CONQUESTV O L U M E 2 2 I S S U E 1S U M M E R 2 0 0 7

G E N E T I C R E P R O G R A M M I N G

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 V A L U E S

CaringBy our words and actions,

we create a caring environment for everyone.

IntegrityWe work together to merit

the trust of our colleagues and those we serve.

DiscoveryWe 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.

C h e c k o u t t h e C o n q u e s t We b s i t e a t w w w. m d a n d e r s o n . o r g / c o n q u e s t

F E A T U R E S

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GENETIC REPROGRAMMING —

AN ACT OF DIPLOMACY

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.

IT TAKES MORE THAN A VILLAGE

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

NCI-sponsored cooperative groups, helping to

set new standards in cancer care.

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CONTENTSS U M M E R 2 0 0 7

C O N Q U E S T

2 FRONTLINE

Who’s On First?

2 4 MOVING FORWARD

Tommy Garcia

2 0 PROFILE

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

3 SYMPTOM RESEARCH

It’s All About the Patient

$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.

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C O N Q U E S T

S U M M E R 2 0 0 7

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

FRONTLINE

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 meet-ing 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 dasa-tinib once daily or 50 mg twice daily.

WHO’S ON FIRST?CML DRUG MAY TAKE STARTING POSITION

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

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

The lack of proper measurement tools and the presence of patient fears are concerningto 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 thepain questionnaire that helps patients describe more effectively the amount of pain theyare experiencing. He also has brought international attention to the reality of pain, lead-ing several important initiatives, including a nationwide one with Veterans Administrationhospitals and another at M. D. Anderson in 2001. He also helped organize a cancer painrelief 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 mea-surement tool to help clinicians identify and assess the most common and predictablesymptoms of cancer and its treatments. At the same time, this has provided language thatallows patients to describe what they are feeling.

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

NARROWING GENERAL SYMPTOMSCleeland’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 differentgroups of patients for the study: an initial outpatient sample, an inpatient sample and anoutpatient sample for cross-validation of the measure. Finally, they used several methodsto reduce the number of core symptoms.

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

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.

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 self-

reporting.

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 medica-

tion; or who worry that symptoms

might indicate a recurrence.

by Sandi Stromberg

3

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

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

For both the core symptoms and the interferences, MDASI posesquestions 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 badas 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 ofdisease and treatments,” Cleeland says. “We have a formal networkworking on these modules, an exciting set of people from severaldepartments across the institution.”

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

“It’s common for people to go from normal, working lifestyles anddoing fine to having a sudden event like a seizure and being thrustinto this world of brain cancer, often with residual deficits,” Armstrongsays. “Problems with strength or sensation or ongoing seizures can bedevastating.”

Interested in the impact of brain cancer on quality of life, Armstrongbegan a literature review. She was amazed to discover that what little was known about the symptomburden of this patient population was from studies with data from as early as 1924.

At the same time, she decided to work toward a doctorate degree in nursing at The University ofTexas 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.

“At first, I wanted to go in and do things to help people, but then I realized we don’t really understandtheir problems,” she says. “It was hard to step back, but that’s where Dr. Cleeland’s group is so helpful.Through them, I learned we have to understand the issues first so we can target interventions.”

GATHERING SYMPTOMS OF PRIMARY BRAIN TUMORSWhile she knew that the core MDASI developed by Cleeland’s group was an important tool for mea-

suring the severity and impact of cancer-related symptoms in general, she also knew it didn’t addressmany 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 wereimportant to this group,” she says.

Somewhat the same as in the development of the core MDASI, Armstrong put together panels withmembers 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 patientsand their caregivers.

When it comes to evaluatingthe symptom burden of patientswith brain tumors, TerriArmstrong, D.S.N., is thego-to person. Using the generalM. D. Anderson SymptomInventory model as her guide,she’s capturing the symptomsthat are more specific andimportant to these individuals.

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“We learned a lot,” she says. “One striking aspect was the issue of pain. Many of the physicianssaid 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 primarybrain 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 wayuntil now to verify,” she says. “People’s symptoms can predict when their tumor is growing.”

