Ian Macara, Ph.D.

Ian Macara, Ph.D., recently joined the faculty as the new chair of the Vanderbilt Department of Cell and Developmental Biology.

Macara, who was also named the Louise B. McGavock Professor, succeeds Susan Wente, Ph.D., associate vice chancellor for Health Affairs and senior associate dean for Biomedical Sciences, in this role.

Macara came to Vanderbilt from the University of Virginia School of Medicine, where he was the Harrison Distinguished Professor of Microbiology and director of the Advanced Microscopy Facility with the UVa’s Center for Cell Signaling.

His research interests include cell polarization mechanisms in epithelia; epithelial morphogenesis in mammary glands and breast cancer; polarity proteins as tumor suppressors and RNA localization. His research has focused on the role of GTP binding proteins as molecular switches which control a wide range of biological processes including: receptor signaling, intracellular signal transduction pathways and protein synthesis.

Macara joins a growing Department of Cell and Developmental Biology. Under Wente’s direction, the department’s extramural research grant portfolio increased by nearly 73 percent and its number of graduate students nearly doubled from 45 to 85.

Macara is a popular presenter among peer professionals, speaking at conferences and symposiums within the U.S. and abroad, and serving as Distinguished Lecturer at Fox Chase Cancer Center; plenary lecturer at the annual meeting of the Korean Society for Molecular and Cell Biology in Seoul, South Korea; and program keynote speaker, U891 INSERM, Marseille, France.

The author of more than 150 research publications, he is also the recipient of professional distinctions such as the University of Virginia Distinguished Scientist Award and UVa’s Harrison Distinguished Professorship.

Macara received his bachelor’s and doctorate degrees in Biochemistry from the University of Sheffield, UK. He underwent postdoctoral training at Brandies University, and Harvard University, and was a Miller Visiting Professor at UC Berkeley in 1997.

Joining Macara at VUMC is his wife Deborah Lannigan, Ph.D., associate professor of Microbiology at the University of Virginia School of Medicine. Lannigan joins Vanderbilt as associate professor in the Department of Pathology, Microbiology and Immunology (PMI).

At the University of Virginia, Lannigan’s research focused on signaling pathways involved in mammary gland homeostasis and breast cancer. Last year, Lannigan and fellow researchers at UVa published a novel study in the journal Genes & Development demonstrating that they could successfully and accurately replicate the early growth of human breast tissue outside of the body by using a novel three-dimensional model developed in their lab.

The model allows researchers to visualize how breast tissue grows in its earliest stages, providing the capability for a close look at the early stages of breast cancer and the potential to understand how and why the normal well- ordered development is lost in cancer.

– by John Howser

Arteaga named to Komen scientific advisory board

Carlos Arteaga, M.D. Photo by Joe Howell

Carlos Arteaga, M.D., associate director for Clinical Research and director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center (VICC), has been named to the Scientific Advisory Board of the Susan G. Komen for the Cure Breast Cancer Research Foundation.

Komen is the one of the largest nonprofit organizations dedicated to funding breast cancer research and providing support for patients, survivors and their families. Since its inception in 1982, Susan G. Komen for the Cure has invested more than $1.9 billion in breast cancer research, education and support programs.

The Komen Scientific Advisory Board is a six-member group of cancer investigators and advocates who work to enhance the organization’s scientific peer review process and support other Komen activities.

Arteaga was named to the advisory board because of his “experience, leadership, knowledge and drive for innovation in breast cancer research.” Board members, who serve a three-year term, provide insight and advice about the best research directions to fund and assist with medical information for breast cancer education.

“I am honored by the invitation to join this important advisory group,” said Arteaga. “Komen has been a great partner and supporter of our breast cancer research here at VICC and I am pleased to assist with their research and education mission.”

Arteaga previously served for two years as a member of the Komen Scholars, a group of international investigators with a wide range of expertise, including clinical and
laboratory research, pathology, radiation oncology, surgery, pathology, prevention and other research disciplines and specialties.

Arteaga holds the Donna S. Hall Chair in Breast Cancer. His research has been instrumental in characterizing the role of several key pathways in breast cancer, including those responsible for cell growth, division and metastasis.

– by Dagny Stuart

Grant renewal boosts GI cancer research program

Vanderbilt-Ingram Cancer Center’s gastrointestinal Specialized Program of Research Excellence (SPORE) has been awarded its third round of funding by the National Cancer Institute (NCI).

“We decided to roll the dice and propose high-risk, high-reward projects,” said Robert Coffey Jr., M.D., Ingram Professor of Cancer Research, professor of Medicine and Cell and Developmental Biology, and director of the GI SPORE. “This included a project focused on colon cancer stem cells and another to develop a drug to inhibit the mutant KRAS oncogene, thought to be an undruggable target.”

The gamble paid off. The NCI — a division of the National Institutes of Health — will provide $11.5 million over the next five years to continue to support the gastrointestinal (GI) SPORE, which focuses on colorectal cancer, the most common form of GI cancer in the U.S., with an estimated 142,820 new cases and 50,830 this year.

The federal SPORE program provides research funding for specific forms of cancer and was created by the NCI in 1992 to support “translational” research which moves knowledge from the laboratory bench to the clinic for patient therapy.

This emphasis on bench-to-bedside research is designed to accelerate the pace of scientific inquiry in support of better patient care.

The competition for these SPORE grants is intense.

Vanderbilt-Ingram’s GI SPORE program encompasses an interdisciplinary team of investigators from basic science, Hematology/Oncology, imaging, Epidemiology, drug discovery, Surgical Oncology, Pathology, Biostatistics and Bioinformatics and patient advocacy.

The team members are focused on learning more about the causes and potential therapies for colorectal cancer.

“A distinguishing feature of our GI SPORE is that patient advocates are integral members of each project,” said Coffey. “I cannot emphasize enough how much our GI SPORE is a team effort.”

Coffey noted the contributions of Meghan O’Loughlin and Leticia Wallace, who worked tirelessly on the grant preparation.

“We are delighted by the renewal of the GI SPORE grant, especially during this time of increasingly tight federal research budgets,” said Jennifer Pietenpol, Ph.D., director of Vanderbilt-Ingram. “Dr. Coffey continues to provide tremendous leadership for this integrated group of investigators.”

“Bob has once again assembled an incredible team and they have the potential to translate discovery into meaningful improvements in the prevention and treatment of colorectal cancer,” said Nancy Brown, M.D., chair of the Department of Medicine.

The National Cancer Institute of the National Institutes of Health is supporting this research under Award Number P50CA095103.

The SPORE grant funding supports four distinct research projects:

• Multimodal Imaging and Targeted Therapeutics of Stem Cell-Derived Colon Cancer, Clinical principal investigator (PI): Robert J. Coffey Jr., M.D., Basic PI: H. Charles Manning, Ph.D., Patient advocate: Ronald Obenauf
• Targeting K-RAS in Colorectal Cancer, Clinical PI: Jordan Berlin, M.D., Basic PI: Stephen Fesik, Ph.D., Patient advocate: Diane Lancaster
• Molecular Markers of Colorectal Cancer Recurrence, Clinical PI: R. Daniel Beauchamp, M.D., Basic PI: Daniel Liebler, Ph.D., Patient advocate: Robb Lent
• Genetic and Epigenetic Markers of Colorectal Adenoma Recurrence, Clinical PI: Harvey Murff, M.D., MPH, Basic PI: Wei Zheng, M.D., Ph.D., MPH, Patient advocate: Ardeth Obenauf

The GI SPORE also provides career development and pilot project funding.

• Translational Pathology and Imaging Core, Director: M. Kay Washington, M.D., Ph.D., Co-director: H. Charles Manning, Ph.D.
• Biostatistics Core, Director: Yu Shyr, Ph.D.

– by Dagny Stuart

VICC debuts outpatient cancer clinic in Springfield

Vanderbilt-Ingram Cancer Center has opened a new outpatient cancer clinic on the NorthCrest Medical Center campus in Springfield, Tenn., to bring high quality care to patients in Middle Tennessee and Southern Kentucky.

Vanderbilt physicians, who are specialists in Medical Oncology and Hematology, will see patients in the new facility. The board-certified cancer specialists, led by Michael Neuss, M.D., chief medical officer at Vanderbilt-Ingram, will provide diagnosis and treatment of cancer as well as blood disorders.

The new outpatient facility, which is located on the second floor of the NorthCrest medical office facility at 500 NorthCrest Drive, Suite 521, is designed to treat adult patients.

The new facility will allow patients to come to one office to receive medical care, including physician and nursing visits, laboratory testing and chemotherapy treatments. Radiology imaging and other services will continue to be provided on NorthCrest Medical Center’s main campus.

