University of CaliforniaSan Francisco

Comprehensive Cancer Center

C O N T E N T S

INTERNATIONAL OUTREACH

FROM A BASE OF EXCELLENCE 1

MORE POWER TO POPULATION

STUDIES 2

CANCER CELLS IN THEIR

SURROUNDINGS 3

NEW TREATMENTS SOUGHT

FOR ENDOCRINE TUMORS 4

LOOKING FOR WAYS TO DETECT

PANCREAS CANCER EARLY 5

HAND IN HAND WITH THE BEST 6

NOREN PANCREATIC CANCER

RESEARCH FUND 7

newspancreas cancer

Pancreas cancer still kills more people inthe United States than all other malignan-cies except lung cancer, colon cancer andbreast cancer, but it is rarely mentioned inthe media. Pancreas cancer researcharguably deserves much more supportand scientific attention.

The number of pancreas cancer investi-gators remains small. We seek to answermany of the same questions. It’s best ifwe obtain more information for analysisby merging the data we gather.

We need to better understand who is atrisk, so that we can establish practicalscreening guidelines for this disease. Theidentification of biological markers thatcan serve as diagnostic or prognosticindicators is another major goal. And, ofcourse, the need for better treatmentsand better treatment outcomes is urgent.

We want to find the best ways to tailortreatment to individual patients. A focusis on identifying biomarkers that canpredict response to specific treatments.With this aim, we are developing a verylarge bio-repository of blood and tissuesamples that will be annotated not onlywith treatment and outcome informa-tion, but also with extensive informationon molecular characteristics. We arecollaborating with Johns HopkinsUniversity on this project.

In a phase II clinical trial at UCSF onbevacizumab, a biologic therapy, wehave found that the drug appears toalmost double the percentage of patientswho survive one year with metastaticpancreas cancer. We anticipate that be-vacizumab might provide a comparablebenefit as a follow-up treatment forpatients with earlier-stage tumors thatcan be targeted surgically, and haveopened a new phase II trial to find out.

We will work with researchers at theUlleval University Hospital in Norway tolearn more about pancreas cancer by study-ing a population with a different diet andgene pool. We also will help the Norwegianresearchers advance new clinical trials.

To better search for risk factors and prog-nostic indicators, we have joined withother medical centers engaging in newstudies in the Western Pancreatic CancerConsortium. With collaborators around theworld, we are revisiting past studies, andconducting a more powerful “meta-analysis.”

By identifying and verifying risk factorsthrough collaborations such as these, wehope to develop a simple questionnaireto gauge an individual’s risk for pancreascancer. With such a tool, we as a societymight be able to cost-effectively screenhigh-risk individuals for this comparativelyrare, but deadly disease.

International Outreach from a Base of Excellence

We need to better understand who is at risk, so that

we can establish practical screening guidelines for this

disease. The identification of biological markers that

can serve as diagnostic or prognostic indicators is

another major goal. And, of course, the need for better

treatments and better treatment outcomes is urgent.MARGARET A. TEMPERO

(continued on p. 8)

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UCSF clinicians and researchers arejoining with counterparts far and wide toconduct large studies that will yield thestatistical power necessary to clearlyidentify factors associated with risk forpancreas cancer.

So far, the only undisputed factors knownto increase one’s chances of gettingpancreas cancer are cigarette smoking –which doubles risk – and a strong familyhistory of the disease.

Because pancreas cancer is rare, it takesa long time to conduct studies with enoughpatients to yield statistically meaningfulresults. The Pancreas Cancer Program atUCSF has joined with Seattle researchersat Group Health Cooperative and FredHutchinson Cancer Research Center, aswell as UC Irvine researchers, to form theWestern Pancreatic Cancer Consortium.As patients are enrolled in new studies,data will be collected similarly, so thatthey may be pooled for analysis.

UCSF Population Scientist Is a Pioneer

Much of the consortium’s research willbuild on earlier studies by UCSF’sElizabeth Holly. Before the UCSF PancreasCancer Program was established, Hollyhad nearly finished collecting data for thelargest-ever population study of pancreascancer: a comparison of 600 diagnosedcases of pancreas cancer and 1,700 con-trols – people who were demographicallysimilar, but did not have pancreas cancer.