FINAL INVENTORYThe 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, walkingFive generalized symptoms – headache or pressure in the head, seizures, change in seizure activity,

difficulty concentrating, sleepinessFive treatment and medication-related symptoms – changes in appearance, appetite and bowel

pattern, irritability, fearCurrently, 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 impacta patient’s daily life,” Armstrong says. “It facilitates communication.”

MELANOMA PATIENTS:AVERAGE SYMPTOMSEVERITY OVER TIME

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.

Melanoma patients wereamong the first to completethe M. D. AndersonSymptom Inventoryquestionnaire, listing thefrequency of their symptomsand the ones they felt weremost distressing.

5

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.

6

by Scott Merville

An Act ofDiplomacy

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

Issa and Leukemia Department Chair Hagop Kantarjian,M.D., are pioneers in the emerging field of epigenetics, the studyof changes in gene expression and cellular behavior that are notcaused by physical damage or mutation of the genes themselves.DNA methylation, for example, is epigenetic.

Issa and Kantarjian revived a failed chemotherapy, forinstance, by turning it from attack to diplomatic mode. Usinga low-dose, low-toxicity, longer-term approach, they showedthat decitabine extends the life of some leukemia patients bydemethylating, or turning on, genes.

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

ONLY THE BEGINNINGBefore the development of decitabine and another epige-

netic agent called azacytidine (Vidaza™), MDS was a disease“with no treatment,” Issa says. There was no chance of puttingit in remission with a drug. Only supportive care, such as a bloodtransfusion, was available. Bone marrow transplants worked fora small number of patients.

“I see this as the beginning of the development of epigenetictherapy,” Kantarjian says. “FDA approval of decitabine was justthe beginning. This is when the real research starts, when thedrug becomes accessible to investigators in an easy manner sothey can develop new concepts and new strategies to optimizethe use of the drug as a single agent, in combinations and acrossmany tumors.”

The leukemia group has a leading program, investigatingepigenetic agents in 18 clinical trials. Four of those trials involveazacytidine, a drug that acts in a similar manner as decitabine.The two medications are the first epigenetic therapies approvedfor cancer.

Kantarjian, Issa, MDS Section Chief Guillermo Garcia-Manero, M.D., and colleagues have pressed ahead refining theoptimal decitabine dosage for MDS, exploring its use in otherleukemias, in combination with other drugs, and addressing

“In this instance, we’re not trying to kill cancer cells, rather we talk to cells and remind them of theirregular 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.

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

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how cancer becomes resistant to the drug. Azacytidine trialsexplore similar issues. Issa also collaborates with a team fromDuke University on the use of decitabine for melanoma andrenal cell carcinoma.

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

DRUG REVIVALKantarjian’s and Issa’s work to revive decitabine is a classic

example of the major role academic medical institutions play indrug discovery and development.

Decitabine was discovered in Czechoslovakia and testedagainst leukemia as traditional high-dose, cell-killing chemo-therapy in Europe. The drug showed activity against the diseasebut 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, PharmachemieBV of Europe, to shelve it in the 1980s.

Decitabine still intrigued Kantarjian, who was followingthe newborn field of epigenetics and suspected the drug hadpotential if used properly.

Pharmachemie was not interested in sponsoring any moreclinical trials, but agreed to provide Kantarjian with decitabine.He filed his own investigational new drug application with theFDA and went to work. Kantarjian recalls that it was the early1990s and he was the only physician in the United States work-ing with the drug.

At the time, Issa was on the faculty at Johns Hopkinsstudying epigenetics. His research in DNA methylation ledhim to believe that decitabine might work epigenetically as ademethylating agent.

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

They developed a Phase I clinical trial using decitabineintravenously for MDS at doses ranging from one-twentieth toone-fiftieth of the doses employed in the European trials. Thetrial showed that the drug was safe and active, with the lowerdose preventing dangerous incidents of myelosuppression. Labresearch indicated it worked by wiping out methyl tags.