NorthCrest Medical Center is a not-for-profit community hospital that has been providing quality health care since 1956. The hospital offers inpatient, outpatient and emergency medical services to patients in northern Middle Tennessee and Southern Kentucky.

The new cancer clinic will make it more convenient for patients to receive comprehensive cancer care close to home, including the opportunity to enroll in the latest clinical research trials under way at Vanderbilt.

A recent affiliation agreement between NorthCrest Medical Center and Vanderbilt University Medical Center affirms the common goal shared by the organizations for a more cost-effective regional health care delivery system,
and a commitment to approach this goal collaboratively.

– by Dagny Stuart

VICC adds colon cancer to gene mutation testing

Emily Chan, M.D. Photo by Anne Rayner

Vanderbilt-Ingram Cancer Center has initiated tumor mutation testing for a limited number of patients with metastatic colorectal cancer.

This pilot project for colorectal cancer is part of Vanderbilt-Ingram’s Personalized Cancer Medicine Initiative (PCMI), a program to identify genetic mutations in a patient’s tumor that may be useful in matching the appropriate therapy with each patient. VICC patients with lung cancer, breast cancer and melanoma already have their tumors tested for specific mutations, and now some colorectal cancer patients will be added as part of a pilot program.

“We’re testing a panel of eight genes, including mutations in the KRAS and BRAF genes,” said Emily Chan, M.D., Ph.D., assistant professor of Medicine and clinical director of GI Oncology. “What we’re looking at are genes that are known to be mutated in some colorectal cancers. Companies are already developing drugs that block the molecular pathway that gets activated in some of these gene mutations. Other genes don’t have drugs available at the moment, but that doesn’t mean they won’t down the road.”

Some of the mutated genes may serve as predictive markers that indicate how patients may respond to a specific therapy. The results may also help physicians match patients to clinical research trials that target certain molecular pathways in the tumor.

The gene tests are conducted on tissue samples from the patient’s tumor. About 200 patients will be tested during this initial colorectal cancer program and the results will be evaluated for future projects.

– by Dagny Stuart

Massion named to lead Cancer Center’s Thoracic Program

Pierre Massion, M.D. Photo by Joe Howell

Pierre Massion, M.D., professor of Medicine and Cancer Biology, has been named director of the Thoracic Program at Vanderbilt-Ingram Cancer Center.

Massion, who joined Vanderbilt in 2001, will lead the wide-ranging program that is designed to perform cutting-edge lung cancer research and provide exceptional services to patients with lung cancer and other diseases of the chest.

“I am very honored and excited about the opportunity to enhance our patient care, education and research programs to galvanize the discoveries and foster the academic mission of Vanderbilt-Ingram,” said Massion, an Ingram Associate Professor of Cancer Research.

“Pierre Massion is a dynamic leader whose research accomplishments and commitment to patient care and education make him the perfect choice to lead this effort,” said Jennifer Pietenpol, Ph.D., director of Vanderbilt-Ingram.

Massion and his colleagues plan to enhance the Thoracic Program, which will be segmented into three arms.

The first arm features a Thoracic Center led by Joseph B. (Bill) Putnam, M.D., and Otis Rickman, D.O. The Thoracic Center will open a new early detection clinic to screen and distinguish benign lung nodules from early stage lung cancer, when there is the best chance for a cure. Clinicians will use innovative technologies for noninvasive diagnosis as well as minimally invasive thoracic surgeries. They will also expand personalized care for patients who are dealing with more advanced disease, including intensive palliative care for patients. There will also be a strong emphasis on the prevention of lung cancer, with an integrated smoking cessation program.

The second arm is a Thoracic Educational Program led by Leora Horn, M.D., Eric Grogan, M.D., and Rickman, which is designed to provide academic training for students, fellows and clinicians in preventive, diagnostic and continuing care, with special emphasis on continuing medical education for physicians.

“We also want to empower our survivorship group and bring education to the forefront for all of our beneficiaries, particularly patients at risk for lung cancer, as well as patient advocates,” said Massion.

The third arm is the Thoracic Research Program, led by William Pao, M.D., Ph.D., and Massion, which will be integrated within the lung cancer center and continue to develop investigator-initiated studies including clinical trials geared toward prevention, early diagnosis, personalized medicine and health services research.

“The Thoracic Program will be a collaborative and interdisciplinary team effort to cultivate an outstanding program with the leading-edge lung cancer care and research in the nation,” said Massion.

– by Dagny Stuart

Jennifer Pietenpol, Ph.D. Photo by Joe Howell

Do you know which physical traits you inherited from your parents and grandparents? I’m fairly tall and so are my parents, so I can surmise that my tall stature was linked to an inherited trait.
Each of us inherits cells with a set of chromosomes containing the genetic information passed down from our parents. Genes within those chromosomes can determine attributes like eye and hair color – brown eyes or red hair are examples of genetically inherited traits.

The risk for developing cancer can also be hard-wired in those inherited genes. Cancer risk can be passed down from one generation to the next, although it’s important to note that having a high risk doesn’t guarantee an individual will develop cancer.

In fact, the vast majority of cancers are linked to DNA mutations that occur inside our cells after birth and during our lifetimes, triggering a cascade of changes at the molecular level. These DNA mutations are called ‘sporadic’ genetic mutations.  Vanderbilt researchers are leaders in identifying cancer-causing mutations that are both inherited and sporadic and currently matching the sporadic mutations with new targeted therapies.

In this issue of Momentum, we highlight cancer patient James C. (Jimmy) Bradford Jr. and his role in advancing this important research. Jimmy Bradford – who also served as a valuable member of the Cancer Center’s Board of Overseers – and his family generously collaborated with Vanderbilt researchers to investigate the molecular underpinnings of his form of melanoma. The legacy from this act of wisdom and generosity is a crucial discovery that is already allowing melanoma patients to be more accurately matched with targeted therapies.

In this issue, we also open a window into the role of heritable traits in cancer risk.

Researchers have discovered key genetic markers that can predict – sometimes with remarkable accuracy – the likelihood that someone has inherited a risk of developing a specific form of cancer. Families whose members harbor these hereditary traits must deal with a heightened risk that children in succeeding generations will develop cancer.

While we don’t yet have the tools to prevent these genetic mutations or render them harmless, we do have the ability to identify many of the individuals who are more likely to develop cancer and offer screening tests and preemptive health care services to reduce their cancer risk.

At Vanderbilt, we are determined to help these patients identify and proactively deal with the genetic influences that have shaped their families’ cancer histories. We recruited Georgia Wiesner, M.D., a nationally known and respected cancer genetics expert, to help us launch the new Clinical and Translational Hereditary Cancer Program. Through this initiative, we are providing a crucial service to individuals and families, and our researchers are gaining new insight to the biology of these genetically-induced diseases.

Sincerely,

Jennifer Pietenpol

New clues to treating melanoma

New therapies for melanoma, like the drug vemurafenib (Zelboraf), have increased survival among patients with a specific mutation the BRAF gene. However, many patients treated with the vemurafenib develop secondary skin cancers. In the Jan. 19 New England Journal of Medicine, Vanderbilt-Ingram investigators Igor Puzanov, M.D., and Jeffrey Sosman, M.D., and colleagues from 12 other cancer centers reported about 60 percent of these secondary skin cancers harbored mutations in a RAS gene.  While vemurafenib did not initiate or promote cancer development, it accelerated growth of existing lesions that harbored RAS mutations. MEK inhibitor drugs blocked the growth of these tumors, suggesting that a combination therapy of BRAF and MEK inhibitors might be beneficial for melanoma patients. In the Nov. 1 New England Journal of Medicine, Puzanov, Sosman and colleagues reported the results of a Phase I/II study using a combination therapy of a different BRAF inhibitor (dabrafenib) and a MEK inhibitor, showing that combination therapy delays resistance, but does not stop it completely. However, combination therapy reduced side effects (skin toxicity and secondary skin cancers) compared to dabrafenib alone.

Study links genes to resistance to breast cancer chemotherapy

A study by Justin Balko, Pharm.D., Ph.D., Carlos Arteaga, M.D., and colleagues has identified a gene expression pattern that may explain why chemotherapy prior to surgery isn’t effective against some tumors. They found that low concentrations of dual-specificity protein phosphatase 4 (DUSP4) is strongly correlated with faster tumor cell growth following neoadjuvant chemotherapy and also with a type of breast cancer known as basal-like breast cancer (BLBC). Cancer cells with DUSP4 experimentally deleted showed a much lower response to chemotherapy. In mice, a combination of chemotherapy (docetaxel) with a MEK inhibitor drug was much more effective than docetaxel alone at eliminating the mouse tumors. The findings, published in the July 2012 Nature Medicine, support exploratory clinical trials combining chemotherapy and MEK inhibitors in patients with DUSP-deficient basal-like breast cancer.

