“If we can understand how genes are tightly regulated, then we might be able to target irregular gene expression for cancer treatment,” said Zu-Wen Sun, Ph.D., assistant professor of Biochemistry and a member of the Vanderbilt-Ingram Cancer Center.

Sun’s group is exploring how cells regulate gene expression, using the budding yeast Saccharomyces cerevisiae as a model system.

From left, Zu-Wen Sun, Ph.D., Mahesh Chandrasekharan, Fu Huang and colleagues are studying how cells regulate gene expression.

One way that cells flip the switches of gene expression is by modifying histone proteins — DNA wraps around groups of these proteins in the cell nucleus. Chemical modifications (“marks”) on the histones signal whether nearby genes should be turned on or off.

Sun and his colleagues have now detailed the activity of a histone-modifying protein called Jhd2. Jhd2 — a yeast protein that is similar to the human protein SMCX — removes chemical “marks” from a particular histone. A mutation in SMCX has been linked to mental retardation, and in collaboration with the group of Scott Hiebert, Ph.D., professor of Biochemistry, the researchers showed that the mutation affects the protein’s stability.

The team’s paper in the Aug. 6 issue of the Journal of Biological Chemistry was selected as a “Paper of the Week.” This distinction is awarded by the editors to the top 1 percent of papers published each year in the journal.

“Our work gives details about Jhd2’s mechanism and how it’s regulated — very basic results — and it also has an implication for human disease,” Sun said. “It begins to explain how a particular mutation in this enzyme can cause mental retardation.”

Sun and his colleagues demonstrated that two regions of the Jhd2 protein interact with each other, and that disruption of this interaction — for example by mutations like the one in SMCX — causes the protein to become unstable.

The investigators discovered that another protein monitors the interaction of the two domains in Jhd2, and targets Jhd2 for degradation if the domains do not interact correctly. Their findings also suggest that this monitoring mechanism is conserved between yeast Jhd2 and human SMCX.

It might be possible, Sun said, to develop drugs that can stabilize the interaction and restore the protein’s function, which could help patients with mental retardation or other diseases caused by mutations in Jhd2-like proteins.

“The potential for helping patients is a long way off, but the more we know, the more likely it will be that we can discover a way to correct the problem.”

The team also probed how Jhd2 binds to the DNA-histone complex known as chromatin. They showed that a part of the Jhd2 protein called the “PHD finger” — a domain that is evolutionarily conserved from yeast to humans — was required for Jhd2 to interact with chromatin. However, it did not bind to the histone site that PHD finger domains in other proteins normally recognize.

Sun and his colleagues are now trying to identify the PHD finger-binding site on histone, which could represent a drug target site for regulating Jhd2/SMCX activity.

Graduate student Fu Huang was the first author of the paper. The National Institutes of Health, Vanderbilt-Ingram Cancer Center and Robert J. and Helen C. Kleberg Foundation supported the research.

Patients and donors helped design the Vanderbilt-Ingram Cancer Center’s newly expanded clinic lobby, waiting areas and additional examination rooms.

The new, 10,000-square-foot space is located on the first floor of The Vanderbilt Clinic, across from the existing Cancer Center reception area.

Patients and donors provided input on the space design, which has the look and feel of a hotel lobby, with soft carpet, warm wood accents and skylights for natural light.

The family resource center, which provides educational materials and a small area with a computer, is now conveniently located in the new waiting area to accommodate the needs of patients.

Perhaps best of all, patients now have direct access to the clinic and will no longer have to walk a long distance to receive care.

“Our goal is to increase patient satisfaction, and we have strived to do that in every aspect of the upgraded space,” said Carol Eck, administrative director of the Cancer Patient Care Center.

The new space is on the first floor of TVC, across from the Cancer Center’s existing reception area.

“We wanted to increase the use of the amenities in the clinic and make sure everything is easily accessible to enhance the experience for our patients,” said Eck.

There are eight additional exams rooms housed in the clinic, a consultation room and support offices.

The expansion was made possible through donations from private donors along with financial support from the University.

This is the latest element in a multi-year expansion of the cancer clinic.

Last year, VICC opened a new Chemotherapy Infusion Clinic with nearly twice the number of patient chairs, in addition to a new reception area and laboratory test space.

These targeted therapies are being tested in melanoma patients whose tumors carry a specific genetic mutation known as V600E BRAF.