Issa came to M. D. Anderson in 1999, where he andKantarjian developed and led a pivotal Phase III multi-centertrial in 2001. Results were reported early last year in the journalCancer, citing that 17 percent of patients had some response,with responders having a median time to disease progression ordeath of 17.8 months, compared with 9.8 months for patientswho 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 purchasedthe drug from SuperGen in September 2004 and shepherdedit through the FDA fast-track process. The frequent change ofcompanies was another challenge in keeping decitabine alive,Kantarjian says.

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

Decitabine, researchers note, is the more potent demethylat-ing agent of the two.

When it comes to genes andcancer cells, it’s all abouthow they express or don’texpress themselves. Beingable to change the way theyinteract and behave is nosmall feat and one of thebiggest challenges forHagop Kantarjian, M.D.

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THINKING OUTSIDE THE BOX“Dr. Issa and Dr. Kantarjian brought a unique assimilation

of scientific and clinical expertise that enabled them to thinkabout developing decitabine in a different way,” says Mary LynneHedley, Ph.D., chief scientific officer of MGI Pharma. “And that’sreally why decitabine ended up being so useful for patients.”

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

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

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

BEYOND MDSKantarjian leads a Phase III clinical trial of decitabine for

acute myelogenous leukemia – the most common form of thedisease in adults. Kantarjian notes that AML also is a leukemiathat has shown the least improvement in treatment outcomesover the last 30 years.

A Phase II trial for decitabine as frontline therapy for AMLin elderly patients, those with the grimmest prospects, also isunder way.

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

chemotherapy used against the disease. Their median survivalis 1.7 months.

A poster presented by the team at the 2007 American Societyof Clinical Oncology meeting showed how decitabine, with itslow-intensity and minimal side effects, might help older AMLpatients. Total response rate was 52 percent, with 24 percent hav-ing complete remissions. Median survival time at the 20-monthmark of the study was 12.6 months.

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

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

David Stewart, M.D., professor in the Department ofThoracic/Head and Neck Medical Oncology, for example, isexploring in a Phase I trial the use of the drug for solid tumorsand 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 thatearlier clinical trials of decitabine against these cancers alsofailed, 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 dosesover longer periods as a demethylating agent against thosecancers,” Issa says.

EPIGENETICS — BY DEFINITION:

Acetylation: a reaction that introduces an acetyl groupinto a molecule of an organic compound. Acetyl tags work byconnecting to specific proteins and act as a genetic on switch.

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

Epigenetics: the study of changes in gene expressionand cellular behavior that are not caused by physical damage ormutation of the genes themselves.

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

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MORE TO LEARNThere is still plenty to understand about how demethylating

agents such as decitabine work. Their effect is global because theydemethylate and switch on many genes. The research team ispinpointing specific cancer-suppressing genes that are silencedby methylation.

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

Initial research in DNA methylation indicated that removingthe tags might promote cancer by turning on oncogenes. However,Issa notes, subsequent research showed that methylation silencedhundreds of genes, inactivating those involved in tumor suppres-sion and programmed cell death of cancerous cells.

Since tumors rely more on gene silencing to survive thannormal adult cells do, the overall effect of demethylation isfavorable for treatment.

TWO FOR ONEOne potential answer to the problem of resistance is to

combine agents, explains Garcia-Manero, M.D., an expert inepigenetics and associate professor of leukemia.

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

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

Combining the two drugs in a group of 54 AML and MDSpatients was shown to be safe and effective, Garcia-Maneronotes. Methyl “off” switches were stripped from DNA, and twotypes of histone acetylation were achieved and an importanttumor-suppressing gene was reactivated.

Of 10 elderly MDS and AML patients, five responded to thecombination, with four of them experiencing remission. Overall,22 percent of patients got some relief from the combination, with19 percent having complete remission. While the study was toosmall to draw conclusions about the drugs’ effectiveness, it pointsto the need for follow-up clinical trials.