Method may refine personalized trials for cancer therapy

A new tool to observe cell behavior has revealed surprising clues about how cancer cells respond to therapy, and may offer a way to further refine personalized cancer treatments. The approach, developed by Vito Quaranta, M.D., and colleagues shows that erlotinib — a targeted therapy that acts on a growth factor receptor mutated in some lung, brain and other cancers — doesn’t simply kill tumor cells as was previously assumed. The drug also causes some tumor cells to go into a non-dividing (quiescent) state or to slow down their rate of division. This variability in cell response to the drug may be involved in cancer recurrence and drug resistance, the authors suggest. The new tool, reported Aug. 12 in Nature Methods, may offer ways to improve personalized cancer therapy by predicting tumor response and testing combinations of targeted therapies in an individual patient’s tumor.

Vitamin E intake linked to liver cancer risk

Liver cancer is the third most common cause of cancer mortality in the world. Approximately 85 percent of liver cancers occur in developing nations, with 54 percent in China alone. Vitamin E is a fat-soluble vitamin which is considered an antioxidant, and studies have suggested that vitamin E may prevent DNA damage. An international team of researchers, including Xiao-Ou Shu, M.D., Ph.D., and colleagues at Vanderbilt-Ingram, analyzed data from a total of 132,837 individuals in China enrolled in the Shanghai Women’s Health Study or the Shanghai Men’s Health Study, two population-based cohort studies jointly conducted by the Shanghai Cancer Institute and Vanderbilt University. The results, published July 17 in the Journal of the National Cancer Institute, revealed that high consumption of vitamin E – either from diet or vitamin supplements – was associated with lower risk of liver cancer.

Study tracks how gene may promote lung cancer tumors

Vanderbilt-Ingram Cancer Center researchers have identified how one of the genes most commonly mutated in lung cancer may promote such tumors. Jin Chen, M.D., Ph.D., and colleagues found that the protein encoded by this gene, called EPHA3, normally inhibits tumor formation, and that loss or mutation of the gene – as often happens in lung cancer – diminishes this tumor-suppressive effect, potentially sparking the formation of lung cancer. The findings, published July 24 in the Journal of the National Cancer Institute, suggest that mutations in EPHA3 may be important drivers of a significant fraction of lung cancers – and could offer direction for personalizing cancer treatments and development of new therapies.

Proteins may point way to new prostate cancer drug targets

The gene encoding NKX3.1, a transcription factor and tumor suppressor protein, is one of the most commonly deleted genes in human prostate cancer and is typically lost early in the disease process. Sarki Abdulkadir, M.D., Ph.D., and colleagues recently identified 282 genes regulated by NKX3.1. Using bioinformatics tools, they found that a quarter of the NKX3.1-regulated genes are also bound by a “famous” oncogene called Myc (which, like NKX3.1, is also a transcription factor), in many cases with NKX repressing expression and Myc activating expression. In mice with NKX3.1 deleted and Myc overexpressed in prostate cells, tumors progressed to advanced cancer. The findings, reported in the (date) issue of the Journal of Clinical Investigation, demonstrate that these two proteins with opposing cellular actions regulate the same set of genes in prostate cancer, pointing to potential new drug targets and prognostic markers for the disease.

Kate McReynolds, MSC, MSN, ANP-BC. Photo by John Russell

When Kate McReynolds, MSC, MSN, ANP-BC, teaches cancer genetics to nursing students, she uses the analogy of a library. A human cell’s nucleus is the physical building, filled with shelves we call chromosomes. On each shelf are hundreds of books called genes. Each book, or gene, contains a recipe for a protein, and together those recipes tell the story of the human form.

“But what if you change just one letter of one word in the recipe?” she asks the class. “In a gingerbread recipe, for example, what if the word ginger changed just its first letter to an F.  You’d have a recipe calling for two teaspoons of ‘finger.’ That would be a mess.”

McReynolds gets a good laugh with this line, but she uses the example to make a serious point: that sometimes a small error can add cancer to anyone’s personal story.

The literary analogies help McReynolds in her work. She is a genetics nurse practitioner in the Hereditary Cancer Clinic. When patients come to see McReynolds, they want answers. They want to know what their genes can tell them about their risk for cancer.

“Five to 10 percent of all cancer is hereditary. Sometimes we can pinpoint a specific change in a gene that will explain the cancer in a family, but sometimes we are unable to find it even though the family story of cancer tells us this has to be hereditary,” McReynolds said.

Patients come for a one-to-two-hour visit, beginning with a review of their personal medical history and their family history of cancers – at least three generations back. Once the family tree is drawn and their risk assessed, McReynolds works to understand hopes and fears about genetic testing.

“People have to be ready for the information and have to be able to put it into perspective. Genetic testing can be very empowering,” McReynolds said.

Those who are negative for a known familial mutation can feel tremendous relief that they are not at increased risk for cancer. Those who test positive can make potentially life-saving medical decisions.

“But it is also important to realize that once a person learns the definitive answer to a genetic test, they cannot unknow it,” she said.

McReynolds’ strong feelings about the deeply personal and ethical concerns inherent in her work serve her well. After all, the U.K.-born and -trained nurse followed her heart into this business.

“It was a calling. I thought I would be a nurse for children with learning disabilities. Then I did a week of work experience on an adult ward, and I came home that first day and cried and cried because I knew beyond a shadow of a doubt that oncology was what I had to do,” she recalled. “You have the relationships with the patients. I consider it a privilege that they share their pain and fears as well as their hopes and dreams for the future.”

This year, cancer was written into McReynold’s own family story. She recently returned to the U.K. to be with her brother who was diagnosed with brain metastasis from a previously undetected lung cancer. There is no familial risk to her or other family members, but she knows one day soon she will lose him to this cancer.

“I am all the time drawing pictures of family histories and drawing lines through siblings to indicate they are deceased. My brother is 46 years old. Hopefully I was empathetic before, but now I really have empathy for someone whose sibling has cancer and especially a young cancer,” she said.

McReynolds uses genetic counseling to help people understand the part of their story genes tell, but her great hope is that, increasingly, through cancer genetics research, medicine will be able to change the storylines for the better.

But so far, unlike books in a library, there is no skipping to the end to see what happens.

– by Carole Bartoo

Kristine Gregoire-Cope (left) and Erin Allmon. Photo by John Russell

With her husband stationed overseas in Korea and an active 1-year-old son and 7-year-old daughter in tow, Erin Allmon decided she was way too busy to have any further complications in life. So when she went to be tested for a familial gene mutation that might cause pancreatic cancer, she was determined that there was no way she had it.

Erin’s sister felt the opposite. Kristine Gregoire-Cope says she was certain she had the same genetic mutation she believed caused their mother’s rapid decline and death from pancreatic cancer in 1995.

“I look more like my mom than my sister, and I already have type 2 diabetes. My mother died at 45, and I was turning 39. For me, I felt like it was not so much fated, but my biggest fear was to wake up and have stage IV cancer and repeat history,” Kristine said.

Both women were tested at Vanderbilt’s genetic counseling office in early 2012. Both results were positive.

Erin’s husband was in the room via online connection when Vanderbilt genetic nurse practitioner, Kate McReynolds, MSc, MSN, ANP-BC, delivered the news. Erin called it “flooring.”
Her first thought: “What does this mean for our children?” Then: “What now?”

Hope for early detection, prevention

There is a sense of urgency where familial pancreatic cancer research is concerned. Pancreatic is the fourth leading cause of cancer death in both men and women in the United States, yet it is so rare, the average person only has a 1 percent chance of getting it in his or her lifetime. But once someone does have a diagnosis, the prognosis is the worst of any major tumor type. Only 6 percent of patients live past five years.

With such poor response to treatment and no known prevention, hope focuses on early detection of pancreatic cancers so they can be removed or treated before they can become deadly. But it would be much better to predict who is at greatest risk for pancreatic cancer before it occurs. This offers the greatest possibility of early detection, and makes prevention at least a hope, even for those at greatest risk.

Those at greatest risk for pancreatic cancers include people with a strong family history of the disease. When two closely related people in one family get the same cancer, epidemiologists consider it a “cluster,” with an increased probability that there is genetic basis, especially if it is a rare cancer like pancreatic. Currently, 17 familial pancreatic cancer registries in the U.S. are tracking patients and their families, searching for genetic mutations that may be involved.

Pre-cancer risk prediction is what Kristine says she hopes for. It’s what she focused on when her uncle was the first of her family members to receive a positive result for a little-known mutation in a tumor-suppressor gene called PALB2. She says the news offered a sense of hope that deaths like her mother’s, and illnesses like her uncle’s, might one day be preventable.

What she didn’t know at the time was how critical her own participation would be in efforts to develop a model to predict the risk of PALB2 familial pancreatic cancers.