Jeff Sosman, M.D., professor of Medicine and leader of the Melanoma Program at Vanderbilt-Ingram Cancer Center, is one of the study’s principal investigators.

Jeff Sosman, M.D.

Melanoma, a form of skin cancer, is especially lethal when it metastasizes to other areas of the body. Less than 10 percent of patients with metastatic melanoma are still alive five years after diagnosis, according to the National Cancer Institute.

About half of melanomas have a mutation in the BRAF gene. A new drug, known by its preclinical name, PLX4032, is a potent inhibitor of the most common mutant form of BRAF (V600E). In a Phase 1 clinical trial, most of the patients whose tumors expressed the BRAF mutation experienced significant tumor shrinkage, but the degree of tumor shrinkage varied greatly and many of the patients who responded eventually developed resistance to the drug.

“We need to identify the mechanisms of resistance to PLX4032 and prove that these mechanisms are clinically relevant,” said Sosman. “Our experience with targeted therapies for other forms of cancer suggests that understanding the causes of resistance will help us select the patients most likely to respond to this drug and to develop effective new drug combinations.”

Testing for specific genetic mutations and matching patients to targeted therapies for those mutations is one of the hallmarks of Vanderbilt’s new Personalized Cancer Medicine Initiative. Melanoma is one of the first forms of cancer being tested at Vanderbilt for relevant genetic mutations.

All of the cancer centers involved in the study have agreed to develop a database to track the acquisition and analysis of clinical specimens, standardize the molecular testing procedures and analyze the biopsies of patients who were treated with PLX4032.

“By forming this consortium, standardizing our procedures and sharing information about tissue specimens, we hope to improve the efficiency of our research,” said Sosman. “This should allow us to speed up the development of promising therapies for this aggressive disease.”

The other Principal Investigators are: David Solit, M.D., and Paul Chapman, M.D., Memorial Sloan-Kettering Cancer Center; Michael Davies, M.D., Ph.D., MD Anderson Cancer Center; Roger Lo, M.D., Ph.D., UCLA; David Fisher, M.D., Ph.D., Keith Flaherty, M.D., and Hensin Tsao, M.D., Ph.D., Massachusetts General Hospital; and Katherine Nathanson, M.D., University of Pennsylvania.

This Young Ambassadors group has made a commitment to raise $35,000 to fund a VICC Discovery Grant, awarded to young cancer investigators who don’t yet have significant government or industry support to test their scientific theories.

Members of the newly formed Young Ambassadors group have pledged to raise funds for research at Vanderbilt-Ingram Cancer Center.

Members of the newly formed organization say the mission is personal. Emily Blake (EB) Jackson, chair of the philanthropic group, has watched three of her grandparents struggle with or succumb to cancer. EB’s husband, Todd, and his family have had their own cancer challenges.

“Nearly everyone has a cancer story. My mother had breast cancer, my father had esophageal cancer and I had a brain tumor,” said Todd Jackson.

The 36-year-old health care IT executive began having seizures when he was a teenager. By 2003, the mass in his head started to grow and Jackson was referred to Reid Thompson, M.D., director of the Vanderbilt Brain Tumor Center and chair of the Department of Neurosurgery. Thompson told the young man they needed to operate on the cancerous tumor, even though the growth was perilously close to the brain’s speech center.

The surgery went so well that Todd was soon running 5k and 10k races again, and he and EB decided to help other families struggling with cancer. They were joined by other young professionals with their own family cancer stories, and by last November, with the help of VICC leaders and Vanderbilt Development and Alumni Relations, they had formed the Young Ambassadors to support cancer research.

“We want to do something productive in the fight against cancer and strongly believe that VICC is the place where the science is being created,” EB Jackson said.

The group decided to focus on young cancer investigators who need a financial jumpstart to make inroads in cancer research.

“These are new researchers coming in with passion and vision and they may be the ones to develop a new cure for cancer,” said Kate Steinbeck.

Kate, and sister Carrie Steinbeck, joined the Young Ambassadors because of the care their father received at Vanderbilt while he was battling lung cancer.

“It’s not an easy time for the family, but the level of care and knowledge shown by the team of doctors at Vanderbilt was incredible. We never felt that our dad was ‘just another patient.’ Our family became part of their family,” said Carrie Steinbeck.

Most members of the Young Ambassadors didn’t previously know one another, but they have found common ground in their commitment to cancer research. They are using e-mail, Twitter, Facebook and other social media in addition to traditional outreach to raise funds. Beth Franklin, VICC Board of Overseers member, local philanthropist, and mother of Young Ambassador Ruth Franklin, has served as a mentor to the group.