Cases for the National Cancer Institute(NCI)-sponsored study were identifiedthrough the Bay Area SEER cancerregistry. Holly’s research team contactedpatients and controls, and asked individ-uals to participate in a survey. In manycases, the researchers also were able tostudy blood or tissue.

From an earlier analysis of the results,Holly concluded that allergies are likely tobe somewhat protective against the

disease. In addition, Holly and UCSFmolecular epidemiologist John Wienckeidentified genetic variations that canamplify a smoker’s risk for the disease.

More recent analysis of the data from thisstudy now indicates that one’s diet may,in some cases, affect the likelihood ofdeveloping pancreas cancer.

Holly has found that individuals who atefive or more servings of vegetables daily

had about 50 percent less risk of pan-creas cancer than people who ate fewerservings. Whole grains, fruits and fiberalso appear to have a protective effect,Holly says. Sweets containing trans fatsappear to increase risk.

Holly also investigated in more detail theprevious observation that pancreatitis anddiabetes are sometimes associated withpancreas cancer. Holly found that pancreascancer is most often diagnosed within justa few years of these other diseases, asopposed to many years later. This suggeststo Holly that undetected pancreas cancersmay, in some cases, cause diabetes andpancreatitis – not the other way around.But she plans to further investigate theseassociations in her next study.

“Gastroenterologists may want tocarefully follow smokers under age 60who develop pancreatitis to see whetherthey have or develop pancreas cancer,”Holly says.

Holly and colleagues recently were fundedby the NCI to collect data on 600 morecases and 600 controls. This time, patientswill be enrolled very close to the time whenthey are first diagnosed and seen in theclinic. A strong emphasis will be placedon molecular epidemiology and on the de-tection of interactions between geneticmakeup and environmental exposures thatinfluence pancreas cancer risk or survival.

Worldwide Collaboration

As part of another, worldwide collabora-tion – funded in part by the NCI – Holly’sresearch results will be analyzed togetherwith data obtained in 14 other studies onpopulations from Baltimore, Houston,Seattle, Connecticut, Florida, Louisiana,Michigan, Minnesota, Australia, Canada,the European Union, China and Egypt.

Nearly 5,000 cases will be included inthis meta-analysis, as well as 7,000controls. With so many more cases tostudy, there will be a greater opportunityto identify gene-environment interactions,and to conduct an open-ended search forgenes that may play a role in pancreascancer, Holly says.

population

More Power to Population Studies

More recent analysis of the data from this study now

indicates that one’s diet may, in some cases, affect the

likelihood of developing pancreas cancer.

ELIZABETH HOLLY

2

sciences

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Cancerous cells no longer function as good team players act-ing within their proper niche. Even so, Douglas Hanahan, aprofessor of biochemistry at UCSF, has found that cancerouscells within a tumor still exchange important signals with nearbynoncancerous cells. These noncancerous cells appear to besubverted – they begin to serve as a supportive structure, or“stroma,” upon which tumors can grow successfully.

Many of the basic research discoveries Hanahan has made inhis explorations of the tumor “microenvironment” have resultedfrom studies of a strain of mice he has bred as a model tostudy how cancer develops at various scales. The scales rangefrom molecules to cells to whole organs. More specifically,the mice are prone to endocrine tumors of the pancreas.

Hanahan studies angiogenesis – the growth of new bloodvessels – and the roles of proteins called growth factors inthis process. New blood vessels are needed to foster thesurvival and spread of tumors.

Normally, we think of immune cells fighting disease. ButHanahan also is investigating how chronic tissue inflammation– a biological process driven by certain cells of the immune

system – may paradoxically serve to stimulate rather thaninhibit tumor growth. He and his UCSF faculty collaboratorsZena Werb, Lisa Coussens and Gabriele Bergers have foundevidence that a protein called MMP9, secreted by certainimmune cells, is involved.

In addition, Hanahan probes the ways in which othernoncancerous cells that exist within and around tumorscommunicate with cancerous cells and help sustain thesurvival and spread of tumors.

Mouse Models for the Most Common Pancreas Cancer

Recently, Hanahan has started working with a new mousemodel of ductal tumors of the pancreas, first developed byRonald DePinho and colleagues at the Dana-Farber CancerInstitute in Boston. Ductal tumors are responsible for the vastmajority of pancreas cancer deaths.