Finding the PALB2 link

In 2009, Kristine’s uncle, Mark Gregoire, a Trumansberg, N.Y., native, was among the first 96 pancreatic cancer patients to participate in a sentinel study with researchers at the Johns Hopkins Medical Institutions to test for mutations related to pancreatic cancers. He was one of only three confirmed to have a non-functional version of the PALB2 tumor suppressor gene. Despite the tiny numbers, Johns Hopkins experts told him their research showed that the broken PALB2 gene was likely involved in the development of his cancer. They advised him to tell his close relatives so they could also be tested for the mutation.

Both Kristine and Erin say they remember the flurry of family emails between their uncle and his five surviving siblings. Their mother – Mark Gregoire’s older sister, Veronica Gregoire Cope – had died from pancreatic cancer before being tested. But one by one, the surviving siblings received good news: they didn’t have the PALB2 mutation.

Kristin and Erin recalled the sense of relief felt by their extended family. That is, until 2011, when their cousin – just months before her father Mark Gregoire passed away from pancreatic cancer – got tested. She had the PALB2 mutation.

“And that’s when we thought, ‘whoa, this is our generation,’ We hadn’t really thought about getting tested ourselves up until then,” Erin said.

Kristine was interested in getting tested right away. But she says none of her own physicians seemed encouraging of genetic testing. None had heard of PALB2, and after all, pancreatic cancers generally occur after age 50. But when Kristine approached S. Sadia Zaidi, M.D., assistant professor of Endocrinology, at the clinic where she is seen for type 2 diabetes, the response was different.

“I walked in and said ‘I may or may not have a PALB2 mutation, but to be on the safe side I wanted to let you know.’ Dr. Zaidi told me she was not familiar with the PALB2 pancreatic cancer link, but right then and there she pulled up the information on the Internet… about four sentences worth,” Kristine said.

“It is more associated with breast cancer and anemia. But because of my personal experience, I told her she shouldn’t just let it go,” Zaidi recalled. “My own father died after a painful course with metastatic pancreatic cancer. Other than my father, I don’t have a strong history of family cancer, but if there had been, I would have been the first to get myself tested for genetic risk.”

What is PALB2?

In 2007 researchers found the PALB2 protein to be a partner and localizer of the BRCA2 protein. The more famous BRCA1 and BRCA2 genes, known for their strong link with familial breast and ovarian cancers, are tumor suppressor genes, working within the body’s cells to isolate genetic mutations, and repair them so they don’t have a chance to produce disease within the body.

The name “PAL”B2 might aptly describe this adjunct gene’s function. It is a friendly helper of BRCA2. It both recruits BRCA2 to sites of DNA breakage and acts as molecular scaffolding to hold it in place as repairs are made. If someone is missing a functional PALB2 gene, tumor suppressor BRAC2 is unable to do its work.

Zaidi suggested Kristine and her sister should contact The Clinical and Translational Hereditary Cancer Program at Vanderbilt-Ingram Cancer Center to talk with a cancer genetic counselor. Kristine quickly made an appointment to visit Kate McReynolds and Erin agreed to go too.

“I tested the sisters for the known family mutation in PALB2, called single site testing. This cost just $200 since we knew what we were looking for,” McReynolds recalled.

But once the positive results were known, McReynolds’ path to guide the sisters became much less clear.

“One of the interesting issues with these new genetic discoveries is that the studies have not been done yet to establish penetrance of the gene. Unlike others, like the BRCA genes, we cannot give people a lifetime risk, even though we know risk is increased,” McReynolds explained.

Waiting for the math

Penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. After the better-known BRCA1 and BRCA2 mutations were linked with breast and ovarian cancers, it took about 10 years and scores of breast and ovarian cancer patients, as well as those with the mutations, but without disease, to allow scientists to generally agree on penetrance. Once penetrance is determined, counselors like McReynolds are able to tell a patient how greatly their lifetime risk is increased by a gene defect. That’s about as specific as information can get about lifetime risk for cancer.

Patients who do not test positive for a known genetic defect are not out of the woods. In some common cancers, like breast cancer, there is enough data today to use family and personal medical history to calculate increases in risk even without a known gene link.

“High risk is anyone with a 20 percent risk or greater, with average risk for a woman being 12.5 percent for breast cancer. When risk is greater than 20 percent, we start talking about management options of three types: surveillance, chemoprevention or risk-reducing surgery,” said Ingrid Meszoely, M.D., a surgical oncologist and clinical director of the Vanderbilt Breast Center.

Sisters Erin Allmon and Kristine Gregoire-Cope enlisted their friends and family to take part in the PurpleStride walk to raise awareness about pancreatic cancer. From left: Erin Allmon, Killian Allmon, Alison Reside, Arden Allmon, Kristine Gregoire-Cope, Laura Kim, Rachel Kramer and Brittany Helton.

Because the penetrance of BRCA1 and BRCA2 genes are fairly well known, doctors have been able to develop a prescribed course of action for each patient. The course of action may vary significantly, depending on the type of gene, the degree of risk and a patient’s wishes.

“Our ability to know more about what these mutations mean has grown vastly. The BRCA genes only came to our awareness in the 1990s. The only prevention option early on was mastectomy. Now there are other choices with good data to back them up including MRI surveillance and chemopreventive drugs,” Meszoely said.

But breast cancers—both familial and sporadic—are far more common than pancreatic cancers. Penetrance, and the lifetime risk of pancreatic cancer for those with PALB2 gene defects, is simply not known. PALB2 mutations occur only in 1 percent to 3 percent of the familial forms of pancreatic cancers, and the volume of cases needed to determine penetrance is quite large. That’s where families like the Gregoires come in.

Alison Klein, Ph.D., M.H.S., lead author of the 2009 paper describing the PALB2 link to pancreatic cancer, directs one of the larger pancreatic tumor registries in the U.S.: the National Familial Pancreas Tumor Registry at Johns Hopkins. She says registries will help uncover the answers, but families will have to be both patient and involved.

“It’s not the technology that’s limiting us, it’s the number of families, and identifying more of them. I am cautious about this, but I am optimistic that what we have learned about PALB2 will ultimately help. First the registries help inform who should be screened and who shouldn’t, and then will quantify what the genes mean in families. Our understanding will improve in the coming years and will inform screening trials and therapies,” Klein said.

Vanderbilt-Ingram is currently in the process of developing a hereditary cancer registry as well. According to the new director of the Clinical and Translational Hereditary Cancer Program, Georgia Wiesner, M.D., registries will help families like the extended Gregoire family in many ways.

“Rare cancer susceptibility syndromes, such as those caused by PALB2 mutations, require coordination as well as a multi-site approach in order to begin to understand both the health and the emotional impact on patients and families.  Registries keep in contact with these families, keeping them informed, helping them to understand more about their risk, while their participation helps to expand our body of knowledge,” Wiesner said.

The Team Approach

Kristine says having stumbled into the opening pages of this cancer story has its benefits. Her family now has access to a cross-country team of top clinicians. She and one of her two brothers have spoken directly with the Johns Hopkins group, and McReynolds has worked with Johns Hopkins to learn about their screening program and implement it with the family here.

Erin and Kristine’s first clinical stop within the Cancer Center, was to Meszoely’s high-risk breast cancer clinic. Meszoely says Kristine and Erin are her first PALB2 patients. Erin’s mammogram showed a suspicious area and so she underwent a biopsy. The biopsy was thankfully negative. That was followed by visits to gastrointestinal specialists where the first round of tests so far, including endoscopies and MRIs, have all been normal.

The sisters will return for annual surveillance for breast and pancreatic cancers. It’s a lot of medical testing to add to the lives of young, healthy and busy women. And even their health care team admits the benefits are unknown.

“Our younger brother hasn’t decided to be tested yet, and that’s fine for him. But if I didn’t have this information, I wouldn’t have this plan. At 36 years old, I had no intention of going for a mammogram for several years, but I am glad I did,” Erin said.

Kristine and Erin say they are glad to be full partners, working with the team writing a new prescription for care of those with PALB2 familial cancers. They have joined a cancer registry. They call themselves “pre-vivors:” free from the rigors of cancer treatment, they can focus on prevention. Kristine and her family remind others that pancreatic cancer is the “most under-funded, under-recognized and least studied of all major cancer killers.” Family and friends recently joined Kristine in a 5K fun run called the PurpleStride to raise awareness about pancreatic cancer. She said that as she looked around at the people at the event – participants who were either patients with pancreatic cancer or their loved ones – it was a poignant reminder of how little is known about PALB2, and how little survival rates have improved for pancreatic cancers as a whole.

“All of those people touched by pancreatic cancer, who knows if some of them might be affected by the PALB2 gene. I would like to be part of this, to keep the momentum up,” Kristine said. “My mom died in four months, for my uncle it was five years. We don’t know if that’s because he participated in PALB2 registry and research trials, but we would like to hope, at least on a personal level, that represents advancement.”

