Conquest - Summer 2007

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GENETIC REPROGRAMMING An Act of Diplomacy

M I S S I O N The mission of The University of Texas M. D. Anderson Cancer Center is to eliminate cancer in Texas, the nation, and the world through outstanding programs that integrate patient care, research and prevention, and through education for undergraduate and graduate students, trainees, professionals, employees and the public.

V I S I O N We shall be the premier cancer center in the world, based on the excellence of our people, our research-driven patient care and our science.

We are Making Cancer History.

C O R E

VA L U E S Caring

By our words and actions, we create a caring environment for everyone.

Integrity We work together to merit the trust of our colleagues and those we serve.

Discovery We embrace creativity and seek new knowledge.

On the Cover: Methyl groups, consisting of a carbon atom surrounded by hydrogen atoms, silence cancer-suppressor genes by attaching themselves to the gene. By removing these chemical “off� switches, investigators are trying to restore the genes normal function and destroy the tumor.

Check out the Conquest Web site at w w w. m d a n d e r s o n . o r g / c o n q u e s t

CONTENTS C O N Q U E S T

SUMMER 2007

2 FRONTLINE

F E AT U R E S

Who’s On First?

6 GENETIC REPROGRAMMING — AN ACT OF DIPLOMACY

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SYMPTOM SYMP S SYM YM M TO RESEARCH RCH It’s A Alll About Abo the th Patient

Instead of targeting cancer cells for death, investigators are testing drugs that may be able to change the way genes and cancer cells interact and behave, and then force the cancer cell to kill itself.

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PROFILE F

Raymond N. DuBois, M.D., Ph.D.

12 IT TAKES MORE THAN A VILLAGE

M. D. Anderson investigators are playing a leading role in

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MOVING FORWARD Tommy Garcia

NCI-sponsored cooperative groups, helping to set new standards in cancer care.

18 $50 MILLION GIFT SETS RECORD FOR M. D. ANDERSON

T. Boone Pickens’ historic gift carries tremendous potential for growth and support of M. D. Anderson’s patient care, research, education and prevention programs.

CONQUEST SUMMER 2007

FRONTLINE WHO’S ON FIRST? CML DRUG MAY TAKE STARTING POSITION What can happen when a drug moves from second to frontline therapy?

Better response.

That’s what M. D. Anderson investigators reported at the American Society of Clinical Oncology’s annual meeting in June.

Researchers are encouraged by early results from an investigational drug study showing that dasatinib – an established second-line drug for chronic myelogenous leukemia – has high response rates when given to newly diagnosed patients as their first therapy for the disease.

Led by Jorge Cortes, M.D., professor in M. D. Anderson’s Department of Leukemia, investigators found that patients taking dasatinib achieved complete cytogenetic response – absence of the abnormal chromosome that drives this disease – more rapidly than what has been observed historically using the current frontline therapy. Dasatinib in these patients, they observed, also appeared to be well tolerated.

Produced by Bristol-Myers Squibb, dasatinib (Sprycel™) was approved by the U.S. Food and Drug Administration in 2006 for use in patients whose disease is unresponsive to or becomes resistant to the frontline therapy imatinib. Both drugs bind to and block a genetically flawed protein known as BCR-ABL, which causes the disease. A key benefit of dasatinib, investigators note, is that it’s active against many imatinib-resistant BCR-ABL mutations.

Investigators hypothesize that using dasatinib first will produce an earlier response, which may translate to a better overall survival. While this hasn’t been proven yet, they say these early results are encouraging.

Thirty-five patients who enrolled in the Phase II clinical trial between November 2005 and December 2006 were evaluated. These patients received either 100 mg of dasatinib once daily or 50 mg twice daily.

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Jorge Cortes, M.D., and Fe Calda, R.N., hope that a secondline drug for chronic myelogenous leukemia will become the next frontline therapy for the disease.

Thirty-four patients had been on the clinical trial for at least three months when Cortes and his team evaluated their data. They found that 77 percent of patients at three months, 92 percent at six months and 95 percent at one year had a complete cytogenetic response.

This rapid response compares favorably to historical data on patients at M. D. Anderson who took imatinib (Gleevec ®) as a first therapy. Produced by Novartis, imatinib’s complete response rates at six months are 54 percent at 400 mg daily and 85 percent for 800 mg daily.

However, at 12 months 72 percent of patients receiving 400 mg of imatinib and 92 percent of those receiving 800 mg had a complete cytogenetic response.

The dasatinib clinical trial, which is set to enroll 100 patients, remains in progress with more than 30 patients currently participating.

The comparison to historical data provides insight into dasatinib’s effect, Cortes notes, but a randomized clinical trial comparing medications directly would present a more detailed picture.

– Scott Merville

Editor’s Note: Gathering symptom-related data to improve survivors’ daily lives is the central focus of M. D. Anderson’s Department of Symptom Research. Beginning with this issue, a series of articles will detail the steps being taken to collect solid, scientific evidence that can be used to design interventions to relieve the symptom burden caused by cancer and its treatments.

Charles Cleeland, Ph.D., and Xin Shelley Wang, M.D., believe that the severity and impact of cancer-related symptoms shouldn’t be overlooked. The newly developed M. D. Anderson Symptom Inventory will help ensure this doesn’t happen.

ASSESSING SYMPTOM DISTRESS: IT’S ALL ABOUT THE PATIENT Cancer survivors know best what the side effects of cancer and its treatments are. Yet, they often lack the words to describe what they feel and the appropriate tools for selfreporting.

Still other barriers may inhibit them, like wanting to be “good” patients who don’t complain; who think that talking about anything else will distract their oncologist’s attention from the cancer; who dread being given more medication; or who worry that symptoms might indicate a recurrence.

by Sandi Stromberg

The lack of proper measurement tools and the presence of patient fears are concerning to Charles Cleeland, Ph.D., chair of M. D. Anderson’s Department of Symptom Research.

An early leader in the field of symptom burden, he was instrumental in the design of the pain questionnaire that helps patients describe more effectively the amount of pain they are experiencing. He also has brought international attention to the reality of pain, leading several important initiatives, including a nationwide one with Veterans Administration hospitals and another at M. D. Anderson in 2001. He also helped organize a cancer pain relief effort in China, together with the Chinese Ministry of Health.

In the last few years, he has broadened that scope, working to develop a viable measurement tool to help clinicians identify and assess the most common and predictable symptoms of cancer and its treatments. At the same time, this has provided language that allows patients to describe what they are feeling.

“Everyone thinks they can design a questionnaire overnight,” he says. “But there is some science to it. We insisted that it be brief so it wouldn’t tire patients, and that it be intuitively understood so it could contribute something to their care.”

NARROWING GENERAL SYMPTOMS Cleeland’s group first generated a list of 26 symptoms working from various other symptom scales and from a work group comprised of medical and radiation oncologists, oncology nurses and symptom management specialists. Then, they recruited three different groups of patients for the study: an initial outpatient sample, an inpatient sample and an outpatient sample for cross-validation of the measure. Finally, they used several methods to reduce the number of core symptoms.

The final product, the M. D. Anderson Symptom Inventory (MDASI), identifies the following 13 side effects as occurring most frequently and being the most distressing

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for patients: pain, fatigue, nausea, disturbed sleep, feelings of being distressed (upset), shortness of breath, not remembering things, lack of appetite, feeling drowsy (sleepy), having a dry mouth, feeling sad, vomiting and numbness or tingling.