Earlier studies of the tumor microenvironment in endocrinepancreas tumors are giving Hanahan and colleagues a leg upin their studies of pancreatic ductal tumors. The organ in whichthe tumors arise is the same, and many of the changes beingobserved are similar. However, there are differences, probablydue in large part to the fact that endocrine and ductal tumorsarise in different types of cells within the pancreas.

Hanahan plans to continue manipulating these powerfulmouse models of pancreas cancer. In addition to using geneticengineering and selective mouse breeding, Hanahan will usedrug-like chemicals to manipulate the activities of specificgenes or proteins made by cancerous or stromal cells. In thisway, he will reveal their roles in fostering cancer growth withinthe tumor microenvironment.

Ductal cancer of the pancreas is very unusual in the degreeto which noncancerous cells migrate to, or proliferate within,the vicinity of the tumor, Hanahan notes. The tissue becomesvery fibrous and heavily populated by cells called fibroblasts,as well as by cells of the immune system. Further explorationof this peculiar development may provide clues as to why

pancreas tumors have been so resistant to treatment,Hanahan suggests.

The mouse model for ductal cancer is a good prospect tobecome a preclinical platform for identifying new drug targetsand for testing potential new treatments.

Traditionally, the development of new cancer treatments hasfocused on targeting cancer cells. However, the successfuldevelopment of drugs such as bevacizumab, which targetnew blood vessel growth, demonstrates that targeting tumor-supporting cells in stromal tissue also can be an effectivestrategy for fighting cancer.

“We are trying to target the stroma,” Hanahan says. “Targetsmay include stromal fibroblasts, as well as the cells thatmake up the tumor vasculature, or even infiltrating immunecells. We have really gained confidence in our knowledge thatthese cell types are mechanistically important in cancer, andtherefore represent potential new drug targets.”

basic research

Cancer Cells in Their Surroundings

DOUGLAS HANAHAN

3

The mouse model for ductal cancer is a good prospect to

become a preclinical platform for identifying new drug

targets and for testing potential new treatments.

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Islet cells of the pancreas – specificallythe islet cells known as beta cells – arebest known for being impaired or lost indiabetes. But islet cells and otherneuroendocrine cells can also give rise topotentially fatal cancers. Neuroendocrinetumors of the pancreas – also called pan-creatic endocrine tumors or islet cellcarcinomas – account for about 1,000new cases of cancer per year in theUnited States.

In general, the prognosis for individualsdiagnosed with islet cell tumors is betterthan for those diagnosed with morecommon pancreas cancers that arise inthe ducts. However, islet cell tumors areoften fatal when they spread beyond thepancreas. The age of peak incidence isearly – the 40s, 50s and 60s – notesUCSF gastrointestinal oncologist andclinical researcher Emily Bergsland.

“The course of these cancers is variable,depending on the patient and the tumor,”Bergsland says.

Islet cell tumors often grow slowly. Theysecrete hormones in more than 50 per-

cent of cases, Bergsland says. As aresult, distinctive symptoms are morelikely to arise with islet cell tumors thanwith ductal tumors. Physicians employCT scans to help diagnose islet celltumors, as well as imaging exams with aninjected radionuclide tracer called 111In-octreotide. The tracer can be used tohighlight a majority of islet cell tumors.

Bergsland is working with oncologicsurgeon Eric Nakakura to build a tissuebank of islet cell tumors for research.They are developing lab methods to trackabnormal gene activity and protein levelsin islet cell tumors.

A goal is to identify islet cell tumor markersthat appear in the blood and that mightbe used to improve diagnosis. One knownmarker – chromogranin A – a protein pro-duced by neuroendocrine cells – is oftenelevated in serum when an islet celltumor is present.

Bergsland is optimistic that analysis ofislet cell tumors will point to molecularmarkers that can help predict patientsurvival or the likelihood of responding toa specific therapy. Furthermore, researchlike this may lead to the discovery ofpreviously unknown drug targets for thetreatment of this disease.

Better Treatment Urgently Needed

Well-contained islet cell tumors may besurgically removed without the need foradditional therapy. In contrast, treatmentfor tumors that have already spread beyondthe pancreas at the time of diagnosis – orthat have returned despite earlier surgery– depends on the tempo of tumor growth,the extent of disease and symptoms.