Illustration by James Steinberg

Family photos tell the tale of genetics, providing visual evidence of hereditary patterns in a family tree. The same features are seen again and again in the faces and bodies of successive generations, physical traits passed down from one branch to the next that help explain why a toddler looks “just like her grandmother.”

Brown eyes, red hair, a set of dimples – these hereditary features are genetic signposts, marking a child as a descendant of a specific family line.

But other inherited traits are less benign. More than 4,000 diseases, including cancer, are linked to altered genes inherited from one or both parents.

In humans, these hereditary characteristics are determined by two sets of genes – one acquired from the mother and one from the father – and whether the gene is dominant enough to cancel out another form of that gene. Inheriting a copy of the same gene from each parent, or inheriting a dominant gene from one parent, determines whether or not a descendant is likely to develop a trait – like brown eyes – or susceptibility to a disease.

Family Secrets

For decades, Patricia Fielding’s genetic inheritance was a mystery. Adopted as a toddler, she didn’t know anything about her biological parents until her mid-30s when she finally contacted and developed an ongoing relationship with her biological mother. She learned that her father had already passed away at age 32 from colon cancer.

It was years later, while she was playing with her son on the floor, that she noticed something odd.

“I felt like I was laying on top of something, like there was this rock in my belly,” she remembered.

Fielding, 54, a former IT technical assistant from Mt. Juliet, Tenn., had no idea that the “rock” in her belly was directly linked to her father’s early death – an ominous clue about her own risk of developing cancer and the risk of passing on that trait to her own children.

Patricia Fielding discovered that her ovarian cancer and her father’s early death from colon cancer were genetically linked. Photo by John Russell

A CT scan revealed a tumor on one of Fielding’s ovaries. Before doctors could operate, the tumor ruptured and the subsequent surgery revealed an aggressive clear cell carcinoma on one ovary and a slower growing cancer on the other. Her Vanderbilt physician performed a hysterectomy, removing the reproductive organs along with some lymph nodes, and Fielding underwent several rounds of chemotherapy to attack any cancer cells that might have spread into other parts of her body.

During Fielding’s cancer treatment, a genetic professional from Vanderbilt-Ingram Cancer Center asked if she wanted to do genetic testing.

“I didn’t know until I was diagnosed with it that ovarian cancer is also hereditary and hadn’t thought about it – had no clue,” said Fielding.

Through Vanderbilt-Ingram’s Clinical and Translational Hereditary Cancer Program, Fielding received individualized counseling and genetic testing. During the consultations, patients and counselors create a family tree, filling in all of the known types of cancer and other diseases that have affected at least three generations of family members. Fielding realized that her father’s colon cancer wasn’t her only potential inherited cancer risk. There was also cancer on her mother’s side of the family.

“I had two aunts that had ovarian cancer and one of them died fairly young…in her 40s,” said Fielding.

DNA Detectives

From a simple blood sample, scientists performed a genetic test and discovered that Fielding had an inherited disease known as Lynch syndrome, a form of hereditary nonpolyposis colorectal cancer (HNPCC) that is passed down from parent to child 50 percent of the time.

Lynch syndrome is caused by mutations in genes involved in repairing mistakes in our DNA. The presence of one of these mutations gives a person up to a 70 percent lifetime risk of developing colorectal cancer. In women, Lynch syndrome increases the chance of developing endometrial (lining of the uterus) or ovarian cancer.

Fielding had one of those mutated genes.

“Even though this is a hereditary colorectal cancer syndrome, endometrial cancer can often be the primary cancer in the family,” explained Duveen Sturgeon, R.N., program coordinator of the Vanderbilt Hereditary Colorectal Cancer Registry.

Among women with HNPCC or Lynch syndrome, the risk of endometrial cancer rises to almost 60 percent. Individuals with Lynch Syndrome are at increased risk for cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, pancreas, prostate and brain. These patients also are more likely to develop multiple cancers or have a recurrence of disease.

While Vanderbilt-Ingram’s genetic counselors are looking for obvious clues on a family tree, they are often surprised by what they don’t see among the genetic branches.

“Even in families that do not appear to have any hereditary features, when the testing is done they do carry a mismatch repair gene mutation which is diagnostic for Lynch syndrome,” said Sturgeon. “Then you have to sit down and look at the rest of the family to see who else is at risk. It’s really important to diagnose these people who have this increased risk so that physicians can do the surveillance and screening necessary to either prevent cancer from developing or catch it early.”

The genetic tests do not indicate someone actually has cancer. They simply screen for a mutation that indicates a patient has a higher likelihood of developing a specific form of cancer.

Genetic Clues

“Cancer is very common, but the true hereditary cancers – the ones where there is an actual gene or gene mutation linked to the development of cancer in a family – are really pretty rare,” explained Georgia Wiesner, M.D., professor of Medicine and director of the Clinical and Translational Hereditary Cancer Program.

Inherited colorectal cancer mutations are a good example. About 160,000 new cases of colorectal cancer are diagnosed in the United States every year but only about 2 percent to 7 percent of these cancers are caused by Lynch syndrome.

“We call those ‘high-risk cancer syndromes,’ meaning if an individual has a mutation they are at very high risk for developing cancer,” said Wiesner. “The marker doesn’t say there is cancer there. The marker says they are at high risk.”

Wiesner, who has been named an Ingram Professor of Cancer Research, was recruited to Vanderbilt-Ingram to lead the new Clinical and Translational Hereditary Cancer Program that will expand and enhance the Cancer Center’s menu of hereditary cancer services for patients and physicians.

“Vanderbilt is a real leader in trying to figure out the specific genes that are causing cancer. We’re doing that at the tumor level now but I think we’ll be able to back up and look at specific markers in people that they were born with that would indicate they are at high risk,” said Wiesner.

In addition to clear-cut cancer markers like Lynch syndrome, scientists already have found specific genes linked to inherited forms of breast cancer.

The BRCA1 and BRCA2 genes, identified in the 1990s, were among the first genes tied to a family risk of breast and ovarian cancer. In normal cells, the BRCA1 and BRCA2 genes help keep the cells’ DNA stable, but when these genes are mutated the tumor suppressor function is turned off, leading to a high risk of cancer among women and men who inherit these mutations.

The mutations are more often found in families with multiple cases of breast cancer and individuals who develop both breast and ovarian cancer. Those from an Ashkenazi (Central and Eastern European) Jewish background are also at higher risk of inheriting this mutation.

According to the National Cancer Institute, women who inherit a BRCA1 or BRCA2 mutation are five times more likely to develop breast cancer.

Family Matters

Sara Lewis, M.S., a Licensed Certified Genetic Counselor at the Vanderbilt-Ingram Hereditary Cancer Program, counsels patients who want to know about their family cancer risk.

As she helps a patient create a family tree, Lewis is looking for patterns among the branches that may suggest a family has a hereditary predisposition to cancer. Features in a family that may raise concern include a relative with early onset cancer diagnosed before age 50, someone who had more than one type of cancer, multiple people in several generations having similar cancers or an unusual form of cancer like male breast cancer or a sarcoma.

“Based on those features we’ll spend a lot of time talking about the genetics of cancer and how those features are related to increased cancer risk over time. We’ll talk about the pros and cons of genetic testing…what the testing will tell us in terms of cancer risk and medical management considerations. We will also discuss how the genetic testing may provide information for family members and their risk of cancer development,” said Lewis.

One of the first questions patients ask is whether insurance will cover the tests. Medicare and most major health insurance companies pay for genetic testing if there is a documented family risk.

A team of genetics professionals, including Duveen Sturgeon, R.N., (left), Georgia Wiesner, M.D., (center), and Sara Lewis, M.S., (right), help patients and families determine and understand their risk of hereditary cancers. Photos by Susan Urmy

Patients are also concerned about privacy and discrimination, worrying that a positive genetic test will keep them from getting a job or keeping their health insurance. But in 2009, the federal government implemented the Genetic Information Nondiscrimination Act (GINA), which prohibits discrimination in health coverage and employment based on genetic information.

Lewis said her patients who opt to do genetic testing have a remarkable instinct about the likelihood of finding a genetic mutation.

“Patients sometimes just know…they know if they’re going to have this risk or not. In the seven years I’ve been a counselor I’ve only had two patients who didn’t expect the results,” said Lewis.

Since Patricia Fielding knew a little about her family history, she wasn’t surprised by her positive test for Lynch syndrome.

“It didn’t devastate me. When you’re in the high risk category, you have to have more testing, more screening. I guess I will just have to be more proactive about what’s going on so if anything comes up I can catch it early,” said Fielding.

Patients who test positive for a mutation are faced with new challenges, including the need for frequent screening or even preventive surgery. Women with specific mutations like the BRCA1 or BRCA2 gene sometimes choose to have their breasts or ovaries removed as a preventive measure. Those with Lynch syndrome may have their ovaries removed or undergo a hysterectomy.

