cancer cells that have lots of human epidermal
growth factor receptor 2 (HER2) proteins on their surface; traditional chemotherapy
blasts all fast-growing cells, cancerous and healthy ones alike.
Just like Herceptin, new biologic therapies will battle certain cancer types
because they go after precise characteristics that make that cancer tick.
Chung believes researchers have a plethora of targets in cancer cells to explore
for the next Herceptin-like drugs.
Chung is enthusiastic about bringing research from the lab bench to fruition through clinical trials at USC/Norris.
“The breast oncologists at Norris already have a large number of clinical
trials here: They have a track record,” she says, holding a list of about
30 current breast cancer trials. “I’d like to expand on that—do
trials of some new biologics and new small molecules.”
Although Chung exclusively treats patients, she is no stranger to the lab.
As a scientist at the National Institutes of Health, she focused on signal
transduction research in the study of alcoholism and drug abuse and infectious
diseases.
Still, she yearned to see how science came alive in patients—so she
returned to academia, graduating from George Washington University’s
medical school. Cancer seemed a natural direction to follow: “Oncology
was where great science was being done,” she says.
After stints at UC San Francisco and Stanford University, Chung moved to
USC/Norris, where she hopes to make a difference by bringing her research
background to patient care.
“Today, in oncology, to be an innovator, you can’t rely on pure basic science or pure clinical science,” she says. “Oncologists need to be a real merger of the two to fight cancer.”
Allen Yang, M.D., Ph.D
One minute Allen Yang, M.D., Ph.D., is an oncologist, caring for patients
with leukemia.
The next, he is a basic scientist, exposing cancer cells in his lab to an
experimental drug that may soon join medicine’s cancer-fighting arsenal.
Balancing his research time with his patient-care time can be tough. “But
there are advantages in both worlds,” Yang says. “And the advances
you make in one benefit the other.”
Yang already has his lab up and running at USC/Norris. On the clinical side,
he is developing a program to offer trials of investigational therapies, based
in epigenetics, to patients with hematologic malignancies that have resisted
traditional medications.
Not bad for someone who started out as a student of the very physicians and
scientists he works with today at USC/Norris.
Yang attended medical school at USC, where he enrolled in the rigorous M.D./Ph.D.
program. While learning to treat patients, he also delved into the basic science
behind cancer’s inner workings. He joined the lab of USC/Norris Director
Peter Jones, Ph.D., a DNA methylation pioneer. The DNA methylation field was
in its infancy, and Jones became Yang’s trusted mentor.
In 2001, Yang joined leukemia experts at the M.D. Anderson Cancer Center
in Houston. There, he began working with decitabine, an experimental methylation-inhibiting
drug he first studied in Jones’ lab. Scientists knew decitabine seemed
to fight blood cancers, but it was hard to tell how well it worked from patient
to patient and why.
Yang developed a sensitive test to show how strongly decitabine stifled DNA
methylation in each patient. The valuable test provides insight into how the
drug acts, and Yang hopes it will help oncologists use decitabine effectively
in the future.
Much of that work will go on at USC/Norris. “I’ve come to the hub
of the epigenetics universe,” Yang says enthusiastically, rattling off
a list of prominent epigenetics researchers based at USC. And he is excited
about the research prospects.
His first set of experiments pair decitabine with hydroxyurea to see if the
drugs work even better in combination.
“We’re also testing new demethylation drugs, and existing drugs
that seem to be methylation inhibitors,” he says. “Once we figure
out how these are inhibiting methylation, we can then try to make them more
potent.
“There’s a lot of work to be done.”
Ana Aparicio, M.D.
“If you’re an oncologist, people seem to think, ‘how depressing,’”
says Ana Aparicio, M.D., a native of Madrid, Spain and assistant professor
of medicine at the Keck School of Medicine. “But oncology really is one
of the areas where you can make the most difference in people’s lives.”
One reason for this bright outlook may lie in new classes of medications
that draw on recent epigenetics research findings.
“These drugs are five years—or even less—away,” Aparacio
says.
She should know; she conducted some of the drugs’ first clinical trials
at USC/Norris, evaluating them in patients with melanoma, breast cancer and
other solid cancers.
When not treating patients—she
specializes in genitourinary cancers, such as malignancies of the bladder—Aparicio
conducts research within the lab of DNA methylation expert and Cancer Center
Director Peter Jones, Ph.D. She is interested in drugs called histone deacetylase
(HDAC) inhibitors, which might form an especially dynamic duo with demethylation
drugs. HDAC inhibitors seem to create cancer roadblocks—such as deterring
tumors from growing new blood vessels to feed themselves, while encouraging
damaged, potentially cancerous cells to annihilate themselves.