“We’re testing a number of epigenetic agents that haveexciting potential,” Garcia-Manero notes. His team has a paperpending in Blood that shows promising results with the combi-nation of valproic acid, azacytidine and all-trans retinoic acidfor AML and MDS patients. Overall, 42 percent of 53 patientsshowed some response to the three-drug combination, with22 percent having complete remissions.

Garcia-Manero also is testing three other epigenetic agents,all of which protect acetyl “on” switches: vorinostat, MGCD0103and LBH589.

Razelle Kurzrock, M.D., professor in the Department ofExperimental Therapeutics and director of M. D. Anderson’sPhase I Clinical Trials Program, leads a clinical trial testingazacytidine and valproic acid in advanced metastatic cancers.

Issa remembers presenting a research poster on epigeneticsto the 1992 annual meeting of the American Association forCancer Research, “There was one other poster on the subjectout of 4,000,” he says.

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

CH3

Guillermo Garcia-Manero,M.D., and his colleagues aretesting several new epigeneticagents that address the problemof drug resistance by reactivatingtumor-suppressor genes.

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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.

“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 envi-

ronmental 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

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

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 environmen-

tal 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

says, but that’s another story.

Genes Misbehaving

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.

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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 toensuring that novel and more effective therapies are made availableto patients sooner.

“To get definitive answers to important research questions, we need large randomized trials thatmay require 1,000 to 2,000 people,” says Maurie Markman, M.D., vice president for clinical research atM. D. Anderson. “Often these studies are comparing novel drugs to existing excellent treatment regimensto try to come up with something even better. The only way to get answers in a reasonable period of timeis 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 conducta scientific research project in only one institution, even one as multidisciplinary as M. D. Anderson. That’swhen 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 trialsof new cancer treatments, explore methods of cancer prevention and early detection, and study quality oflife issues and rehabilitation both during and after cancer treatment.

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

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

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

by Carol Bryce

Cooperativegroups help setthe standard in

cancer care

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ENCOURAGING INNOVATIONOne 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, com-munity hospitals, community-based physician cooperatives and individual offices.

Although SWOG’s member institutions were concentrated in the Southwestern United Stateswhen the group was established in the late 1950s, today the group’s research trials are conducted byinvestigators at more than 550 institutions across the country, including 17 of NCI’s 61 designatedcancer 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 benefitedfrom the group’s trials, while millions more have received improved care as new standards of treatmentand prevention have been developed by the group.

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

Joann Ater, M.D., says youngpatients like Osman Shegow arenow benefiting from large clinicaltrials that were conducted throughthe Children’s Oncology Group.

C O O P E R A T I V E G R O U P S

13

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

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

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

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

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

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

“Currently, the process governing concept submission to open aclinical study involves oversight by several procedural committees.Opportunities for participation in this process come annually withphased roster rotation.”

MAKING A DIFFERENCEThe cooperative group setting is of particular value when con-

ducting research on uncommon cancers, such as cancers in children,according to Joann Ater, M.D., professor in the Department ofPediatrics and the chair of NCI’s Children’s Oncology Group atM. D. Anderson. COG grew out of several cooperative groups estab-lished by NCI in the 1950s and is now the world’s largest childhoodcancer research organization.

“To conduct a Phase III study where you need to randomize patientsbetween two different therapies to find out which one is best, you needseveral hundred patients. Childhood cancer is rare, so you really can’tdo that at a single institution,” Ater explains.

In addition to its research projects, COG offers educationalresources for patients and families. It also advocates for childhoodcancer research funding.

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

Since the 1950s, Ater adds, cooperative research has helpedimprove the overall survival rates for childhood cancer from less than10 percent to more than 77 percent.

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

“Distinguishing researchfrom clinical care can

be a very fine line.But the best patient care

is frequently donein the context ofclinical research.”

— Maurie Markman, M.D.,vice president for clinical research

Knowing that it’s not always feasible to conduct late-phase clinical trialsin only one institution, Ashraful Hoque, M.D., Ph.D., and others turnto the Southwest Oncology Group for help with patient accrual.

People all around thecountry are benefitingfrom National Cancer

Institute cooperativegroup studies, which

aim to bring newtherapies to

patients sooner.