Since Fielding already had her ovaries and uterus removed, her current risk from the Lynch syndrome mutation is related to colorectal cancer. She manages to laugh when she talks about her new cancer screening regimen.

“Now I get to have a colonoscopy every year and have to do the endoscope every two years. They’re no fun but there’s no alternative. I’d rather go through a colonoscopy than having to go through chemo again if I can help it.”

The decision to test or not to test can be difficult because the presence of a genetic mutation can have implications for succeeding generations. The lab results – both positive and negative – can trigger strong emotions. Guilt is at the top of the list.

Parents often express a sense of guilt for having passed on a genetic mutation to their children.

Lewis helps patients consider the genetic information in a different light.

“You couldn’t have prevented it and you also didn’t cause it,” said Lewis. “You’re providing your child a gift of information that will allow us to take care of your son or daughter and help them obtain appropriate cancer screenings at the proper time.”

Then there is survivor guilt for individuals who don’t have a targeted mutation, especially if several other family members already have cancer or are at high risk.

Vanderbilt-Ingram’s genetic counselors work with patients to put these strong emotions in perspective.

“It’s not an easy emotion to put aside but we help them reframe it so maybe they can take that pressure off of themselves,” said Lewis.

Fielding feels empowered by the knowledge of her family heritage and has encouraged her adult son and her sister to undergo genetic testing.

“It’s not something to be fearful of. Just because you have the mutated gene doesn’t mean you are going to get cancer, but it does let you know that you need to be more proactive. It gives you a place to start,” said Fielding.

While scientists have identified several genetic mutations linked to various forms of cancer, the genetic underpinnings of some hereditary cancers are still a mystery. Genetic tests may come back negative even among families with a strong history of cancer. Scientists simply may not have identified the important mutations and, in those cases, family members may still choose to get more frequent screenings.

While genes play an important role in cancer development, environmental factors may also be at play. Families with a history of smoking or a poor diet may have an increased disease risk.

Georgia Wiesner believes most cancer may be the result of a more subtle interplay of factors.

“Where cancer research is going very quickly is this dual component of heredity and our environment. That is where I believe most cancers are linked. We are all born with beneficial markers or detrimental markers and then we live our lives and are exposed to certain carcinogens. The person who has a modest susceptibility coupled with a carcinogen or a lifestyle choice may have an enhanced risk for cancer. That’s where the explanation for most cancers will be found,” Wiesner predicted.

Families whose members have a history of colon polyps may have a genetic mutation that makes them more susceptible to colorectal cancer.

The Vanderbilt Hereditary Colorectal Cancer Registry, which was launched in January 2007, is dedicated to the understanding of hereditary colorectal cancers by gathering information on patients and their family members who have been diagnosed with colorectal cancer or who, because of family history, are at high risk of developing colorectal cancer. The registry also provides services to families with colorectal cancer syndromes.

More than 600 patients are now included in the Registry.

Tissue samples from every colorectal cancer patient who undergoes surgery at Vanderbilt, regardless of age, are automatically sent to Vanderbilt University Medical Center’s molecular genetics laboratory for a special test that screens for Lynch syndrome, a hereditary colorectal cancer syndrome also known as hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. If the test shows a possible hereditary cause, then further genetic investigation is indicated.
Lynch syndrome, which is caused by a mutation in one of the DNA mismatch repair genes, is perhaps the best-known hereditary cause of colorectal cancer. Patients who have or are suspected of having this mutation are encouraged to have a colonoscopy every one to two years starting at 20 to 25 years of age along with other important screening tests.

Polyps can often be removed during the colonoscopy before they become cancerous.

But too many polyps can be a marker for another type of hereditary colorectal cancer syndrome. In familial adenomatous polyposis (FAP), the colon is carpeted with polyps from one end to another. Patients with FAP have a nearly 100 percent risk of developing colon cancer by the age of 40. The gene responsible for FAP is passed down from parent to child 50 percent of the time.

“We talk to some patients who tell us ‘Everybody in my family dies of colon cancer,’ and it’s because it’s never been diagnosed,” explained Duveen Sturgeon, R.N., program coordinator of the Registry. “With proper treatment we can reduce that risk.”

Sturgeon provides counseling for patients who know or think they may be at risk for some type of colorectal cancer. She also helps patients decide if genetic testing is appropriate.

Individuals who are interested in participating or who would like to find out more about the Registry are encouraged to contact Sturgeon at (615) 322-1590 or (800) 340-7752 or email duveen.sturgeon@vanderbilt.edu.

Arthur Boyd “Bull” Hancock Jr. Photo courtesy of Keeneland-Meadors

Dell Hancock remembers the day 40 years ago that the idea for the A.B. Hancock Jr. Memorial Laboratory for Cancer Research at Vanderbilt took form. Her father, Arthur Boyd “Bull” Hancock Jr., had recently died from pancreatic cancer. The family planned for memorial donations to go to a national cancer foundation, but one particularly large donation gave her mother, Waddell Walker Hancock, pause.

“She put the check in her robe pocket and she said, ‘we can do something with this that will be better,’” Dell Hancock recalls.

Waddell Hancock, an alumna of Vanderbilt University, consulted with family friend F. Tremaine “Josh” Billings, M.D., Bull Hancock’s college roommate and a Vanderbilt physician.

“They came up with the idea of a lab,” Dell Hancock says. “Mama was hell-bent and determined to find out the cause of cancer, and that’s what they set out to do in the Hancock Lab.”

This year, as it celebrates its 40th anniversary, the Hancock Laboratory continues its focus on the causes of cancer – and on the development of novel agents for cancer imaging, prevention and treatment.

Bringing the best together

Bull Hancock was a third-generation horse breeder. He grew up at Claiborne Farm, the Paris, Ky. farm his father started in 1910 (his grandfather owned a breeding farm in Virginia).

Claiborne Farm is “the magic kingdom of Thoroughbred breeding,” according to Keeneland magazine, which covers the sport. More Triple Crown winners – six of the 11 – have been conceived at Claiborne Farm than at any other farm. The famed horse Secretariat stood stud at Claiborne following his Triple Crown win.

Bull and Waddell Hancock (center) with their children (standing) Arthur and Clay, and (seated) Seth and Dell. (Photo courtesy of the Hancock family)

Bull Hancock had a simple answer to the question he often got about how to breed winners, says Larry Marnett, Ph.D., director of the Hancock Laboratory.

“He said, ‘you breed the best to the best and hope for the best,” Marnett says.

And that philosophy – of bringing “the best” together – has also contributed to the successes of the Hancock Laboratory.

“I’ve tried to use the resources of the Hancock Lab to catalyze multi-investigator science, to bring excellent scientists together to focus on challenging problems,” says Marnett, who has directed the lab since 1989.

This strategy of providing “seed” funding to promote multi-investigator studies became part of the philosophy of the Vanderbilt-Ingram Cancer Center when it was founded in 1993, 21 years after the Hancock Laboratory was established.

“The Hancock Lab was one of the first named laboratories in the country for cancer research,” Marnett says. “It was a very important building block for the Vanderbilt-Ingram Cancer Center.”

“I think some people might even call it the cornerstone of the Cancer Center,” Dell Hancock says. “When you look at the whole thing now and realize what it’s become – it sure made mama proud – and it makes all of us proud to think that we were part of the very beginning.

“I believe great things have happened at Vanderbilt for everybody who’s been touched by cancer.”

Hancock Lab highlights

Lubomir Hnilica, Ph.D., was the first director of the Hancock Laboratory.

Hnilica’s research focused on the effects of cancer-causing chemicals on histone proteins (DNA winds around histones like thread winds around a spool).

“He was working on chromatin (the combination of DNA and proteins in the cell nucleus) – and the changes in nuclear proteins during cancer – before anybody cared about chromatin,” Marnett says. “He was way ahead of his time.”

Hnilica was killed in an automobile accident in 1986.

After Marnett joined the Vanderbilt faculty as the Mary Geddes Stahlman Chair in Cancer Research and director of the Hancock Laboratory, the focus of the lab shifted to inflammation and its role in the development of cancer.

One of the lab’s first multi-investigator efforts began with the observation in the early 1990s that people who took aspirin regularly had reduced mortality from colon cancer.

Marnett was studying the protein target of aspirin – an enzyme called cyclooxygenase (COX), which comes in multiple forms, including COX-1 and COX-2. He gathered a team of “thoroughbred” scientists at Vanderbilt to explore aspirin’s cancer-slowing action in the gastrointestinal tract. They demonstrated that COX-2 was aspirin’s target in the gut and that the COX-2 enzyme was expressed in many cancers as they develop.