Daily activities they identified as possibly affected by these symptoms were: general activity, mood, work (including work around the house), relations with other people, walking and enjoyment of life.

For both the core symptoms and the interferences, MDASI poses questions about the level at which these are affected. Patients, in turn, answer on a scale of 0-10, 0 meaning not affected at all, 10 as bad as you can imagine.

MOVING FROM GENERAL TO SPECIFIC “One of our aspirations when we did the MDASI was to develop additional modules that would focus on specific diseases, stages of disease and treatments,” Cleeland says. “We have a formal network working on these modules, an exciting set of people from several departments across the institution.”

Among them is Terri Armstrong, D.S.N., an advanced practice nurse in the Department of Neuro-Oncology. She had been with the department only a short time before realizing patients with primary brain tumors were having similar experiences. That made her acutely aware that an aspect of the disease wasn’t being addressed – the symptom burden.

“It’s common for people to go from normal, working lifestyles and doing fine to having a sudden event like a seizure and being thrust into this world of brain cancer, often with residual deficits,” Armstrong says. “Problems with strength or sensation or ongoing seizures can be devastating.”

Interested in the impact of brain cancer on quality of life, Armstrong When it comes to evaluating the symptom burden of patients began a literature review. She was amazed to discover that what little was known about the symptom burden of this patient population was from studies with data from as early as 1924. with brain tumors, Terri At the same time, she decided to work toward a doctorate degree in nursing at The University of Armstrong, D.S.N., is the go-to person. Using the general Texas Health Science Center at Houston, School of Nursing. Her advisor and mentor, Marlene Cohen, Ph.D., also a professor at M. D. Anderson, introduced her to Cleeland’s work.

M. D. Anderson Symptom “At first, I wanted to go in and do things to help people, but then I realized we don’t really understand Inventory model as her guide, their problems,” she says. “It was hard to step back, but that’s where Dr. Cleeland’s group is so helpful. she’s capturing the symptoms Through them, I learned we have to understand the issues first so we can target interventions.” that are more specific and important to these individuals. GATHERING SYMPTOMS OF PRIMARY BRAIN TUMORS While she knew that the core MDASI developed by Cleeland’s group was an important tool for measuring the severity and impact of cancer-related symptoms in general, she also knew it didn’t address many of the specific symptoms of those with primary brain tumors.

“I wanted to add something to the existing instrument and try to capture the symptoms that were important to this group,” she says.

Somewhat the same as in the development of the core MDASI, Armstrong put together panels with members from both inside and outside M. D. Anderson. These included people from nursing, social work, neuro-psychology, physical therapy, radiation, neuro-oncology and neurosurgery, as well as patients and their caregivers.

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MELANOMA PATIENTS: AVERAGE SYMPTOM SEVERITY OVER TIME

Melanoma patients were among the first to complete the M. D. Anderson Symptom Inventory questionnaire, listing the frequency of their symptoms and the ones they felt were most distressing.

“We learned a lot,” she says. “One striking aspect was the issue of pain. Many of the physicians said their patients didn’t complain about pain. But we found that patients on the panel used other words.

They would say, ‘I have pressure in my head’ or ‘I have a sensation in my head.’”

She also learned what she was wrong about. For example, she didn’t think patients with primary brain cancer had shortness of breath, but learned that 20 percent do.

“One of the most important things we learned was something we had suspected but had no way until now to verify,” she says. “People’s symptoms can predict when their tumor is growing.”

FINAL INVENTORY The final inventory for patients with primary brain tumors was narrowed to 18 symptoms divided into three categories: Eight focal symptoms – weakness on one side of the body, changes in body sensation and in vision, difficulty understanding, speaking, remembering, starting or completing tasks, walking Five generalized symptoms – headache or pressure in the head, seizures, change in seizure activity, difficulty concentrating, sleepiness Five treatment and medication-related symptoms – changes in appearance, appetite and bowel pattern, irritability, fear Currently, patients in certain clinical trials complete a questionnaire listing these symptoms on the same scale as the general MDASI. “These instruments are such a good thing because they force us to address these questions. If we use Dr. Cleeland’s instrument and this module, they make us ask: How severe is it? How does it impact a patient’s daily life,” Armstrong says. “It facilitates communication.”

In the next issue, the series continues with a look at the symptom burden of patients with lung cancer and the use of interactive voice response systems in thoracic surgery.

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Genetic Reprogramming

To radiation, chemotherapy, surgery and biological therapies deployed to wage war on cancer, M. D. Anderson researchers have added a new approach – diplomacy.

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An Act of Diplomacy

by Scott Merville

Jean-Pierre Issa, M.D., has found that a little persuasion – aka genetic manipulation – can go a long way in convincing cancer cells to stop misbehaving.

“In this instance, we’re not trying to kill cancer cells, rather we talk to cells and remind them of their regular programming. We persuade them to return to their normal behavior,” says Jean-Pierre Issa, M.D., professor in M. D. Anderson’s Department of Leukemia.

The instruments of persuasion are drugs that awaken cancersuppressing genes in cancer cells by sweeping away chemical “off” switches connected to those genes. Methyl groups – which consist of a carbon atom surrounded by hydrogen atoms – silence genes by attaching at a certain spot, hanging off the gene like a tag or bookmark.

Issa and Leukemia Department Chair Hagop Kantarjian, M.D., are pioneers in the emerging field of epigenetics, the study of changes in gene expression and cellular behavior that are not caused by physical damage or mutation of the genes themselves.

DNA methylation, for example, is epigenetic.

Issa and Kantarjian revived a failed chemotherapy, for instance, by turning it from attack to diplomatic mode. Using a low-dose, low-toxicity, longer-term approach, they showed that decitabine extends the life of some leukemia patients by demethylating, or turning on, genes.

Based on a clinical trial led by Kantarjian, the U.S. Food and Drug Administration last year approved decitabine (Dacogen™) for treatment of myelodysplastic syndrome, a lethal failure of the bone marrow to produce enough normal blood cells. The latest research by the group shows 70 percent of patients experienced some relief from MDS, with 35 percent experiencing complete remission. The median time of remission was 20 months.

ONLY THE BEGINNING Before the development of decitabine and another epigenetic agent called azacytidine (Vidaza™), MDS was a disease “with no treatment,” Issa says. There was no chance of putting it in remission with a drug. Only supportive care, such as a blood transfusion, was available. Bone marrow transplants worked for a small number of patients.

“I see this as the beginning of the development of epigenetic therapy,” Kantarjian says. “FDA approval of decitabine was just the beginning. This is when the real research starts, when the drug becomes accessible to investigators in an easy manner so they can develop new concepts and new strategies to optimize the use of the drug as a single agent, in combinations and across many tumors.”

The leukemia group has a leading program, investigating epigenetic agents in 18 clinical trials. Four of those trials involve azacytidine, a drug that acts in a similar manner as decitabine.

The two medications are the first epigenetic therapies approved for cancer.

Kantarjian, Issa, MDS Section Chief Guillermo GarciaManero, M.D., and colleagues have pressed ahead refining the optimal decitabine dosage for MDS, exploring its use in other leukemias, in combination with other drugs, and addressing

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When it comes to genes and cancer cells, it’s all about how they express or don’t express themselves. Being able to change the way they interact and behave is no small feat and one of the biggest challenges for Hagop Kantarjian, M.D.

how cancer becomes resistant to the drug. Azacytidine trials explore similar issues. Issa also collaborates with a team from Duke University on the use of decitabine for melanoma and renal cell carcinoma.