“We are all business people and not scientists, so leaders in the Cancer Center are going to give us a list of Discovery Grant-ready projects that they would fund if they could. We will interview the researchers and choose the project we find most compelling,” said EB Jackson.

The Board of Overseers has agreed to match the money raised by the Young Ambassadors to fund a second Discovery Grant. The group — which has raised nearly 75 percent of its goal — will award the first grant this fall.

“There are two ways to deal with life — proactive and reactive,” said Todd Jackson. “You can take control and search for ways to beat cancer, and the way to beat it is through research.”

For more information about the Young Ambassadors initiative, go to www.vicc.org/youngambassadors.

Those named were selected based on professional accomplishments, nomination strength and community involvement.

Dana Backlund, M.D.

• Dana Backlund, M.D., assistant professor of Medicine, was recognized in the Health Care Newcomer category.

Backlund received her medical degree from the University of North Carolina, Chapel Hill, then served her residency at Vanderbilt and was a fellow in the Division of Hematology/Oncology before joining the Vanderbilt faculty.

She is a member of Vanderbilt-Ingram Cancer Center and specializes in malignancies of the gastrointestinal tract, including pancreatic cancer.

This year she completed her Master of Science in Clinical Investigation at Vanderbilt.

Clifton Meador, M.D.

• Clifton Meador, M.D., executive director of the Meharry-Vanderbilt Alliance, was selected for the Lifetime Achievement Award in health care.

Meador came to Vanderbilt University at the age of 16 and went on to graduate from the Medical School with the highest award — the Founder’s Medal for Scholastic Honors.

He served as dean of the University of Alabama-Birmingham School of Medicine from 1968 to 1973 before returning to Vanderbilt to set up a teaching program at Saint Thomas Hospital for the residents at VUMC. He served in that role for 25 years.

Bonnie Pilon, D.S.N., R.N.

• Bonnie Pilon, D.S.N., R.N., senior associate dean for Faculty Practice at Vanderbilt University School of Nursing, was named a Health Care Hero in the Community Leader category.

During the past 11 years under Pilon’s leadership, VUSN has seen explosive growth in its faculty practice program, providing care to more than 19,000 individuals each year.

Pilon is program director for VUSN’s health systems management track in the school’s master’s program and teaches in the Doctor of Nursing Program.

Additionally, she is chief operating officer of University Community Health Services, a nonprofit Federally Qualified Healthcare Center dedicated to improving health care among vulnerable populations.

Jay Groves, Ed.D.

• Exercise physiologist Jay Groves, Ed.D., administrative director of the Vanderbilt Dayani Center for Health and Wellness and Vanderbilt Center for Integrative Health, was recognized as a Health Care Hero in the Innovator category.

Groves recently received VUMC’s Five Pillar Leader Award, which recognizes superior performance in the areas of service, quality, finance, people and innovation.

Under Groves’ leadership, the Dayani Center and the Center for Integrative Health had approximately 21,000 combined patient visits last fiscal year.

This year’s Health Care Heroes will be honored during a luncheon Oct. 1 at the Embassy Suites Cool Springs, Franklin, Tenn.

Data from the Phase 1 trial of drug PLX4032, developed by Plexxikon Inc. and Roche Pharmaceuticals, showed that nearly all patients with the mutation who were treated with the drug showed some response and 81 percent of patients had tumor shrinkage of at least 30 percent. The data were published in the New England Journal of Medicine.

Igor Puzanov, M.D., assistant professor of Medicine, and Jeffrey Sosman, M.D., professor of Medicine, Vanderbilt-Ingram Cancer Center (VICC), are among the Principal Investigators on the study. Keith Flaherty, M.D., Massachusetts General Hospital Cancer Center of Harvard University, is lead author.

Melanoma, a form of skin cancer, is curable when caught in its early stages but it can be lethal when it metastasizes to other areas of the body. Less than 10 percent of patients with metastatic melanoma are still alive five years after diagnosis, according to the National Cancer Institute.

“In the more than 20 years that I have been taking care of melanoma patients, I have not seen this kind of patient response to a therapy,” said Sosman, leader of the VICC Melanoma Program. “We finally have a way to identify patients with a specific genetic mutation who are most likely to benefit from a treatment, and a drug that targets that mutation. This is the promise of personalized medicine and Vanderbilt’s patients are benefiting from this approach to cancer treatment.”