“At the pre-malignant stage, most solid tumors express COX-2, and the levels of COX-2 increase as the tumors progress,” Marnett says. “COX-2 helps drive cancer progression. So it was an obvious target for cancer prevention.”
Drugs that specifically block COX-2’s action (such as Celebrex and Vioxx) were in development at the time, and they turned out to be excellent cancer preventive agents. Unfortunately, cardiovascular side effects associated with these medicines have blunted their use (Vioxx was withdrawn from the market).

To help catch cancer early, Larry Marnett, Ph.D., director of the Hancock Laboratory, is developing imaging agents that mark cells—and, importantly, tumors—that express the enzyme COX2. (Photo by Daniel Dubois. Image at right, originally published in Nature Chemical Biology, courtesy of Marnett lab.)

In more recent studies, Marnett and his colleagues have developed a series of imaging agents targeted to COX-2. They have tethered fluorescent tracers or radioactive tracers to COX-2 specific drugs, for optical and positron emission tomography (PET) imaging.

The new agents are making it possible to “see” tumors in their earliest stages, before they turn deadly, by detecting increasing levels of COX-2.

“I think that these imaging agents may be our legacy – because the best way to treat cancer is to catch it early and get rid of it,” Marnett says.

He adds that it might even be possible to use the imaging agents – with chemotherapeutic drugs attached instead of imaging tracers – to deliver cancer-killing medicines directly to tumor cells that express COX-2.

As it moves forward into its next decade, the Hancock Laboratory will continue to follow the philosophy of bringing great people together to tackle challenging problems, Marnett says.

And the Hancock family will be there to support and celebrate along the way.

“Mama was so dedicated to the Hancock Lab and its mission, and we’re proud to continue her commitment,” Dell Hancock says. “Cancer took our father’s life at an early age, and I think the more we can do to get rid of that damn disease, the better off the world will be.

“Hopefully the Hancock Lab and Claiborne farm are both winners.”

Photo by iStockphoto.com

Twelve months after James Bradford Jr.’s, initial diagnosis of melanoma, his tumor had spread to other organs. While the 75-year-old Nashville banking magnate died 13 days later, his legacy lives on.

Early on in his disease course, Bradford’s cancer tissue had been tested for the most common melanoma-associated mutations. These mutations – in genes called BRAF and KIT – respond to targeted therapies called BRAF and KIT inhibitors, respectively. However, his tumor was negative for these mutations, which left only standard chemotherapy or immunotherapy for treatment.

In hopes of helping future patients, Vanderbilt-Ingram Cancer Center investigators – led by William Pao, M.D., Ph.D., Jeffrey Sosman, M.D., and Zhongming Zhao, Ph.D. – were determined to see if Bradford’s tumor could have been targeted with other existing or emerging targeted therapies.

To identify all of the mutations that could potentially make the cancer grow, the researchers performed “whole genome sequencing” on Bradford’s tumor and identified a different mutation in the BRAF gene, called BRAF L597.

In lab experiments, they found that a new class of drugs called MEK inhibitors could shut down the abnormal cell signaling induced by the BRAF L597 mutation. Additionally, they found that a patient with metastatic melanoma harboring a similar mutation had a dramatic response to treatment with an experimental MEK inhibitor.

Identification of this new mutation has had a relatively swift and striking clinical impact – just the kind of thing cancer “gene hunters” hope for when setting out to uncover new cancer-associated gene variants.

Cancer is often referred to as a “genetic disease.” This means that the disease results from a dysfunctional or defective gene or set of genes. It does not mean that all cancers are hereditary or passed down through a family.

In fact, only about 5 percent to 10 percent of cancers are truly hereditary – meaning that a mutation that predisposes one to cancer is passed from parent to child.

“We classify cancer into two groups,” said Wei Zheng, M.D., Ph.D., MPH, professor of Medicine, chief of the Division of Epidemiology and director of the Vanderbilt Epidemiology Center.

“One is familial syndromes, but those are a very small percent of the population. Most cases, 90 percent to 95 percent, are called ‘sporadic.’ For those people, there is no distinct familial pattern.”

Most cancer-causing mutations occur after birth, explained Pao, Cornelius Abernathy Craig Chair and director of the Division of Hematology and Oncology and of Personalized Cancer Medicine at Vanderbilt.

“These mutations can lead to activation of signaling pathways or loss of cell control pathways,” molecular disruptions that can cause cells to escape the normal processes that control their growth, Pao noted.

Researchers have been searching for mutations and genetic variations linked to both hereditary and sporadic cancers for decades.

These variations are often mutations – mistakes or changes – in the sequence of a cell’s DNA. Mutations can result from environmental sources such as toxins or radiation exposure, or can be the result of simple errors that occur during normal cellular processes.

Mutations originating in the germ cells (sperm and egg) are called “germline mutations” and are passed from parent to child. Some of these mutations can predispose an individual to hereditary cancers. Mutations originating in all other body cells are called “somatic” mutations and typically occur after birth.

Another type of genetic variation, called “single nucleotide polymorphisms,” or SNPs, differs from germline and somatic mutationsprimarily in how common it is: mutations are rare (usually less than 1 percent of the population) whereas SNPs generally are present in at least 1 percent of the population (and often much higher). The search for disease-linked variations includes germline mutations, somatic mutations, and SNPs.

Finding ‘needles in the haystack:’ breast cancer example

Breast cancer provides an important example of the ongoing search for cancer genes.

When researchers began the quest to identify genetic links to breast cancer, which has an estimated heritability of around 25 percent, they initially focused on families in which several women (and/or men) developed breast cancer.

First, researchers identified approximate locations in the genome that were associated with the disease using a method known as “linkage analysis.” Then, by finer and finer mapping of the DNA sequence in those regions, were able to zero in on mutations in the BRCA1 and BRCA2 genes in the mid-1990s. Hundreds of mutations in these genes have now been identified, some of which are more strongly associated with cancer than others.

The identifications of the BRCA mutations are among the most important discoveries in the field of cancer genetics. The findings have led to screening tests that have helped women determine their risk of such cancers and – if positive for one of the mutations – to take preventive action (such as prophylactic mastectomy and/or hysterectomy) to reduce their risk.

Wei Zheng, M.D., Ph.D., MPH, Xiao-Ou Shu, M.D., Ph.D., MPH, and William Blot, Ph.D. Photo by John Russell

However, only a small fraction (about 5 percent) of breast cancers are attributable to mutations in these genes. That means that many more mutations that contribute to breast cancer remain to be found. And the remaining genetic factors are unlikely to be as easy to find as the BRCA mutations.

“Initially, there was a simple view that you could approach study of a disease like breast cancer as if it were Mendelian – caused by one or a very few genes of large effect,” said Jeffrey Smith, M.D., Ph.D., associate professor of Medicine and Cancer Biology.

But after attempts to identify more BRCA-like gene variants failed, the search strategy changed, Smith noted. Over the past decade, researchers began turning to broader methods – called GWASs or “genome-wide association studies” – to identify common variants in large populations of individuals without any specific family history of breast cancer.

These efforts have been successful in identifying many new variants, said Zheng, whose research group has identified several variants in large epidemiological studies.

“Before GWAS, virtually none of the common genetic variants had been identified for breast cancer,” he said. “Now, we have at least 65 (variants identified) within about five years.”

One problem with the GWAS studies, however, is that they’ve mostly been conducted in European populations, Zheng said. Looking at different ethnic groups is important, he said, because the genetic structures can be different enough that variants identified in one population do not explain risk in other populations. So to get a more complete picture of cancer risk variants, he and colleagues have focused their research on non-European populations.

Zheng, Xiao-Ou Shu, M.D., Ph.D., MPH, and colleagues at Vanderbilt-Ingram and the Shanghai Cancer Institute have been following a large group of women in Shanghai to identify genetic and environmental factors associated with cancer risk. They also have organized a large consortium of East Asian women from multiple countries, including the United States, to study genetic factors for breast cancer.

From these studies, they’ve published a series of papers identifying new genetic loci and SNPs linked to breast cancer risk. They’ve also confirmed some of these variants in other ethnic (European and African) groups.

This tactic has led to the identification of variants that were initially missed in European populations.

“We identified some common genetic variants in non-European populations and later did a detailed, focused study and actually found risk variants in the same regions in Europeans. So they were there, we just couldn’t find them easily in studies conducted in European populations. This has happened multiple times for breast and for colon cancers,” Zheng said.

Confirming variants in multiple populations is critical to establishing whether a variant is truly linked to disease or just a “false positive.”

Recently, Smith and William Dupont, Ph.D., professor of Biostatistics and Preventive Medicine, led a study to identify SNPs associated with breast cancer in four independent breast cancer study populations – including two Vanderbilt patient populations.

Jeffrey Smith, M.D., Ph.D.