Nearly one-half of the 32 epigenetic trials at M. D. Anderson study decitabine. Not bad for a drug that was left for dead 25 years ago.

DRUG REVIVAL Kantarjian’s and Issa’s work to revive decitabine is a classic example of the major role academic medical institutions play in drug discovery and development.

Decitabine was discovered in Czechoslovakia and tested against leukemia as traditional high-dose, cell-killing chemotherapy in Europe. The drug showed activity against the disease but was dogged by dangerous and unpredictable myelosuppression – the shutting down of blood production in the bone marrow.

This side effect caused the drug’s manufacturer, Pharmachemie BV of Europe, to shelve it in the 1980s.

Decitabine still intrigued Kantarjian, who was following the newborn field of epigenetics and suspected the drug had potential if used properly.

Pharmachemie was not interested in sponsoring any more clinical trials, but agreed to provide Kantarjian with decitabine.

He filed his own investigational new drug application with the FDA and went to work. Kantarjian recalls that it was the early 1990s and he was the only physician in the United States working with the drug.

At the time, Issa was on the faculty at Johns Hopkins studying epigenetics. His research in DNA methylation led him to believe that decitabine might work epigenetically as a demethylating agent.

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The two met in 1993 at a scientific meeting when Issa sought out Kantarjian and his poster on use of decitabine for chronic myelogenous leukemia. A collaboration was born.

They developed a Phase I clinical trial using decitabine intravenously for MDS at doses ranging from one-twentieth to one-fiftieth of the doses employed in the European trials. The trial showed that the drug was safe and active, with the lower dose preventing dangerous incidents of myelosuppression. Lab research indicated it worked by wiping out methyl tags.

Issa came to M. D. Anderson in 1999, where he and Kantarjian developed and led a pivotal Phase III multi-center trial in 2001. Results were reported early last year in the journal Cancer, citing that 17 percent of patients had some response, with responders having a median time to disease progression or death of 17.8 months, compared with 9.8 months for patients who didn’t respond.

By the time the FDA approved decitabine in May 2006, the drug had been held by four companies: Pharmachemie, TEVA, SuperGen and finally MGI Pharma, which purchased the drug from SuperGen in September 2004 and shepherded it through the FDA fast-track process. The frequent change of companies was another challenge in keeping decitabine alive, Kantarjian says.

Azacytidine, developed on a parallel track by a team at Mount Sinai Medical Center in New York, and owned by Pharmion, was approved by the FDA in 2004.

Decitabine, researchers note, is the more potent demethylating agent of the two.

EPIGENETICS — BY DEFINITION: Acetylation: a reaction that introduces an acetyl group into a molecule of an organic compound. Acetyl tags work by connecting to specific proteins and act as a genetic on switch.

Demethylation: the chemical process of removing a methyl group from a molecule, which, in turn, can reactivate tumor-suppressor genes that are silenced by methylation.

Epigenetics: the study of changes in gene expression and cellular behavior that are not caused by physical damage or mutation of the genes themselves.

Methylation: an enzyme-mediated chemical modification that adds methyl groups at selected sites on proteins, DNA and RNA. Methyl tags work by attaching to specific areas of genes and act as a genetic off switch.

THINKING OUTSIDE THE BOX “Dr. Issa and Dr. Kantarjian brought a unique assimilation of scientific and clinical expertise that enabled them to think about developing decitabine in a different way,” says Mary Lynne Hedley, Ph.D., chief scientific officer of MGI Pharma. “And that’s really why decitabine ended up being so useful for patients.”

They upset three dogma of drug development and patient care, Hedley notes. First, they took a general cell-killing drug and by understanding its biological activity, transformed it into an early version of targeted therapy.

Second, they rejected the common practice of administering the maximum tolerated dose of a medication. And third, they focused on longer-term courses of therapy and disease management, rather than short courses of treatment.

The key to improved outcomes seen in the MDS follow-up study was prolonged treatment at low doses, Kantarjian says. “The best results with decitabine will be achieved by giving the drug to patients for one or two years, consisting of 20 to 24 courses of treatment, rather than three or four courses.”

BEYOND MDS Kantarjian leads a Phase III clinical trial of decitabine for acute myelogenous leukemia – the most common form of the disease in adults. Kantarjian notes that AML also is a leukemia that has shown the least improvement in treatment outcomes over the last 30 years.

A Phase II trial for decitabine as frontline therapy for AML in elderly patients, those with the grimmest prospects, also is under way.

Most patients over 65 go untreated, except for receiving supportive care, because of the toxicities associated with

chemotherapy used against the disease. Their median survival is 1.7 months.

A poster presented by the team at the 2007 American Society of Clinical Oncology meeting showed how decitabine, with its low-intensity and minimal side effects, might help older AML patients. Total response rate was 52 percent, with 24 percent having complete remissions. Median survival time at the 20-month mark of the study was 12.6 months.

A study published this year comparing the effectiveness of decitabine to that of high-intensity chemotherapy in high-risk MDS patients showed comparable remission rates for each option, but those receiving decitabine had nearly double the mean survival time – 22 months versus 12 months. “Chemotherapy gets patients to remission, but it’s very toxic and remissions tend to be short-lived,” Issa says.

Other M. D. Anderson researchers also are testing epigenetic drugs alone or in combinations against solid tumors as well as myeloma and lymphoma.

David Stewart, M.D., professor in the Department of Thoracic/Head and Neck Medical Oncology, for example, is exploring in a Phase I trial the use of the drug for solid tumors and lymphomas that have resisted other treatment.

Some solid tumors, such as colon and head and neck cancers, are known to have a great deal of methylation. Issa notes that earlier clinical trials of decitabine against these cancers also failed, but they repeated the same mistake as the European trials, using maximum tolerated doses for short periods.

“This drug really hasn’t been properly tested at low doses over longer periods as a demethylating agent against those cancers,” Issa says.

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CH3 Guillermo Garcia-Manero, M.D., and his colleagues are testing several new epigenetic agents that address the problem of drug resistance by reactivating tumor-suppressor genes.

MORE TO LEARN There is still plenty to understand about how demethylating agents such as decitabine work. Their effect is global because they demethylate and switch on many genes. The research team is pinpointing specific cancer-suppressing genes that are silenced by methylation.

MDS eventually becomes resistant to decitabine. Issa says resistance starts as early as six months or as late as 3.5 years. The drug strips away all methyl tags, both normal and abnormal (see sidebar, pg. 11). The normal tags come back quickly, while the abnormal tags return more slowly. “If they come back, the drug stops working,” Issa notes.

Initial research in DNA methylation indicated that removing the tags might promote cancer by turning on oncogenes. However, Issa notes, subsequent research showed that methylation silenced hundreds of genes, inactivating those involved in tumor suppression and programmed cell death of cancerous cells.

Since tumors rely more on gene silencing to survive than normal adult cells do, the overall effect of demethylation is favorable for treatment.

TWO FOR ONE One potential answer to the problem of resistance is to combine agents, explains Garcia-Manero, M.D., an expert in epigenetics and associate professor of leukemia.

Garcia-Manero was lead author of a major study published in the journal Blood late last year. It combined decitabine with valproic acid, an anti-convulsant drug used for epilepsy.

Valproic acid hits a different epigenetic target, GarciaManero explains, inhibiting the removal of chemical “on” switches – acetyl tags – that activate genes.