14

NO GUARANTEESScientists 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 formedical research. A proposed research protocol must be backed bysolid preliminary data from smaller studies and go through a rigorousevaluation process before it’s allowed into an NCI cooperative group.Once a study is approved and opened, group members must followstrict criteria as they conduct their research.

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

James Abbruzzese, M.D., chair of the Department ofGastrointestinal Medical Oncology, has seen firsthand the value ofexpanding small studies into the cooperative research group setting.Abbruzzese is a member of the institutional executive committeefor M. D. Anderson’s SWOG grant and a former chair of SWOG’sGastrointestinal Committee.

Abbruzzese cites a small Phase II clinical trial of 40 pancreaticcancer patients that was conducted at M. D. Anderson a few yearsago with promising results.

“Based on our findings, we took the trial to SWOG and got theminterested in developing a large, randomized Phase III clinical trial ofapproximately 700 patients. In the study, we compared gemcitabinealone, which is the standard of care for patients with advanced pan-creatic cancer, to a combination of gemcitabine plus an epidermalgrowth factor receptor inhibitor called cetuximab.”

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

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

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

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

This study, Abbruzzese notes, demonstrates how conductingresearch through cooperative groups such as SWOG should be anongoing process.

“The basic idea is to pilot new studies and ideas here atM. D. Anderson and develop a proof of concept that shows a treatmentappears to be useful. Then, to really see if we can alter the standard ofcare for patients, we can go to SWOG where our results can be testedin a larger patient population,” Abbruzzese explains. “While all this ishappening, we can go back and begin to pilot the next concept throughour SPORE grant and other institutional avenues.”

REACHING THE GATEKEEPERSThe American College of Surgical Oncology Group is different

from other NCI cooperative groups because it’s organized and directedby surgeons, many of whom are in private or group practice. Thisstructure and ACOSOG’s individual practitioner membership modelenable ACOSOG to reach patients who might not otherwise havethe opportunity to participate in multi-institutional clinical trials.

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

Surgeons frequently are the first physicians to see and treatpatients with solid tumors that later are found to be cancer. Oncepatients are diagnosed with cancer and undergo surgery, it’s oftentheir surgeons who counsel them about further treatment optionsand refer them to medical or radiation oncologists, as needed.

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

C O O P E R A T I V E G R O U P S

After an investigational drugshows promise in early phasestudies, James Abbruzzese,M.D., takes it to the SouthwestOncology Group where theresults can be tested in a largerpatient population.

15

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

“Since we’re the people who take the tumors out, we’re in aunique position to acquire these resources,” Pisters explains. “Foreach of our research protocols, we have important correlative scienceprojects that dovetail with the clinical questions.”

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

FOLLOWING THE RULESOne of M. D. Anderson’s longest cooperative group relationships

is with the Radiation Treatment Oncology Group. This group, madeup of 250 major research institutions across the United States andCanada, currently is conducting more than 40 active studies thatinvolve radiation therapy, given either alone or in conjunction withsurgery, chemotherapy or molecular therapeutics.

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

“The criteria to be a full RTOG member is very strict,” saysRitsuko Komaki, M.D., professor in the Department of RadiationOncology. Komaki serves as M. D. Anderson’s principal investigatoron RTOG, which is supported by NCI and the American College ofRadiology. Smaller institutions that can’t meet the 25 patient annualenrollment requirement join RTOG as affiliate members.

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

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

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

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

Ritsuko Komaki, M.D., says thequality of radiation treatmenthas greatly improved nationwidebecause of the strict review processof Radiation Treatment OncologyGroup clinical protocols.

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

C O O P E R A T I V E G R O U P S

16

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 treat-ment 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 adminis-tered 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 che-motherapy and emerging novel agents.

SETTING THE STANDARDM. 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.”

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 multi-institutional clinical trials.

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INGENUITY. INNOVATION. FOCUS. DRIVE.It’s not surprising to hear these words used in conversations

regarding T. Boone Pickens – certainly they’ve been spoken aroundboardroom conference tables for years. Now, they’re being used inphilanthropic circles just as frequently.