One important population is the Nashville Breast Cohort – a study, ongoing since 1954, of 17,030 Nashville-area women diagnosed initially with benign breast masses. Archived tissue samples were available on 8,395 of these patients, 903 of whom have later developed breast cancer. Because the original tissue samples of the benign breast mass – representing the “germline” genome – had been preserved, researchers can compare that genome to the genomes of the breast cancer samples to identify genetic changes that might be contributing to the disease. The study also offers to identify potential mutations that may have occurred in the benign breast lesions themselves, many years prior to the diagnosis of cancer.

BioVU, Vanderbilt’s repository of patient DNA samples linked to de-identified medical records, was another crucial resource. From this population, the researchers found 1,172 breast cancer cases and could compare those DNA samples to the DNA of patients with no evidence of breast cancer.

Smith and colleagues were able to validate a set of previously identified breast cancer risk variants. Importantly, they identified two previously unreported variants – on chromosome 10 and chromosome 16 – that were associated with breast cancer risk in three of the four study populations.

Because most common variants each have a relatively small effect on disease risk individually (compared to something like a BRCA mutation), the hope is to identify “sets” of variants that could more reliably predict cancer risk, Smith said.

Such sets of gene variants could then help researchers continue to improve breast cancer prediction models to help identify women at high risk of breast cancer who may benefit from enhanced screening and prevention strategies.

“If you had a comprehensive set of all of these (variants), that would possibly hold some useful predictive power,” said Smith.

Beyond the genome

Despite the important role of genetic variants in cancer, other factors are also at play – specifically environmental factors.

A host of environmental factors have been linked to cancer risk: cigarette smoking, sun exposure, exposure to industrial chemicals, various dietary factors, etc.

But as Vanderbilt-Ingram researchers are finding out, the same environmental factor – for example, a particular carcinogen (cancer-causing compound in the environment) – may impact individuals differently based on their genetic makeup.

Zheng and colleagues in the Vanderbilt Epidemiology Center are investigating these links between genes and environment and how individuals may differ in how they respond to carcinogens.

“Carcinogens in the environment are somewhat inactive – that’s why they can stay there,” Zheng explained. “When they get into the body, there are multiple enzymes there to activate these carcinogens…and when they become active, they can bind to DNA, causing DNA damage and mutations.”

The body also has other enzymes to “detoxify” carcinogens, chemically modifying them so that they can be excreted from the body.

This carcinogen activation/detoxification pathway is well understood. But, Zheng noted, “in the past, most research just looked at one SNP at a time in this pathway. But we’re using a different approach because we feel that one SNP, one gene in the whole pathway only plays a relatively minor role – we have to combine them to really describe a person’s pattern of carcinogen metabolism.”

Using this approach, Zheng and colleagues recently studied genetic factors involved in the metabolism of heterocyclic amines – carcinogenic chemicals found in well-done or burnt meat – and their risk of colon polyps (which can progress to colon cancer).

Their findings suggest that, with this genetic information, it may be possible to classify people into risk categories: those with genetic profiles conferring higher risk of developing colorectal polyps when they have a high intake of well-done meat (and thus a high heterocyclic amine exposure) and those with a lower risk genetic profile.

Zheng’s group has identified similar differences in the metabolism of isothiocyanates (chemicals found in cruciferous vegetables like cauliflower and broccoli that have protective effects against cancer).

“In people who are very efficient at metabolizing these (chemicals), the isothiocyanates will only stay in the body a short time. So for those people, the benefit for isothiocyanates will not be as good as for people in which isothiocyanates can stay in the body a long time.”

Gene-environment interactions will play an important role in advancing personalized cancer medicine, noted William Blot, Ph.D., a professor of Medicine and associate director of Cancer Prevention, Control and Population-Based Research.

“The hope is that increased knowledge of such gene-environment interactions may lead to the development of personalized prevention strategies, with cancer prediction models tailored to the individual,” he said.

“In the emerging area of personalized medicine, a major focus of research is the discovery of genetic traits that may provide advantage for cancer survival,” said Blot. “Such variants could help identify persons more likely to benefit from specific cancer therapies. Similar research is now addressing how genetic variation influences risk of developing cancer, which may in turn lead to improved strategies to prevent the cancer from occurring at all.”

Genomics key to personalized care

Ultimately, the goal of cancer genetics – in addition to improving prediction and prevention of cancer – is to improve cancer treatment and reduce cancer deaths. But the mounting knowledge about cancer genetics is revealing a multitude of gene variants involved in cancer – and revealing that each patient’s cancer is unique.

“In the past, we were used to treating cancers according to what they looked like under the microscope and so we treated many patients with the same drugs,” said Pao. “But we now know that even cancers that look the same under the microscope are different at the molecular level and should be treated accordingly. Everyone’s cancer is personal.”

William Pao, M.D., Ph.D., believes that everybody's cancer is personal. Photo by Susan Urmy

Providing individualized cancer care is a priority at Vanderbilt-Ingram. In 2010, the center launched the Personalized Cancer Medicine Initiative (PCMI) to realize that goal for several types of cancer, initially melanoma and non-small cell lung cancer but now also colorectal cancers and breast cancers.

The initiative, directed by Pao, aims to genotype tumors and match the appropriate therapy to the genetic changes, or mutations, that drive the cancer’s growth.

Pao believes that advances in genomics technology will help achieve this goal.

“As the cost of (gene) sequencing continues to decline … soon, every patient with cancer will have tumor genetic profiling done to help prioritize therapy based on that profile.”

Pao also notes that genetics is becoming so important that cancers are now beginning to be identified less with their organ of origin than their molecular makeup.

This is true in the case of BRAF-associated cancers, like melanoma. In recent years, similar BRAF mutations have been identified in about 10 percent of colorectal cancers. The genetic testing of colorectal cancers in the PCMI includes BRAF mutations. Colon cancers with the BRAF mutation do not seem to respond as well to the targeted therapies effective in melanoma, but as more drugs are developed and more genetic drivers of cancer are identified, more specific, individualized cancer treatment is possible.

“Based upon promising trends, we believe a genotype-driven approach is much better than our current standards. If you select the right mutation, and you give the right drug, you can already double the survival of patients with certain metastatic lung cancers or melanomas,” Pao said.

Another recent initiative, My Cancer Genome, an online database of cancer-associated genes and mutations linked to information about recommended therapies, can be a tool to help physicians select the appropriate therapies. It can be found at mycancergenome.org.

“It will be a challenge, but hopefully we can get to better, more individualized, treatments for our patients,” Pao said.

But in February 2010, Jimmy had been battling melanoma for over a year – and the Bradfords received some bad news that could have derailed the trip.

“Jimmy found out he had a terrible scan on Feb. 2, and on Feb. 3, we were supposed to go on this ski trip,” recalled Tooty. “His only question to Dr. Sosman was ‘Can I just go on my trip, I feel fine?’”

Jimmy’s oncologist Jeffrey Sosman, M.D., Ingram Professor of Cancer Research, told him to go ahead. But he did offer Tooty a word of caution.

“Dr. Sosman told me that he would begin to have symptoms, and he did have some pains while we were there for 10 days. But he had a good trip, all told, and we got back home all right.”

Jimmy passed away about a month after the ski trip, on March 8, 2010. But his legacy lives on through a financial gift the family made to fund a discovery grant in melanoma research at Vanderbilt-Ingram Cancer Center.

The support of Sosman, along with the rest of Jimmy’s medical team – including surgeon James Netterville, M.D., and oncologist William Pao, M.D., Ph.D. – were major factors in the Bradfords’ decision to support discovery research.

Because of their guidance, medical expertise and emotional support, “You just felt like they were really going to bat for you,” Tooty said.

The Bradford’s discovery grant actually funded the sequencing of Jimmy’s tumor, which led to the discovery of a new melanoma mutation and the identification of a promising new therapy (see main story).

The research was recently featured on the front cover of the journal Cancer Discovery that published the findings, with an artistic representation of the genetic sequence of his tumor.

“Jimmy’s finally on the front cover,” Tooty said, cheerfully. “It’s better than being a centerfold!”

“It’s wonderful that they have taken this money and gone on to really break it down and find out more detail (about these melanoma mutations)… and that they are having some success, getting the findings to the clinic.”
Tooty acknowledges that there’s still much to learn about melanoma – and cancer, in general – and that it won’t likely be learned in her lifetime. But with the support of individuals like the Bradfords, meaningful progress is being made.

The Bradford family recently established an endowed fund in Jimmy’s name to keep pressing forward against this disease. Endowments created by our philanthropic partners have a critical role in funding our innovative edge in research, medical education and cancer care.

James C. Bradford, Jr. Endowed Fund in Melanoma Research will provide a continuous source of support for investigators studying this cancer.

“Even if you can’t be helped personally,” Tooty said, “at least you can help someone else.”