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Combining the two drugs in a group of 54 AML and MDS patients was shown to be safe and effective, Garcia-Manero notes. Methyl “off” switches were stripped from DNA, and two types of histone acetylation were achieved and an important tumor-suppressing gene was reactivated.

Of 10 elderly MDS and AML patients, five responded to the combination, with four of them experiencing remission. Overall, 22 percent of patients got some relief from the combination, with 19 percent having complete remission. While the study was too small to draw conclusions about the drugs’ effectiveness, it points to the need for follow-up clinical trials.

“We’re testing a number of epigenetic agents that have exciting potential,” Garcia-Manero notes. His team has a paper pending in Blood that shows promising results with the combination of valproic acid, azacytidine and all-trans retinoic acid for AML and MDS patients. Overall, 42 percent of 53 patients showed some response to the three-drug combination, with 22 percent having complete remissions.

Garcia-Manero also is testing three other epigenetic agents, all of which protect acetyl “on” switches: vorinostat, MGCD0103 and LBH589.

Razelle Kurzrock, M.D., professor in the Department of Experimental Therapeutics and director of M. D. Anderson’s Phase I Clinical Trials Program, leads a clinical trial testing azacytidine and valproic acid in advanced metastatic cancers.

Issa remembers presenting a research poster on epigenetics to the 1992 annual meeting of the American Association for Cancer Research, “There was one other poster on the subject out of 4,000,” he says.

At this year’s AACR meeting, there were 500 posters on epigenetic approaches – genetic diplomacy marches on.

Genes Misbehaving Cancer remains a disease of genes and genetic mutations, changes that drive cancer and make it hard to treat. But it’s also a disease of genetic expression – genes behaving badly – and that, Jean-Pierre Issa, M.D., explains, is where epigenetics comes in.

To understand epigenetics, you have to start at the beginning, at the embryonic stage. An embryo’s cells all have an identical set of genes. Its next job is to use those genes to differentiate cells into varied organs and tissues to build the body. This is accomplished with epigenetic signals that turn on the genes needed to create an organ while blocking other genes, explains Issa, professor in M. D. Anderson’s Department of Leukemia.

The crucial actors here are methyl groups (off switches) and acetyl groups (on switches). Methyl tags attach to specific areas of genes.

Acetyl tags have a more complex story, connecting with histone proteins to turn genes on.

Histones wrap around DNA. This histone-DNA combination forms the chromatin complex, which in turn composes chromosomes. When acetyl groups attach to histones, they turn on the accompanying gene.

When acetyl tags are removed, the histone tightens around genes, turning them off.

Epigenetic drugs wipe out the methyl groups temporarily or block the stripping of acetyl groups from histones.

While some cancers are tied to inherited genetic variations, others are launched by damage to DNA. Mutated or damaged genes generally are impervious to repair by treatment. Therapies generally target these cells for death. Genes that are suppressed, Issa notes, can be manipulated through epigenetics – a more diplomatic approach.

Like any good detective, Cheryl Lyn Walker, Ph.D., and her team are focusing on all suspects, from diet to environmental toxins, that can turn normal cells into cancer cells.

“Our genome is set. It can’t be modified. Our epigenome is more dynamic. It’s something we can affect with epigenetic drugs or by our behavior,” Issa says.

Think of genes as hardware and epigenetics as the operating system software, explains Cheryl Lyn Walker, Ph.D., professor in M. D. Anderson’s Department of Carcinogenesis at the Virginia Harris Cockrell Cancer Research Center in Smithville, Texas.

External carcinogenic factors such as diet, tobacco use or environmental toxins can cause cancer both via direct DNA damage and epigenetic effects, Walker says. She and her colleagues are focusing on all suspects that turn normal cells into cancer cells.

Walker, for example, studies genetic predisposition to cancer and how cancer-causing chemicals, or carcinogens, interact with genetic factors to cause cancer.

She examines the impact of xenoestrogens – chemicals present

environmental exposures or in food, such as a plant phytoestrogen that is present in soy. Walker studies how exposure to xenoestrogens affects the development of uterine fibroids. Fibroids occur in upwards of 50 percent to 75 percent of women, and these tumors are the principal reason for hysterectomy in women of reproductive age.

Working in a rodent model, Walker found that those with a genetic predisposition to develop fibroids and who are exposed to environmental estrogens at crucial times during development have dramatically increased risk of developing tumors later.

“This is called developmental reprogramming. When you disrupt a tissue while it’s developing, you worsen the risk of disease in adulthood,” Walker says. “We’re finding that for this type of environmental exposure, it’s all about timing.”

Reprogramming probably is accomplished through an epigenetic mechanism, Walker says, and so may be susceptible to epigenetic treatment.

Interestingly, Issa has found that methyl tags accumulate over time, shutting down genes. It’s a tantalizing possible connection to aging, he

in our environment that act like estrogens – which are taken in through

says, but that’s another story.

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Cooperative groups help set the standard in cancer care

by Carol Bryce

More isn’t always better, an old adage says.

But when it comes to conducting late-phase clinical research trials, having more participants isn’t just better, it’s essential to ensuring that novel and more effective therapies are made available to patients sooner.

“To get definitive answers to important research questions, we need large randomized trials that may require 1,000 to 2,000 people,” says Maurie Markman, M.D., vice president for clinical research at M. D. Anderson. “Often these studies are comparing novel drugs to existing excellent treatment regimens to try to come up with something even better. The only way to get answers in a reasonable period of time is to do the trials on a national level.”

Research discoveries can result from close collaborations among an institution’s physicians, scientists, nurses, biostatisticians and other health professionals. But it’s not always feasible or even advisable to conduct a scientific research project in only one institution, even one as multidisciplinary as M. D. Anderson. That’s when the National Cancer Institute’s clinical trials cooperative groups can enter the picture.

The NCI Clinical Trials Cooperative Group Program is designed to promote and support clinical trials of new cancer treatments, explore methods of cancer prevention and early detection, and study quality of life issues and rehabilitation both during and after cancer treatment.

M. D. Anderson plays a leading role in many NCI cooperative groups, whose members include cancer centers and individual researchers and community physicians throughout the United States, Canada and Europe. While the groups differ in their structure and focus, they share a common purpose: to develop and conduct large-scale clinical trials in multi-institutional settings.

As one of the world’s largest and most respected cancer centers, M. D. Anderson makes important contributions to cooperative research groups, Markman says.

“By participating in the trials, we help increase patient accrual and help get the studies completed in a timely manner. Through our leadership, we also can influence in a very positive way the kinds of trials that take place, the quality of questions that are asked and the analyses that are done,” Markman adds.

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C O O P E R AT I V E

Joann Ater, M.D., says young patients like Osman Shegow are now benefiting from large clinical trials that were conducted through the Children’s Oncology Group.

G R O U P S

ENCOURAGING INNOVATION One of the largest NCI cooperative groups is the Southwest Oncology Group, which includes more than 5,000 physician-scientists. SWOG members work in university teaching hospitals, community hospitals, community-based physician cooperatives and individual offices.

Although SWOG’s member institutions were concentrated in the Southwestern United States when the group was established in the late 1950s, today the group’s research trials are conducted by investigators at more than 550 institutions across the country, including 17 of NCI’s 61 designated cancer centers. Approximately 120 SWOG clinical trials are under way at any given time.

SWOG estimates that over the last 25 years, more than 170,000 patients have directly benefited from the group’s trials, while millions more have received improved care as new standards of treatment and prevention have been developed by the group.