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

The size of the gift alone holds great promise for the future ofcancer research and patient care programs, but what speaks to itsingenuity and innovation is the manner in which it’s constructed.M. D. Anderson must grow the original $50 million into $500 millionwithin 25 years before the funds are used. That same day, Pickensmade a similar gift to The University of Texas Southwestern MedicalCenter, 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” moneyto create special funds at both M. D. Anderson and UT Southwestern.Each institution may choose to grow these funds from earnings onthe original principal or from new outside donations, or from acombination of both. When the $500 million mark is reached, eachinstitution 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 StateUniversity, Pickens’ alma mater.

“These gifts carry tremendous potential to change the face of the future of health care. On behalf of the more than70,000 patients M. D. Anderson sees each year, along with their friends and family members, I extend our gratitude toBoone Pickens,” M. D. Anderson President John Mendelsohn, M.D., says. “Pickens’ innovation in business has resultedin extraordinary success and returns, and his goal is to have the same hold true for his philosophy of giving. His forwardthinking 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 academicbuilding the T. Boone Pickens Academic Tower. The tower, scheduled to open in spring 2008, will be the tallest structureat M. D. Anderson and includes executive and faculty offices, classrooms and conference facilities. The top floor willfeature a state-of-the-art cancer research library, which is being designed to facilitate both independent study and groupinteractions.

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

T . B O O N E P I C K E N S G I F T

T. Boone Pickens’ gifts aim to leave a $1 billion legacy.

by DeDe DeStefano

18

INVESTING IN GREATNESSPickens’ 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 PickensDistinguished Professorship for the Early Prevention of Cancer at M. D. Anderson. His gift to create that professorshipencouraged M. D. Anderson to expand its horizons and push forth ideas to prevent cancer in the first place, rather thanjust treating cancer after it developed.

More recently, Pickens formed the T. Boone Pickens Foundation to “increase my focus on investments outside thetraditional business world and into the philanthropic marketplace. My objective is to invest in programs, initiatives andpeople who could have a great impact in America. Of course, that’s why I picked these two institutions. I have witnessedfirsthand 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 ofVisitors from 1977 to 1986, including a term as chair from 1983 to 1984.

AN ENTREPRENEUR FROM THE STARTBorn 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 fromOklahoma State University, Pickens worked for Phillips Petroleum for three years before starting his own company, MesaPetroleum, 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 independentoil 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 theChronicle of Philanthropy’s top U.S. philanthropists for the second straight year. His $220 million of giving in 2005 placedPickens 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 firefor the future of health care for generations to come.

M. D. Anderson PresidentJohn Mendelsohn, M.D.,takes Pickens on a tour ofthe institution’s new 21-storyacademic tower that will bearPickens’ name.

19

Discovering a textbook on the molecu-lar basis for medicine in the Texas A&MUniversity library was a defining momentfor young Ray DuBois in 1975.

“I had no experience in medicine or science,” DuBoisremembers, “and it intrigued me to read that certainbiomolecules were known to exist and could play a rolein disease.”

Today, Raymond N. DuBois, M.D., Ph.D., is aninternationally respected physician-scientist whosetranslational research has advanced understanding of themolecular and genetic aspects of colon cancer. His researchduring the 1990s demonstrated how the prostaglandinbiosynthetic pathway produces inflammatory mediatorsthat promote colorectal cancer and led to an importantclinical trial showing the drug Celebrex® can reducepre-cancerous colon polyps. Findings from his laboratoryare helping other investigators develop promising cancerprevention and treatment strategies.

DuBois’ latest milestone occurred in June when hecame to M. D. Anderson as the new provost and executivevice president for academic affairs. His responsibilitiesinclude directing the institution’s extensive research andeducational programs along with managing all facultyrecruitment, resourcing and mentoring activities.

Raymond N. DuBois, M.D., Ph.D.P R O F I L E :

by Mary Jane Schier

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.