On their own, demethylation drugs are intriguing, too.
For one, she says, demethylation drugs such as decitabine are surprisingly
more effective in low doses than high ones. That means researchers need to
do some homework through clinical trials, studying how various doses of the
drugs affect tumors in patients.
“But the problem with solid tumors, such as breast or colon cancer,
is that you can’t keep going in and testing a person’s cancer cells
to see how active the drugs are in their body,” she explains. “You
need to find another way.”
So Aparicio is seeking out convenient biomarkers—tests that can be done
on blood or saliva—that signal how well the drugs are fighting solid
tumors during treatment. It is a perfect assignment for someone who admits
to being “curious about everything.”
“The research simply makes me a better oncologist,” Aparicio says.
“You need to understand the drugs you’re working with to apply them
better in the clinic.”
Judd Rice, Ph.D. 
Judd Rice, Ph.D., regularly peers into the tangled mess of DNA, proteins and
enzymes that fill a cell’s nucleus and are the lynchpins in the development
of cancer. And yet, he remains notably optimistic.
Perhaps that is because Rice believes in the potential that lies in the pioneering
work he and other scientists at USC/Norris are doing on epigenetic gene regulation—the
turning on and off of genes by chemical modifications to structures in the
nucleus.
In a cell that is not currently dividing—which is most cells, most of
the time—DNA is a component of chromatin, a mix of proteins and nucleotides
in the cell’s nucleus.
The DNA is wrapped around a core of proteins called histones; DNA plus a
histone protein is called a nucleosome, and it is the way nucleosomes are
strung together—whether their structure is tight or loose, for instance—that
determines whether the wrapped DNA is able to be physically reached and read
by the cell’s protein-producing machinery.
“What I’m trying to do is to understand better just how nucleosome
structure is regulated, and the effect that has on translation and transcription
of DNA,” Rice says.
Specifically, Rice studies the “tails” of the histone proteins,
which tend to stick out of the bundled-up nucleosome and into the nucleus
itself, and serve as lightning rods for an epigenetic process known as methylation—the
addition of a methyl group to a stretch of protein or DNA. Rice and his colleagues
have shown that changes in chromatin structure due to histone tail methylation
can vary depending on where the methyl group is placed—or even what enzyme
places it there.
For now, Rice’s laboratory, located in the Zilkha Neurogenetic Institute
pending completion of the Harlyne J. Norris Cancer Research Tower, is working
to understand the biological significance of these modifications.
“My ultimate goal,” he says, “is not only to understand how these enzymes and protein modifications are important to normal development, but to also understand how dysmodifications lead to certain diseases—cancer, in particular.
Woojin An, Ph.D 
As a biochemisy and molecular biologist, Woojin An. Ph.D., focuses mainly on the inner workings of cells - specifically, on the exposed bits of protein and DNA that play key roles in determining which genes get expressed and which proteins are produced in the human body.
Like his colleague, Judd Rice, Ph.D., An studies chromatin and the way DNA is wound tightly around histone proteins and then, ultimately, unwound to be translated into enzymes and other proteins for the cells to use. Ann mainly focuses on decoding the transcriptionally active role played by the histone tails that stick out of these bundles in the cell's nucleus.
These histone tails, An explanis, are studded with chemical tags of methyl groups, acetyl groups and/or phospo groups. These chemical changes are important to determine what happens to the rest of the histone-and-DNA complex- whether it relaxes and unwinds exposing long stretches of DNA to transcrption machinery, or whether it curls up into ever tight tangles, making gene transcription virtually inpossible.
An says thse post-synthetic changes to the histone tails "act as signals, letting the transcription machinery know to gather at that site so gene transcription can take place."
An is looking specifically at the way the tumor-supressor protein p53 activates gene transcription that promotes cell-growth arrest for damaged DNA repair.
In June 2004 issue of the journal Cell, An demonstrated that p53 not only calls in one protein that can place an actyl group on the histone tail, bust also two different proteins that place methyl group on the histone tail - and theu do so in a very specific order.
An's next step is to determine what happens at the cellular level when p53, the most frequently mutated gene in human cancers, does not work with various histone modifications. "It's important to know how differnet histone modifications are functioning in the normal cell", An says. "But it's equally important to find out what happens when p53 is mutated, as it is 50 percent of human cancers. Most of the genes p53 affects play an important role in stopping cell growth or promoting cell death. If p53 can't do its job, then the cell is in trouble. And we know exactly how all p53-responsive genes are controlled by chemical modifications of histones.
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