SWOG enables its members to participate in clinical trials that probably couldn’t be conducted at just one institution, according to Ashraful Hoque, M.D., Ph.D., assistant professor in the Department of Clinical Cancer Prevention. Hoque is co-principal investigator on M. D. Anderson’s SWOG grant and Scott Lippman, M.D., chair of the Department of Thoracic/Head and Neck Medical Oncology, serves as principal investigator.

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“Distinguishing research from clinical care can be a very fine line.

But the best patient care is frequently done in the context of clinical research.”

— Maurie Markman, M.D., vice president for clinical research Knowing that it’s not always feasible to conduct late-phase clinical trials in only one institution, Ashraful Hoque, M.D., Ph.D., and others turn to the Southwest Oncology Group for help with patient accrual.

“Although M. D. Anderson is a big institution, it’s still difficult to do Phase III studies here because it can take years to accrue enough patients to conduct the trials,” Hoque says.

Hundreds or even thousands of patients may be needed to conduct a Phase III trial in which researchers track whether a new treatment is better than, the same as or less effective than the standard treatment.

“The cooperative group mechanism represents a key strategic method for rapidly accruing patients,” adds Robert Coleman, M.D., professor in the Department of Gynecologic Oncology, who serves as M. D. Anderson’s institutional principal investigator to NCI’s Gynecologic Oncology Group.

“If I have a clinical study concept that merits investigation, I can develop it locally. But accrual may take several years to reach its primary objectives. Alternatively, if I can develop it through the GOG, the accrual window can be significantly shortened,” Coleman says.

Like other NCI cooperative groups, GOG offers opportunities for junior faculty to progress in their clinical research careers.

“Within the GOG, there’s no hierarchical structure in terms of who may submit a concept, and there’s a concerted effort within GOG to engage junior investigators,” Coleman says.

“Currently, the process governing concept submission to open a clinical study involves oversight by several procedural committees.

Opportunities for participation in this process come annually with phased roster rotation.”

MAKING A DIFFERENCE The cooperative group setting is of particular value when conducting research on uncommon cancers, such as cancers in children, according to Joann Ater, M.D., professor in the Department of Pediatrics and the chair of NCI’s Children’s Oncology Group at M. D. Anderson. COG grew out of several cooperative groups established by NCI in the 1950s and is now the world’s largest childhood cancer research organization.

“To conduct a Phase III study where you need to randomize patients between two different therapies to find out which one is best, you need several hundred patients. Childhood cancer is rare, so you really can’t do that at a single institution,” Ater explains.

In addition to its research projects, COG offers educational resources for patients and families. It also advocates for childhood cancer research funding.

“A lot of our progress in childhood cancer has been made thanks to COG and its predecessors,” Ater says. “For instance, childhood cancer mortality has decreased by 25 percent just in the last 10 years.”

Since the 1950s, Ater adds, cooperative research has helped improve the overall survival rates for childhood cancer from less than 10 percent to more than 77 percent.

“Cooperative group research also has established the standard of care for childhood leukemia,” she says. “In fact, it has established the proven best therapy for many childhood cancers.”

People all around the country are benefiting from National Cancer Institute cooperative group studies, which aim to bring new therapies to patients sooner.

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NO GUARANTEES Scientists who approach cooperative groups with an idea for a protocol have no guarantees that their project will be accepted.

This is especially true in today’s climate of tight federal funding for medical research. A proposed research protocol must be backed by solid preliminary data from smaller studies and go through a rigorous evaluation process before it’s allowed into an NCI cooperative group.

Once a study is approved and opened, group members must follow strict criteria as they conduct their research.

“M. D. Anderson has to accrue a minimum of 50 patients in SWOG trials each year. And we follow every patient for life,” Hoque says. “We have to submit regular progress reports on each project, and SWOG also conducts regular audits of patient charts. If they find violations, they can shut down the program.”

James Abbruzzese, M.D., chair of the Department of Gastrointestinal Medical Oncology, has seen firsthand the value of expanding small studies into the cooperative research group setting.

Abbruzzese is a member of the institutional executive committee for M. D. Anderson’s SWOG grant and a former chair of SWOG’s Gastrointestinal Committee.

Abbruzzese cites a small Phase II clinical trial of 40 pancreatic cancer patients that was conducted at M. D. Anderson a few years ago with promising results.

“Based on our findings, we took the trial to SWOG and got them interested in developing a large, randomized Phase III clinical trial of approximately 700 patients. In the study, we compared gemcitabine alone, which is the standard of care for patients with advanced pancreatic cancer, to a combination of gemcitabine plus an epidermal growth factor receptor inhibitor called cetuximab.”

The epidermal growth factor, which instructs cells to grow and multiply, is known to be overexpressesd in pancreatic cancer.

“While the SWOG study didn’t meet its primary goal of significantly extending the survival of patients with advanced pancreatic cancer, it did tell us something important. It suggested that EGFR may not be an optimal target for treatment of pancreas cancer.

G R O U P S

It may be that we need to target more than one specific molecule to see a major effect,” Abbruzzese says.

He and his colleagues now are continuing this research at M. D. Anderson through the NCI-awarded Specialized Programs of Research Excellence grant in pancreatic cancer.

This study, Abbruzzese notes, demonstrates how conducting research through cooperative groups such as SWOG should be an ongoing process.

“The basic idea is to pilot new studies and ideas here at M. D. Anderson and develop a proof of concept that shows a treatment appears to be useful. Then, to really see if we can alter the standard of care for patients, we can go to SWOG where our results can be tested in a larger patient population,” Abbruzzese explains. “While all this is happening, we can go back and begin to pilot the next concept through our SPORE grant and other institutional avenues.”

REACHING THE GATEKEEPERS The American College of Surgical Oncology Group is different from other NCI cooperative groups because it’s organized and directed by surgeons, many of whom are in private or group practice. This structure and ACOSOG’s individual practitioner membership model enable ACOSOG to reach patients who might not otherwise have the opportunity to participate in multi-institutional clinical trials.

“Many patients with localized forms of cancer enter the cancer care system through their surgeons,” explains Peter Pisters, M.D., professor in the Department of Surgical Oncology and co-chair of ACOSOG’s Gastrointestinal Committee.

Surgeons frequently are the first physicians to see and treat patients with solid tumors that later are found to be cancer. Once patients are diagnosed with cancer and undergo surgery, it’s often their surgeons who counsel them about further treatment options and refer them to medical or radiation oncologists, as needed.

“We formed ACOSOG about 10 years ago, recognizing that a good way to recruit these new patients to clinical trials was to organize the surgeons who are their gatekeepers,” Pisters says.

After an investigational drug shows promise in early phase studies, James Abbruzzese, M.D., takes it to the Southwest Oncology Group where the results can be tested in a larger patient population.

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G R O U P S

Ritsuko Komaki, M.D., says the quality of radiation treatment has greatly improved nationwide because of the strict review process of Radiation Treatment Oncology Group clinical protocols.

ACOSOG’s research projects deal primarily with breast, thoracic and gastrointestinal cancers. Because of the group’s surgical focus, ACOSOG members have two particular interests: preoperative therapy and correlative science studies that involve harvesting tumor tissue.

“Since we’re the people who take the tumors out, we’re in a unique position to acquire these resources,” Pisters explains. “For each of our research protocols, we have important correlative science projects that dovetail with the clinical questions.”