“M. D. Anderson is a phenomenal cancer centerwith a global operation and an unparalleled record oftranslational research. We’re in an exciting new ageof cancer research, and I’m honored to be joining thisfantastic faculty and staff who are totally dedicated tochanging the face of cancer,” DuBois says.

Before moving to M. D. Anderson, DuBoisdirected the Vanderbilt-Ingram Cancer Centerin Nashville. He also was the B.F. Byrd Jr. Professorof Medical Oncology and a professor of medicine, cell-developmental biology and cancer biology at VanderbiltUniversity Medical Center.

DuBois began his academic research career in 1991as an assistant professor at Vanderbilt and was promotedto full professor in six years. During that time, his labora-tory identified and characterized the cyclooxygenase-2(COX-2) gene as important in intestinal epithelial cellgrowth and transformation. His team was the first todefine a series of critical molecular steps involved inCOX-2 expression. They later discovered the interactionbetween the prostaglandin and epidermal growth factorreceptor signaling pathways, thereby providing a ratio-nale for combining a variety of different inhibitors thatmay prevent and/or treat colorectal and other cancers.

In 1997, the DuBois team found COX-2 selectiveinhibitors blocked human colon cancer cells fromgrowing in the laboratory. That finding facilitated thenotable clinical trial– conducted at M. D. Anderson andSt. Mark’s Hospital in London – which showed theCOX-2 inhibitor Celebrex could reduce polyp burdenin familial adenomatous polyposis (FAP) patients. FAPis a genetic disorder that leads to numerous pre-cancerouspolyps in the colon. Based on that study, the drug wasapproved by the U.S. Food and Drug Administration fortreating patients with FAP.

“I’ve enjoyed working with many investigators atM. D. Anderson over the years,” says DuBois, one of 17authors who reported findings from the historic clinicaltrial published in the June 2000 issue of the New EnglandJournal of Medicine.

20

DuBois is aninternationallyrespected physician-scientist whosetranslational researchhas advancedunderstanding of themolecular and geneticaspects of coloncancer.

21

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 Vanderbilt-Ingram 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.”

DuBois was raised in Runge, Texas, a small farming and ranching community about 75 miles southeast of San Antonio. The third of six children, 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

so well at the Houston Livestock Show and Rodeo that DuBois received a four-year scholarship to the Texas col-lege 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 labora-tory 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 inves-tigated 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.”

After getting his bachelor’s degree in biochem-istry 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 and 1991, he completed a residency in internal medicine and fellowship in gastroenterology at The Johns Hopkins Hospital and was a Howard Hughes research associate at 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.

Raymond N. DuBois, M.D., Ph.D.P R O F I L E :

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.

22

DuBois thrived in that environment because “I finallycould put all my training together and see how basic sci-ence can apply to clinical disease.”

Within a few years of going to Vanderbilt, DuBoisdiscovered the link between COX-2 and cancer pro-gression. Having lost his father to lung cancer added apersonal incentive to understand the differences in genesthat regulate normal and abnormal cells. It turns out thatCOX-2 inhibitors may have a role in lung cancer treatmentas well as colorectal cancer prevention.

Among his numerous honors was induction intothe Royal College of Physicians of the United Kingdomin 2000. In May 2007, he was inducted into the JohnsHopkins Society of Scholars. He is president-elect of boththe American Association for Cancer Research and theInternational Society for Gastrointestinal Cancer.

Currently, DuBois is principal investigator on threeNIH grants, including a 10-year renewable MERIT(Method to Extend Research in Time) Award from theNational Institute of Diabetes and Digestive and KidneyDiseases. He has transferred these and other projects tohis new laboratory in M. D. Anderson’s Smith ResearchBuilding, where several junior faculty and postdoctoralfellows have joined him.

“Keeping my laboratory functioning at a very high levelis important and will allow me to stay attuned to the issuesfacing all investigators at M. D. Anderson,” says DuBois.In addition to his executive roles, he is a professor in theDepartment of Gastrointestinal Medical Oncology.