Treatment for islet cell tumors that havespread ranges from observation to sur-gery, and may include chemotherapy.

Octreotide is used not only as an im-aging tracer, but also as a treatment tocontrol hormone-mediated symptoms.Unfortunately, in most cases, there is nocure for islet cell cancer once it spreadsbeyond the pancreas.

“There is an urgent need for better treat-ments for advanced disease,” Bergslandsays. “However, the identification ofnovel therapeutic strategies has beenhampered by the fact that islet celltumors are so rare.”

For her part, Bergsland has alreadybegun early-stage clinical trials at UCSFto test new treatments for metastaticislet cell tumors.

In one unique study, Bergsland is combin-ing an alternative chemotherapy regimenwith the targeted drug, bevacizumab(Avastin). Bevacizumab is already approvedby the Food and Drug Administration forthe treatment of lung and colon cancer.It is an anti-angiogenesis drug, meaningthat it was designed to fight new bloodvessel growth in tumors.

Previously, Bergsland had studied the basicbiology of blood vessel growth in tumors.She also had been at the forefront amongclinicians who helped evaluate the role ofbevacizumab in the treatment of coloncancer. She continues to collaborate withlaboratory scientist Doug Hanahan (seepage 3) to determine whether what hasbeen learned from a mouse model of isletcell cell carcinoma can be used to helphumans with the disease.

“My interest is to translate lab develop-ments into the clinic, taking advantage ofnewly identified drug targets and emergingbiological therapies,” she says.

clinical research

New Treatments Sought for Pancreatic Endocrine Tumors

Islet cell tumors often

grow slowly. They secrete

hormones in more than 50

percent of cases, Bergsland

says. As a result, distinctive

symptoms are more likely to

arise with islet cell tumors

than with ductal tumors.

EMILY BERGSLAND

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Grace Kim is an anatomic surgical pathologist. Like other kinds of physicians, shehas a doctor’s office. But if you visit her there, you won’t find a waiting room filledwith patients. The patients are represented by boxes upon boxes of tissue samples,sliced thin and preserved on microscope slides on shelves lining her walls.

Surgical pathologists like Kim help clinical colleagues make disease diagnoses usingclues and evidence from tissues obtained from biopsies or surgeries. In her office, amicroscope occupies prime desktop real estate. It seems to beckon a visitor to takea peek through a lens into another world.

When Kim began her medical residency at Stanford University in the mid-1990s,pathologists had not yet settled on how to uniformly classify early-stage abnormalgrowths of the ductal pancreas. Nor did they understand the significant genetic andbiologic processes associated with their development. These abnormal growths, or“lesions,” now called PanIN – short for pancreatic intraepithelial neoplasia – arethought to develop into invasive pancreas cancer. Kim became interested in thesequestions, and decided to participate in research to help answer them.

In a research study completed after she joined UCSF, Grace Kim and colleagues inYoung Kim’s laboratory at San Francisco Veterans Affairs Medical Center trackedchanges in genes and protein production in these PanIN lesions. The researchers de-termined that specific genes and proteins tended to change earlier than others, andthat some of these changes were most likely to be associated with invasive cancer.

Further research along these lines may lead to the identification of early markers ofpancreas cancer that could be detected noninvasively in blood samples, Kim says.

Rare Specialization

Some academic medical centers are able to employ surgical pathologists who spe-cialize in gastroenterology. But by the time Kim started to work at UCSF in 2000,she had already opted to become even more specialized. While fulfilling her normalpathology duties, she was determined to devote special emphasis to pancreaspathology. The choice was possible only because of the comparatively large numberof pancreas surgeries performed at UCSF.

Only a few institutions worldwide have a pathologist with this level of expertise. In fact,most of those tissue samples on Kim’s office shelves are from pancreata. That fact isperhaps best appreciated by her UCSF colleagues in the Pancreas Cancer Program.

Thanks in part to UCSF’s being a major center for even the most difficult-to-performpancreas surgeries, Kim has honed her expert eye quickly and thoroughly. Just as im-portant, her associations with UCSF Comprehensive Cancer Center colleagues are lead-ing to new research aimed at a better understanding of the origins of pancreas cancer.