To facilitate this research, ACOSOG maintains a centralized, independently funded tumor bank at Washington University in St. Louis that ACOSOG investigators can access when they conduct clinical research trials.

“We rank high because our institution is very organized and protocol-oriented. We have shown nationwide that our quality is exceptional and that we can work collaboratively with people from other modalities,” she says.

Like SWOG, ACOSOG and other cooperative group studies, potential and ongoing RTOG trials undergo a stringent NCI review process.

“We have biannual meetings where we go through all the active protocols. Once a trial opens nationwide, the chair of the protocol gets monthly accrual reports. We have to make sure we’re enrolling the

FOLLOWING THE RULES One of M. D. Anderson’s longest cooperative group relationships is with the Radiation Treatment Oncology Group. This group, made up of 250 major research institutions across the United States and Canada, currently is conducting more than 40 active studies that involve radiation therapy, given either alone or in conjunction with surgery, chemotherapy or molecular therapeutics.

M. D. Anderson is a full member of RTOG, which means the institution must enter at least 25 patients on RTOG protocols each year. As with SWOG, RTOG members are followed for life.

“The criteria to be a full RTOG member is very strict,” says Ritsuko Komaki, M.D., professor in the Department of Radiation Oncology. Komaki serves as M. D. Anderson’s principal investigator on RTOG, which is supported by NCI and the American College of Radiology. Smaller institutions that can’t meet the 25 patient annual enrollment requirement join RTOG as affiliate members.

When it comes to patient accrual for RTOG trials, M. D. Anderson usually ranks in the top five nationally and often is either number one or number two, according to Komaki.

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Kian Ang, M.D., and his colleagues have been involved in several large Radiation Treatment Oncology Group trials comparing different types of treatment for head and neck cancer against the standard.

Peter Pisters, M.D., is part of a cooperative group that enables surgeons, many of whom are in private or group practice, to reach patients who might not otherwise have the opportunity to participate in multiinstitutional clinical trials.

expected number of patients and that none of the patients in the trial are violating any of the eligibility requirements,” Komaki explains.

RTOG has strict rules related to all facets of research and conducts biennial audits at participating institutions.

“They check all the details, such as institutional review board approval for newly activated RTOG protocols and amendments, adverse treatment events, radiation treatment fields, dosimetry, dosage documentation for chemotherapy and radiation, treatment facilities and equipment,” Komaki says.

Institutions are given a specific amount of time to fix any problems and then are re-audited. Failure to take the recommended actions will lead to closure of a research trial.

“Nationwide, it’s amazing to see how much radiation treatment quality has improved thanks to RTOG requirements and the quality assurance of RTOG treatment protocols,” says Komaki, noting the leadership role radiation physics professors Michael Gillin, Ph.D., and Geoffery Ibbott, Ph.D., have played in chairing RTOG’s Medical Physics Committee and Radiation Physics Radiological Physics Center, respectively.

“Our treatment quality has improved enormously because of image-guided radiation treatment. We owe the quality assurance of radiation treatment planning and portal imaging to deliver treatment by intensity modulated radiation therapy or three-dimensional conformal radiation therapy to RTOG,” Komaki adds.

Her colleague Kian Ang, M.D., professor in the Department of Radiation Oncology, has been involved in several large RTOG trials comparing different types of treatment for head and neck cancer against the standard.

For example, Ang was co-principal investigator on a Phase III study that looked at more rational distribution of radiation dose over time,

known as altered fractionation. Dosage distribution is one of the most important factors in determining the outcome of radiation therapy.

Investigators compared the standard fractionation schedule, in which radiation is given once a day, to a hyperfractionation regimen, with radiation therapy given more frequently in smaller-than-usual doses, or given at an accelerated fractionation schedule, with radiation administered over a shorter total time period but in more intense doses.

“This was the largest randomized trial ever conducted of altered fractionation in the radiation therapy of locally advanced head and neck cancer,” Ang says.

Investigators found that both hyperfractionation and accelerated fractionation improved local and regional tumor control with no significant increase in long-term complications. This is an important finding since rational modification of a radiation regimen doesn’t cause an appreciable increase in health care expenses, Ang notes.

Ang and his colleagues now are studying the effects of altered fractionation regimens when administered concurrently with chemotherapy and emerging novel agents.

SETTING THE STANDARD M. D. Anderson’s internationally recognized experts in areas such as medical oncology, surgery, radiation oncology, biostatistics and prevention are sharing their knowledge on many levels because of the institution’s involvement in cooperative groups.

“These groups aren’t just made up of the major institutions. They also include smaller hospitals and community doctors,” Markman says.

“So to the extent that we’re interacting with these people, we’re in fact helping to improve the quality of cancer care that’s being delivered around the country.”

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$50 Million Gift Sets Record for M.D. Anderson

by DeDe DeStefano

INGENUITY. INNOVATION. FOCUS. DRIVE. It’s not surprising to hear these words used in conversations regarding T. Boone Pickens – certainly they’ve been spoken around boardroom conference tables for years. Now, they’re being used in philanthropic circles just as frequently.

In a move that made M. D. Anderson history on May 16, Pickens gave the institution its largest gift to date – $50 million. The gift also was the largest for the T. Boone Pickens Foundation, which he created just five months prior.

The size of the gift alone holds great promise for the future of cancer research and patient care programs, but what speaks to its ingenuity and innovation is the manner in which it’s constructed.

M. D. Anderson must grow the original $50 million into $500 million within 25 years before the funds are used. That same day, Pickens made a similar gift to The University of Texas Southwestern Medical Center, with an identical charge.

Through both gifts, Pickens is focusing his efforts on building a $1 billion legacy for health care. His initial gifts provide “seed” money to create special funds at both M. D. Anderson and UT Southwestern.

Each institution may choose to grow these funds from earnings on the original principal or from new outside donations, or from a combination of both. When the $500 million mark is reached, each institution will be able to apply the funds to high-priority projects.

If the goal is not reached, each institution still keeps the original $50 million, but the interest earned will go to Oklahoma State T. Boone Pickens’ gifts aim to leave a $1 billion legacy.

University, Pickens’ alma mater.

“These gifts carry tremendous potential to change the face of the future of health care. On behalf of the more than 70,000 patients M. D. Anderson sees each year, along with their friends and family members, I extend our gratitude to Boone Pickens,” M. D. Anderson President John Mendelsohn, M.D., says. “Pickens’ innovation in business has resulted in extraordinary success and returns, and his goal is to have the same hold true for his philosophy of giving. His forward thinking regarding health care issues has long helped patients at M. D. Anderson and truly around the world.”

In recognition of Pickens’ gift, M. D. Anderson will name its new 21-story, 730,000-square-foot signature academic building the T. Boone Pickens Academic Tower. The tower, scheduled to open in spring 2008, will be the tallest structure at M. D. Anderson and includes executive and faculty offices, classrooms and conference facilities. The top floor will feature a state-of-the-art cancer research library, which is being designed to facilitate both independent study and group interactions.

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M. D. Anderson President John Mendelsohn, M.D., takes Pickens on a tour of the institution’s new 21-story academic tower that will bear Pickens’ name.

INVESTING IN GREATNESS Pickens’ pioneering approach to supporting cancer research at M. D. Anderson began more than 20 years ago. Before the notion that cancer could be prevented was grounded in science or was popular, Pickens established the Boone Pickens Distinguished Professorship for the Early Prevention of Cancer at M. D. Anderson. His gift to create that professorship encouraged M. D. Anderson to expand its horizons and push forth ideas to prevent cancer in the first place, rather than just treating cancer after it developed.