In the melanoma extension cohort of the clinical trial, in which 32 metastatic melanoma patients with the BRAF mutation were enrolled, there were two complete responses with no evidence of disease, and 24 partial responses with tumor shrinkage of at least 30 percent. The estimated progression-free survival (PFS) among these patients was at least seven months as of January 31, 2010, compared less than two months in most clinical trials.

”This is a paradigm changing trial in melanoma treatment and a real breakthrough in melanoma research,” said Puzanov, associate director of the Phase 1 Drug Development Program at Vanderbilt-Ingram. “Our team is now involved in the next wave of trials, trying to improve these results further, hopefully leading to longer survival for patients.”

The PLX4032 drug, which is administered as a pill, is currently in parallel and ongoing Phase 2 and Phase 3 trials. The drug is a small molecule that is selective for a key oncogenic driver in melanoma and other cancers. Sosman is leading the Phase 2 trial.

While the majority of patients showed tumor shrinkage while taking the drug, the tumors eventually progressed in some cases. Investigators are now trying to determine other genetic pathways that are important in the progression of melanoma as they search for additional targeted therapies.

Drug-related adverse events during the trial included rash, joint pain, nausea, photosensitivity and fatigue. Some patients developed cutaneous squamous cell carcinoma in sun-exposed areas of the skin that was treated with surgery while treatment with PLX4032 was continued.

Learn More

See VIDEO interview with ABC News: Dr. Jeff Sosman explains how drug targets mutation.

Watch more about personalized cancer medicine in Your Genome and the Future of Medicine.

Learn more about the genome-driven therapy at Vanderbilt-Ingram Cancer Center.

Get information about our melanoma team and services, plus other resources.

Visit profiles for Drs. Puzanov and Sosman.

The annual Komen for the Cure 5K event will be in Maryland Farms on Saturday, Oct. 9.

Information breakfasts will be offered:

• Tuesday, Aug. 31, 8 a.m., breakroom at the Vanderbilt Breast Center at One Hundred Oaks
• Thursday, Sept. 2, 8 a.m., theater at the Monroe Carell Jr. Children’s Hospital at Vanderbilt
• Thursday, Sept. 9, 8 a.m., breakroom at the Vanderbilt-Ingram Cancer Center at Franklin

A fourth breakfast session will be offered at a date and time yet to be set at the Vanderbilt-Ingram Cancer Center at Cool Springs.

Register for Team Vanderbilt or learn more.

You may also call Jennifer Rice, coordinator for Team Vanderbilt, at 936-0301.

The funding establishes the Membrane Protein Structural Dynamics Consortium, comprising investigators from 14 institutions in four countries, including a team at Vanderbilt University Medical Center led by Hassane Mchaourab, Ph.D., professor of Molecular Physiology & Biophysics, Physics and Chemistry.

“This is a tremendous opportunity to combine the expertise of experimentalists and theoreticians to take on the ‘grand challenge’ of defining the mechanisms through which conformational dynamics impart function to key membrane protein classes,” said Mchaourab.

Crystal structure of the bacterial membrane protein LeuT (green), showing two sodium ions (red) and the amino acid leucine in a central cavity. (courtesy of Derek Claxton/Mchaourab lab)

In addition to providing new insights about normal cell function, the research supported by this grant could help scientists better understand a wide range of diseases caused by faulty membrane proteins, such as heart disease, diabetes and some neurological disorders. And, because more than half of today’s medicines target membrane proteins, the findings could pave the way for new or improved drugs.

Mchaourab’s team has two projects within the consortium. The goal, he said, is to “establish the energy landscape that governs the dynamics and function” of two protein “archetypes,” or representatives, of two important classes of membrane proteins.

The first project focuses on the dynamics of P-glycoprotein, a type of multi-drug transporter implicated in the resistance of cancer cells to chemotherapy. This protein acts as an “efflux pump,” ejecting drugs from the cell and rendering them ineffective. Identifying how these transporters work might reveal strategies to combat or prevent the development of drug resistance in cancer as well as resistance to antibiotics.

The second project focuses on LeuT, a bacterial protein that represents a family of transporters, the neurotransmitter: sodium symporter (NSS).

These proteins transport neurotransmitters like serotonin, norepinephrine and dopamine (chemicals involved in mood regulation and addiction) into cells, clearing them from the extracellular space and stopping neurotransmission.