Kim now has begun working with Thea Tlsty, co-leader of the Cancer Center’s CellCycling and Signaling Program. Tlsty had long been investigating genetic changesthat are among the earliest to occur during breast cancer. Specifically, Tlsty hasfound that a gene called p16 is lost early in tissue in which breast cancer arises.

Each type of cell in the body develops differently, activating different suites of genesand making different proteins. Even so, based on earlier research, Kim and Tlstysuspect that p16 may also be an early feature of pancreas cancer.

“We’re going to be looking at both normal and precancerous tissue to track p16 andother potential markers,” Kim says. “We will be acquiring fresh tissue samples, butall these preserved samples also are a valuable resource for these studies.”

young investigator

Looking for Ways to Detect Pancreas Cancer Early

Further research along

these lines may lead to the

identification of early markers

of pancreas cancer that could

be detected noninvasively in

blood samples, Kim says.

5

GRACE KIM

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Calling a busy clinic in this modern day and reaching a caregiverwho knows what you’re going through is a rare event – but notat UCSF’s pancreas cancer clinic. The practice is able to employthree nurse specialists, thanks in large part to donor generosity.

Not surprisingly, these nursing professionals are available duringclinic visits for consultation and medical treatment, but they alsoare regularly reachable at other times.

It is difficult to imagine anyone more qualified to provide profession-al nursing care to pancreas cancer patients than Brian Schillinger.

Schillinger already had had two decades of nursing experience– including many years working with AIDS patients and helpingto coordinate clinical trials – before joining the pancreas cancerservice.

Family Experience

But there is another experience that makes Schillinger and thepancreas cancer service a good match. Several years ago, hisown mother died from pancreas cancer.

Fortunately, Schillinger relates, he was able to devote time tohis mother during the last four months of her life. He feltblessed that he could remain close and take care to meet herbasic needs, just as she had earlier in life cared for him and hissiblings for so many years.

But even as family members naturally turned to Schillinger – theprofessional – to lead in a time of medical crisis, he felt that hetoo was in uncharted territory without the answers.

“I think my family’s experience was largely shaped by a lack ofinformation. We did not have anyone providing the service that I and others do here. The physicians were not often available,and there was no education provided by anyone on the nursing

staff. There were a lot of unknowns about what to expect. I found that very frustrating.”

As a case manager, Schillinger spends about half his workinghours on the phone, educating patients and family membersand helping them cope. He explains to patients why they areexperiencing symptoms, and helps them to understand whatthey may experience in the future and to plan for it. He assistspatients and families in navigating a complex disease in acomplicated health care system.

Advancing Clinical Trials

Most pancreas cancer patients at UCSF are taking part inclinical trials of new treatments. Schillinger helps to managethese trials, making sure that each protocol is followed correctly.He joined the pancreas cancer service just as new treatmentsbegan having a greater impact.

“We have a chemotherapy regimen that has taken somepeople who were very sick when they walked in the door andreally reduced their symptoms and improved their quality oflife,” Schillinger says.

“Some people have gained the energy and relief from symptomsto go back to doing the things they enjoy, to take care of unfinishedbusiness in a peaceful way and to live a fairly normal life for manymore months than would have been possible a few years ago.”

If progress continues to accelerate, Schillinger may one day behelping many more patients understand what to expect as along-term cancer survivor.

Hand in Hand with the Best

clinical care

Most pancreas cancer patients at UCSF are taking part in clinical

trials of new treatments. Schillinger helps to manage these trials,

making sure that each protocol is followed correctly.

6

BRIAN SCHILLINGER

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Noren Pancreatic CancerResearch Fund

7

Rombauer Vineyards will host their 9th annual Joy of Wine Fundraiser on August 4, 2007, from 10 a.m.to 3 p.m. The event benefits the UCSF Rombauer Cancer Research Fund for Pancreas Cancer andHospice of Napa Valley. Last year’s event raised $150,000 for UCSF and the hospice. Margaret Tempero,deputy director of the UCSF Comprehensive Cancer Center, greeted visitors, as did other UCSFresearchers. The event included jazz entertainment, walks through nearby caves, jewelry sales and,of course, food and wine tasting. For more information, visit www.rombauervineyards.com.