More recently, Pickens formed the T. Boone Pickens Foundation to “increase my focus on investments outside the traditional business world and into the philanthropic marketplace. My objective is to invest in programs, initiatives and people who could have a great impact in America. Of course, that’s why I picked these two institutions. I have witnessed firsthand the great work being done at UT Southwestern and M. D. Anderson.”

Pickens also has supported M. D. Anderson for many years with his time. He served on M. D. Anderson’s Board of Visitors from 1977 to 1986, including a term as chair from 1983 to 1984.

AN ENTREPRENEUR FROM THE START Born in the small town of Holdenville, Okla., Pickens became an entrepreneur at an early age. While he was still a teen, he expanded his newspaper route sales by acquiring surrounding routes one by one. Then, after graduating from Oklahoma State University, Pickens worked for Phillips Petroleum for three years before starting his own company, Mesa Petroleum, in 1956, with no reserves and a $2,500 stake.

Through a series of mergers and acquisitions, Pickens grew Mesa Petroleum to one of the world’s largest independent oil companies. Since selling the company in 1996, Pickens has given away a substantial portion of his earnings.

In 2006, his charitable activities were an estimated $175 million and ensured his continued ranking as one of the Chronicle of Philanthropy’s top U.S. philanthropists for the second straight year. His $220 million of giving in 2005 placed Pickens fifth on the magazine’s list.

The passion and drive that earned Pickens the business reputation he has today is alive and well and fueling the fire for the future of health care for generations to come.

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Raymond N. DuBois, M.D., Ph.D.

by Mary Jane Schier

D

iscovering a textbook on the molecular basis for medicine in the Texas A&M University library was a defining moment for young Ray DuBois in 1975.

“I had no experience in medicine or science,” DuBois remembers, “and it intrigued me to read that certain biomolecules were known to exist and could play a role in disease.”

Today, Raymond N. DuBois, M.D., Ph.D., is an internationally respected physician-scientist whose translational research has advanced understanding of the molecular and genetic aspects of colon cancer. His research during the 1990s demonstrated how the prostaglandin biosynthetic pathway produces inflammatory mediators that promote colorectal cancer and led to an important clinical trial showing the drug Celebrex® can reduce pre-cancerous colon polyps. Findings from his laboratory are helping other investigators develop promising cancer prevention and treatment strategies.

DuBois’ latest milestone occurred in June when he came to M. D. Anderson as the new provost and executive vice president for academic affairs. His responsibilities include directing the institution’s extensive research and educational programs along with managing all faculty recruitment, resourcing and mentoring activities.

Raymond N. DuBois, M.D., Ph.D., is collaborating with Wei Zhang, Ph.D. (left), whose team is using sophisticated microarray technology to scan genes for abnormalities.

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“M. D. Anderson is a phenomenal cancer center with a global operation and an unparalleled record of translational research. We’re in an exciting new age of cancer research, and I’m honored to be joining this fantastic faculty and staff who are totally dedicated to changing the face of cancer,” DuBois says.

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Before moving to M. D. Anderson, DuBois directed the Vanderbilt-Ingram Cancer Center in Nashville. He also was the B.F. Byrd Jr. Professor of Medical Oncology and a professor of medicine, celldevelopmental biology and cancer biology at Vanderbilt University Medical Center.

DuBois began his academic research career in 1991 as an assistant professor at Vanderbilt and was promoted to full professor in six years. During that time, his laboratory identified and characterized the cyclooxygenase-2 (COX-2) gene as important in intestinal epithelial cell growth and transformation. His team was the first to define a series of critical molecular steps involved in COX-2 expression. They later discovered the interaction between the prostaglandin and epidermal growth factor receptor signaling pathways, thereby providing a rationale for combining a variety of different inhibitors that may prevent and/or treat colorectal and other cancers.

In 1997, the DuBois team found COX-2 selective inhibitors blocked human colon cancer cells from growing in the laboratory. That finding facilitated the notable clinical trial – conducted at M. D. Anderson and St. Mark’s Hospital in London – which showed the COX-2 inhibitor Celebrex could reduce polyp burden in familial adenomatous polyposis (FAP) patients. FAP is a genetic disorder that leads to numerous pre-cancerous polyps in the colon. Based on that study, the drug was approved by the U.S. Food and Drug Administration for treating patients with FAP. “I’ve enjoyed working with many investigators at M. D. Anderson over the years,” says DuBois, one of 17 authors who reported findings from the historic clinical trial published in the June 2000 issue of the New England Journal of Medicine.

DuBois is an internationally respected physicianscientist whose translational research has advanced understanding of the molecular and genetic aspects of colon cancer.

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Raymond N. DuBois, M.D., Ph.D.

From 1998 to 2004, DuBois directed the Division of Gastroenterology, Hepatology and Nutrition at Vanderbilt.

While broadening his own research, he earned a reputation for leadership marked by substantial growth in faculty, with more than a doubling of the division’s research funding and clinical revenue during his tenure. Major grants included a National Cancer Institute Program Project award for the discovery of novel cancer prevention targets and a National Institutes of Health Digestive Disease Research Center grant, one of only 16 in the country. In early 2005, he was selected to serve as the second director of the VanderbiltIngram Cancer Center, which was established in 1993.

Leaving Vanderbilt was not an easy decision.

“We were in a period of substantial growth, had great faculty conducting outstanding research, and I had many plans. But in the final analysis, I felt that joining M. D. Anderson would allow me to have a bigger impact on the worldwide problem of cancer,” DuBois explains.

In addition, he confides, “a part of my heart had never left Texas.”

As a young boy, DuBois (right) raised prize-winning steers.

His success earned him a four-year scholarship to the Texas college of his choice.

so well at the Houston Livestock Show and Rodeo that DuBois received a four-year scholarship to the Texas college of his choice.

“Winning that scholarship was the most momentous event in my life because there was no way my parents could afford to pay for college,” says DuBois, whose original major at Texas A&M was agriculture education. He also was supported by a National Honor Society scholarship.

After switching to biochemistry and reading about the molecular basis for medicine, DuBois worked in the laboratory of Edward D. Harris, Ph.D., a professor of biochemistry and biophysics known for his research on the molecular action of copper. It was an unforgettable period for both the Aggie student and his professor.

“It didn’t take me long to get hooked on doing the lab projects,” DuBois reminisces. “For Dr. Harris, I investigated the role of copper in the development of chick blood vessels.”

More than three decades later, Harris reflects, “Many students taking the introductory course to research don’t like the nitty-gritty of the lab, but Raymond was the exception. Right away, I could see he had a strong aptitude and keen interest in everything. He was so excited that we could actually control and regulate cell growth, and he helped me determine that a lack of copper in the chicks’ diet caused their blood vessels to rupture.”

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After getting his bachelor’s degree in biochemistry in 1977, DuBois went to The University of Texas Southwestern Medical Center at Dallas for his Ph.D. in biochemistry, which he received in 1981. He earned his medical degree in 1985 from the UT Health Science Center at San Antonio. Between 1985

DuBois was raised in Runge, Texas, a small and 1991, he completed a residency in internal medicine farming and ranching community about 75 miles and fellowship in gastroenterology at The Johns Hopkins southeast of San Antonio. The third of six children, Hospital and was a Howard Hughes research associate at he was named for his father, who worked in the South Texas oil fields while his mother operated a roadside icehouse. His first two jobs were selling watermelons and chopping cotton.