Mchaourab’s group hopes to determine the structural dynamics of LeuT that allow it to transport the amino acid leucine into and out of bacterial cells. Because neurotransmitter transporters are primary targets for psychostimulant drugs (for example, cocaine and amphetamine) and for some antidepressants, understanding how they work could suggest new methods for treating addiction and mood disorders.

Eduardo Perozo, Ph.D., at the University of Chicago, is leading the consortium, which also involves scientists at Cornell University, Columbia University, Johann Wolfgang Goethe-Universität (Germany), the National Institutes of Health, Stanford University, the University of California-Los Angeles, the University of Illinois, the University of Pittsburgh, the University of Toronto (Canada), the University of Virginia, the University of Wisconsin, and Utrecht University (the Netherlands).

Debra Friedman, M.D., and colleagues assessed the incidence of subsequent cancers occurring five years or more after initial diagnosis among participants in the Childhood Cancer Survivor Study. They report in the July 21 issue of the Journal of the National Cancer Institute that the risk of developing subsequent cancers increases with age, with survivors of Hodgkin lymphoma at the greatest risk. Increased risk was also seen in female survivors, survivors diagnosed at an older age, and survivors treated with radiation. This risk did not decrease with time.

The findings demonstrate that childhood cancer survivors continue to be at increased risk of subsequent cancers through the second and third decades of life. Because many adult survivors do not appreciate the increased risk related to their childhood cancer diagnosis, continued surveillance and medical follow-up is essential.

Friedman directs the REACH for Survivorship Program at Vanderbilt, which provides education and surveillance for subsequent malignancies and other health issues for which survivors of both childhood and adult cancer may be at risk.

For other research highlights from Vanderbilt University Medical Center laboratories, see ‘Aliquots‘ in the VUMC Reporter.

Fesik, the Orrin H. Ingram II Chair in Cancer Research, is the first investigator from Vanderbilt to receive this coveted award. The 17 researchers honored this year join the 81 other investigators who have received these awards since the program began in 2004.

The award provides $2.5 million in direct costs over five years.

Fesik — a member of the Vanderbilt-Ingram Cancer Center, the Vanderbilt Institute of Chemical Biology, and the Center for Structural Biology and professor of Biochemistry, Pharmacology and Chemistry — plans to use these funds to develop new approaches for discovering drugs to target proteins currently considered “undruggable.”

Stephen Fesik, Ph.D.

Only about 10 percent of proteins encoded by the human genome are thought to be druggable, or able to be modulated by small-molecule drugs. The remaining “undruggable” targets include proteins involved in protein-protein interactions, which play a central role in nearly all signaling processes in a cell and, therefore, could represent important drug targets.

But targeting these challenging proteins will require a new set of tools beyond those traditionally used in drug discovery. Fesik plans to develop the needed methods by employing fragment-based methods.

This approach involves screening small chemical fragments for their ability to bind to small pockets on a protein target and linking the chemical fragments together guided by structural information on how they bind.

In addition to establishing the approaches for drugging challenging targets, Fesik also plans to examine what molecular features make a molecule “drug-like,” safe, and orally bioavailable.

The Fesik group is applying these methods first to highly validated cancer targets. If successful, the strategy could have a major impact on cancer therapies. The methods being developed could also have even more widespread importance.

“Expanding the ‘druggable genome’ could allow more drugs to be obtained against new targets and improve our ability to treat disease in all therapeutic areas,” Fesik said.

The research could “revolutionize our approach to drug discovery and have a dramatic impact on human health.”

The Pioneer Award is “designed to support individual scientists of exceptional creativity who propose pioneering — and possibly transforming approaches — to major challenges in biomedical and behavioral research,” according to the NIH website.

“Having served on the (selection) committee previously, I know that the competition is extraordinary,” said Jeff Balser, M.D., Ph.D., vice chancellor for Health Affairs, who chaired the Pioneer Award review committee in 2007.

“This award is a great honor for Steve and for Vanderbilt and is further evidence that our faculty are among the most innovative thinkers in the nation.”

“NIH is pleased to be supporting scientists from across the country who are taking considered risks in a wide range of areas in order to accelerate research,” said NIH Director Francis S. Collins, M.D., Ph.D. “We look forward to the results of their work.”

More information on the Pioneer Award is at http://nihroadmap.nih.gov/pioneer.