Rombauer Vineyards

t would be wrong to say Don Noren conformed to any mold, says Lynn, his wife for 52years until his death. Still, Don charted an archetypal path to Silicon Valley success –from engineer to inventor to entrepreneur. He founded Noren Products in 1968 andeventually was granted hundreds of patents, mostly for heat transfer devices, which areused to cool a wide range of high-tech equipment.

The Santa Cruz native, Eagle Scout and UC Berkeley-trained chemical and electricalengineer and varsity basketball player was always the ever-active achiever – until oneday a few years ago, too exhausted to enjoy a scuba outing, he realized for certain thatsomething was wrong.

Physicians to whom he described gastrointestinal symptoms, loss of appetite andexcessive sleeping concluded it was essentially a case of digestive discomfort. An earlyimaging exam revealed nothing of concern.

However, Lynn’s brother, a former professor of pathology at University of Nebraska, wassuspicious. He suggested that Don have another imaging exam, this time with a contrastagent – a chemical tracer that helps highlight abnormal tissue. The exam led to adiagnosis of pancreas cancer. Just one in 25 pancreas cancer patients lives five years;but at least the tumor came into view early enough to go after it by surgery.

For follow-up care, Lynn’s brother recommended a former student of his, MargaretTempero, a pancreas cancer specialist and deputy director of the National Institutes ofHealth-designated Comprehensive Cancer Center at UCSF, just 25 miles from theNorens’ home. Don was interested in aggressive experimental treatments to kill unseen,far-flung tumor cells. He hoped that Tempero might learn something valuable whilehelping him to live longer. With treatment, Don became active again; he and Lynn took aspringtime trip to Barcelona and a cruise to Chile.

Knowing Don was likely to appreciate seeing science in action, Tempero introduced himto cancer biology researcher Martin McMahon. Shown a robot used for high-throughputgene microarray analysis, Don immediately began suggesting ways to improve it. Soonhe offered to help support McMahon’s research. This research has led to a detailedgenetic and molecular analysis of dozens of human pancreas cancer cell lines, nowavailable for study to all UCSF pancreas cancer researchers.

Don died in November 2005, three and a half years after the diagnosis. Lynn continuesto actively support the Noren Pancreatic Cancer Research Fund, which is used toleverage support for a variety of laboratory and clinical research projects at UCSF.

I

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how to help

pancreas cancer newsUCSF Comprehensive Cancer CenterUniversity of CaliforniaSan FranciscoBox 0248San Francisco, CA 94143

University of CaliforniaSan Francisco

Comprehensive Cancer Center

Pancreas Cancer NewsVolume 2, Number 1April 2007

Pancreas Cancer News is publishedby the Pancreas Cancer ResearchGroup at the University of California,San Francisco

Co-Leaders:Margaret Tempero, MDMartin McMahon, PhD

Writer/Editor: Jeffrey NorrisDesigner: Laura ShapiroPhotography: Elisabeth Fall, Kaz Tsuruta

© 2007 The Regents of the Universityof California

Produced by UniversityPublications/Public Affairs, PR607

Our program depends on your support. We welcome your contributions to thisspecial fund. Please make your check payable to UCSF Pancreatic CancerResearch Fund, Box 0248, San Francisco, CA 94143-0248.

Nonprofit Org.

US Postage

PA I D

San Francisco, CA

Permit No. 8285

(continued from p. 1)

Thanks to donors, we now can purchase computer hardware and soft-ware to support this research through the establishment of an analyticalrelational database. We will use the database to merge large data sets,incorporating information ranging from molecular data to informationon potential risk factors, treatment outcomes and survival.

The Pancreas Cancer Program has steadily drawn the interest andcommitment of growing numbers of biological researchers since wefirst organized in 2002. Recent advances include the complete geneticcharacterization of many pancreas cancer cell lines that can be grownin the lab for scientific study. In addition, UCSF researchers have de-veloped models in which genetic abnormalities found in human pancreascancers are programmed into mice, which then become susceptible tothe disease. The development of pancreas cancer, as well as itstreatment, can be studied in these models.

The still-new Pancreas Cancer Program now is on equal footing withother established programs within the UCSF Comprehensive CancerCenter. For the first time, the program now will be included in the NationalCancer Institute’s core grant to the center. This support is a testimonialto the quality of the science within the Pancreas Cancer Program.

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