During high school, he raised steers for a Future Farmers of America project. One steer was chosen grand champion at the Runge Livestock Show, and others did

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Johns Hopkins Medical School.

“A really significant moment for me was the chance to work in the lab of Nobel Laureate Daniel Nathans at Johns Hopkins,” DuBois says.

Known as one of the fathers of molecular biology, Nathans was a demanding mentor who expected trainees to work long hours on difficult gene-cloning projects.

DuBois thrived in that environment because “I finally could put all my training together and see how basic science can apply to clinical disease.”

Within a few years of going to Vanderbilt, DuBois discovered the link between COX-2 and cancer progression. Having lost his father to lung cancer added a personal incentive to understand the differences in genes that regulate normal and abnormal cells. It turns out that COX-2 inhibitors may have a role in lung cancer treatment as well as colorectal cancer prevention.

Among his numerous honors was induction into the Royal College of Physicians of the United Kingdom in 2000. In May 2007, he was inducted into the Johns Hopkins Society of Scholars. He is president-elect of both the American Association for Cancer Research and the International Society for Gastrointestinal Cancer.

Currently, DuBois is principal investigator on three NIH grants, including a 10-year renewable MERIT (Method to Extend Research in Time) Award from the National Institute of Diabetes and Digestive and Kidney Diseases. He has transferred these and other projects to his new laboratory in M. D. Anderson’s Smith Research Building, where several junior faculty and postdoctoral fellows have joined him.

“Keeping my laboratory functioning at a very high level is important and will allow me to stay attuned to the issues facing all investigators at M. D. Anderson,” says DuBois.

In addition to his executive roles, he is a professor in the Department of Gastrointestinal Medical Oncology.

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DuBois cites marrying Lisa Abrams in 1980 and having two children as “the best of all my milestones.” His wife has been a freelance writer for many years, and her first book tracing the founding of Vanderbilt Children’s Hospital will be published soon.

Their daughter Shelley recently received a degree in bioanthropology from the University of California, San Diego, and son Ethan is a high school senior.

At M. D. Anderson, DuBois succeeds Margaret L. Kripke, Ph.D., former executive vice president and chief academic officer. She remains on the faculty in a part-time capacity and continues her national leadership on the three-member President’s Cancer Panel.

DuBois is the first executive to have the title of provost.

“We’ve chosen this title to reflect the importance of our expanding research endeavors, our degree-granting status, and the climate of scholarship and discovery that we strive to achieve in all mission areas,” explains John Mendelsohn, M.D., president of M. D. Anderson.

DuBois believes he’s joined M. D. Anderson “in an exhilarating period when progress is being made faster through translational research and the face of cancer is changing. I expect survival rates for cancer to keep improving and for many cancers to be detected earlier while most treatments will get much better. And I am particularly optimistic about the increasing number of targeted therapies emerging from our laboratories that must be brought forward for clinical testing.”

At the same time, DuBois worries about decreasing federal support for research and its impact on recruiting young people into cancer-related fields.

“It’s crucial to intensify our efforts to expand funding for cancer research so we don’t lose any of our momentum,” he stresses. “Nothing would be more tragic in our battle to treat and cure cancer than to lose a generation of brilliant young scientists because they couldn’t get funding for their valuable and worthy projects.”

DuBois says his wife, Lisa, and their two children, Shelley and Ethan, are the “best of all my milestones.”

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Moving Forward: Tommy Garcia

by Mary Jane Schier

Tommy Garcia

Tommy Garcia didn’t notice the festive decorations when he and his wife Mary walked into M. D. Anderson two days after Christmas in 1999. He was still dazed from hearing the family doctor say, “You have cancer.”

After definitive tests, Garcia learned the lump he had felt a few weeks earlier was inoperable esophageal cancer. He was losing

Once chemotherapy was completed, Garcia returned fre-

weight and having trouble swallowing, so he would need a feeding

quently to see Jaffer A. Ajani, M.D., professor in M. D. Anderson’s

tube for nourishment to build him up before undergoing aggressive

Department of Gastrointestinal Medical Oncology.

chemotherapy.

“Not long after the feeding tube was inserted, I developed an infection and had to be hospitalized at M. D. Anderson for more than

During a recent checkup, Ajani walked in and smilingly told his patient, “You’re still cancer-free after five years, so I believe you’ll be fine.”

three weeks, during which the tumor started bleeding. The doctors

The Garcias, who have eight grandchildren, shared a hug and

and nurses worked 24 hours a day to stop the bleeding and to pull me

happy tears with Ajani before calling their four grown children to

through,” recalls Garcia, who received 17 units of blood.

report the good news.

Garcia also remembers “lots of chaplains” coming to pray for

“We feel truly blessed,” comments Garcia, who retired in 1996

and with them, then adds, “Mary never left my side, so I call her my

after 28 years as a boilermaker welder for Dow Chemical Company.

chief guardian angel.”

That same year, his wife was successfully treated for early-stage breast

Slowly, Garcia recovered from the complications and was strong enough for chemotherapy, which continued for almost two years.

The drugs steadily shrank the golf ball-sized tumor located midway between his throat and the top of his breastbone. After 14 months, the feeding tube was removed.

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“That was a big day for Mary and me to celebrate,” he says.

cancer at Brazosport Medical Center in Lake Jackson, Texas.

As cancer survivors, both Tommy and Mary Garcia often talk with others about eating healthy and getting regular checkups.

“And I tell everyone diagnosed with cancer that M. D. Anderson is the best place to go,” Garcia stresses.

THE UNIVERSITY OF TEXAS SYSTEM BOARD OF REGENTS

James Richard Huffines, Austin Chair

Rita C. Clements, Dallas Vice Chair

Cyndi Taylor Krier, San Antonio Vice Chair

John W. Barnhill, Jr., Brenham H. Scott Caven, Jr., Houston Judith L. Craven, M.D., Houston Robert A. Estrada, Ft. Worth Colleen McHugh, Corpus Christi Robert B. Rowling, Dallas Randal Matthew Camarillo, Houston Student Regent

Francie A. Frederick Counsel and Secretary THE UNIVERSITY OF TEXAS SYSTEM ADMINISTRATION

Mark G. Yudof Chancellor

Kenneth I. Shine, M.D. Executive Vice Chancellor for Health Affairs THE UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER EXECUTIVE COMMITTEE

John Mendelsohn, M.D. President

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Articles and photos may be reprinted with permission.

Stephen C. Stuyck, Vice President for Public Affairs Sarah Palmer, Associate Vice President for Communications David Berkowitz, Director of Publications and Creative Services Sandi Stromberg, Program Manager of External Publications Editor: Eileen A. Ellig Writers: Mary Jane Schier, Carol Bryce, DeDe DeStefano, Scott Merville, Sandi Stromberg Design: Michael Clarke Photography: John Everett, Wyatt McSpadden, John Smallwood, F. Carter Smith

Thomas W. Burke, M.D. Executive Vice President and Physician-in-Chief

Raymond N. DuBois, M.D., Ph.D. Provost and Executive Vice President for Academic Affairs

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For information on supporting programs at M. D. Anderson Cancer Center, please contact Patrick B. Mulvey, Vice President for Development, 713-792-3450, or log on to the Development Office Web site at www.mdanderson.org/gifts.

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