DuBois cites marrying Lisa Abrams in 1980and having two children as “the best of all mymilestones.” His wife has been a freelance writer formany years, and her first book tracing the founding ofVanderbilt Children’s Hospital will be published soon.Their daughter Shelley recently received a degree inbioanthropology from the University of California, SanDiego, and son Ethan is a high school senior.

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

DuBois is the first executive to have the title ofprovost.

“We’ve chosen this title to reflect the importance ofour expanding research endeavors, our degree-grantingstatus, and the climate of scholarship and discovery thatwe strive to achieve in all mission areas,” explains JohnMendelsohn, M.D., president of M. D. Anderson.

DuBois believes he’s joined M. D. Anderson “in anexhilarating period when progress is being made fasterthrough translational research and the face of cancer ischanging. I expect survival rates for cancer to keep improv-ing and for many cancers to be detected earlier while mosttreatments will get much better. And I am particularlyoptimistic about the increasing number of targeted therapiesemerging from our laboratories that must be brought forwardfor clinical testing.”

At the same time, DuBois worries about decreasingfederal support for research and its impact on recruitingyoung people into cancer-related fields.

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

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

23

24

Tommy Garcia

by Mary Jane Schier

Moving Forward: Tommy Garcia

After definitive tests, Garcia learned the lump he had felt a

few weeks earlier was inoperable esophageal cancer. He was losing

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

tube for nourishment to build him up before undergoing aggressive

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

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

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

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

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

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

chief guardian angel.”

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.

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

Once chemotherapy was completed, Garcia returned fre-

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

Department of Gastrointestinal Medical Oncology.

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.”

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

happy tears with Ajani before calling their four grown children to

report the good news.

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

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

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

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.

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.”

AFFILIATIONS

M. D. Anderson Cancer Center Orlando, Orlando, Florida

Centro Oncológico M. D. Anderson International España, Madrid, Spain

M. D. Anderson-Clinical Care Center in the Bay Area

M. D. Anderson Radiation Treatment Centers in Bellaire, Fort Bend and The Woodlands

Christus Spohn Stem Cell Program affiliated with M. D. Anderson Cancer Center Outreach, Corpus Christi, Texas

THE UNIVERSITY OF TEXAS SYSTEM BOARD OF REGENTS

James Richard Huffines, AustinChair

Rita C. Clements, DallasVice Chair

Cyndi Taylor Krier, San AntonioVice 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, HoustonStudent Regent

Francie A. FrederickCounsel and Secretary

THE UNIVERSITY OF TEXAS SYSTEM ADMINISTRATION

Mark G. YudofChancellor

Kenneth I. Shine, M.D.Executive Vice Chancellor for Health Affairs

THE UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTEREXECUTIVE COMMITTEE

John Mendelsohn, M.D. President

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

Leon J. LeachExecutive Vice President

THE UNIVERSITY CANCER FOUNDATION BOARD OF VISITORSOFFICERS

Marc J. ShapiroChair

Peter R. ConewayPast Chair

Ernest H. CockrellChair-Elect

Nancy B. LoefflerVice Chair

For information on patient services at M. D. Anderson, call askMDAnderson at 1-877-MDA-6789, or log on to www.mdanderson.org/ask

© 2007 Not printed at State expense.

Printed on recycled paper with soy-based ink.

Conquest is published quarterly by The University Cancer Foundation Board of Visitors on behalf of The University of Texas M. D. Anderson Cancer Center. All correspondence should be addressed to the Office of Public Affairs -Unit 229, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, 713-792-0658. E-mail: eellig@mdanderson.org. Articles and photos may be reprinted with permission.

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.

Stephen C. Stuyck, Vice President for Public AffairsSarah Palmer, Associate Vice President for CommunicationsDavid Berkowitz, Director of Publications and Creative ServicesSandi Stromberg, Program Manager of External PublicationsEditor: Eileen A. ElligWriters: Mary Jane Schier, Carol Bryce, DeDe DeStefano, Scott Merville, Sandi StrombergDesign: Michael Clarke Photography: John Everett, Wyatt McSpadden, John Smallwood, F. Carter Smith

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