c o n t e n t s

BEFORE IT IS TOO LATE 1

LOOKING FAR AFIELD FOR PANCREAS CANCER CLUES 2

NEW DRUGS FOR SPECIAL DEL IVERY 3

TUMORS MEET THEIR GENETIC MATCH 4

CELLS THAT SEED TUMORS 5

GENETIC COUNSELOR HELPS WITH TROUBLING HERITAGE 6

THE R ICHARD G. KLE IN RESEARCH FUND 7

newspancreas cancer

We already know that patients with small pancreas tumors that can be surgically removed fare better on average than those whose cancers have grown larger. But early detection usually happens by chance – when the location of the tumor causes symptoms a patient and physician recognize as unusual, or when imaging undertaken for other reasons reveals an abnormality in the pancreas.

To meet this challenge of early detection, UCSF experts in fields ranging from basic biology to clinical studies have made identifying molecular and clinical clues to pancreas cancer risk and early detection a priority.

Current techniques for screening and preliminary diagnosis of pancreas cancer already can be used to detect tumors early, sometimes even before they have become truly cancerous.

As it stands, screening is expensive, somewhat inconvenient and slightly “invasive,” meaning that, very rarely, the tests themselves can cause harm. And ironically, without major pancreas surgery, there are some cases in which we are not certain whether imaging abnormalities point to inevitable, invasive cancer. Only about 1 percent of the general population will ever be diagnosed with pancreas

cancer. Working first with the highest-risk families, clinical researchers are trying to assess what degree of risk warrants screening.

About 10 percent of all pancreas cancers arise in families with a pattern of inherited cancer. Genetic counselor Amie Blanco and other members of the Cancer Risk Program at UCSF consult with individuals from affected families who suspect or know that they are at risk. (See page 6.) Counselors refer individuals to clinical trials when appropriate. They provide the latest information on risk and prevention, and can notify patients when new research sheds light on their risk status.

For these families and for the rest of the population, we want to better gauge pancreas cancer risk. So far, we know that smoking doubles risk. We know that a family history poses an even greater risk. Population scientists affiliated with the Pancreas Cancer Program, including UCSF’s Elizabeth Holly, PhD, and Paige Bracci, PhD, are working to identify additional pancreas cancer risks and interactions among risk factors.

Holly’s research team has been exploring the role of diet, and earlier identified a gene variant that amplifies a smoker’s risk for pancreas cancer. Holly has begun

Before It Is too Late

Developing the capability to detect pancreas cancer early

is an immediate goal at UcsF. For many types of cancers,

detecting a tumor early increases a person’s chances for

long-term survival. Few pancreas cancers are detected early,

and few pancreas cancer patients survive.

MARGARet A. teMPeRo

(continued on p. 8)­­

Consider the lab mouse. The rodent is used to model tumor growth in countless studies of genes and cancer. About 99 percent of mouse genes also appear in humans. Mouse and human also are similar when one compares the DNA code within these genes. Mice get cancer, and they get more cancer when genetically engineered with human cancer-causing genes.

But Allan Balmain, PhD, has strayed from his geneticist colleagues in his choice of mouse. Other researchers, to help care-fully control experimental variables, use only genetically uniform laboratory strains of the species Mus musculus. Several years ago, Balmain began breeding their country cousins, a Mediterranean field mouse known as Mus spretus. Like humans, but unlike the old lab strains, these field mice exhibit a wealth of genetic diversity.

Why is that important? Clearly, common DNA variations in genes that we inherit from our mothers and fathers affect us in more substantial ways than simply determining whether our eyes are blue or brown. Some gene variations alter disease risk, including risk for diseases that – like cancer – arise most often later in life.

Balmain shares with most cancer geneti-cists an interest in rare gene mutations – DNA alterations – that arise within cells over a lifetime. If a mutation hits the wrong gene in the wrong place, it may set the stage for cancer to develop eventually. But Balmain also is exploring the subtler influence of more common variations in the genes we are born with. Balmain uses Mus spretus, as well as inbred lab mice, to explore how different inherited versions of the same gene affect cancer risk.

He can manipulate genes and interbreed mice of both species to determine how gene variants act in mice with different genetic backgrounds. He can investigate how the effects of rare mutations that

population

Looking Far Afield for Pancreas cancer clues

ALLAN BALMAIN

2

sciences

some gene variations alter disease risk,

including risk for diseases that – like cancer –

arise most often later in life.

some of which Balmain already has iden-tified as being important in cancer.

While continuing these experiments, Balmain next plans to collaborate with pharmaceutical industry scientists to tar-get an old foe in a new way. The nemesis is a mutated gene that drives the growth of almost every tumor that arises in the ducts of the pancreas.

Mutations that rev up this same gene, called K-ras, also appear to drive the development of tumors in many different organs. UCSF boasts several research-ers who are seeking strategies to block the activity of mutated K-ras and its

molecular partners in cellular crime. (See Pancreas Cancer News 2005 online at cancer.ucsf.edu/research/pancan2005.pdf.)

For his part, Balmain has found that the same K-ras mutation can act differently when it arises in different inherited forms of the gene. Furthermore, the version of the K-ras gene we inherit from one par-ent may influence and sometimes work against the activity of the gene copy we inherit from the other parent. (Our cells contain 23 chromosomes from each par-ent – matching pairs.)

In other words, some lucky individuals may inherit a version of K-ras that can inhibit the activity of the mutant gene on the other chromosome, in effect acting as a tumor suppressor. These people may be less likely to develop an aggres-sive malignant tumor.

Balmain has begun collaborative studies with UCSF epidemiologist Elizabeth Holly, PhD, to evaluate how this wrinkle in K-ras genetics affects pancreas cancer risk and survival.

In addition, Balmain has confirmed that there is more than one way to splice bits of DNA together to form the complete K-ras gene, and this too may be important in cancer and its treatment.

Allan Balmain’s research is funded in part by a generous donation from the Schwartz Foundation.

arise in cancer-associated genes are influenced by the activity of other genes and gene variants. He can apply what he learns from human DNA to mice, and vice versa.

The amount of raw data generated by these experiments is tremendous. Previous generations of biological scientists did not have the tools to collect so much data, nor the task of analyzing such a complex array of information.

UCSF postdoctoral fellows in mathematics and computational biology have developed unique and powerful programs to visual-ize and quantify the degree to which the activity of one gene affects others.

These studies have led to new discover-ies of biochemical relationships among the proteins encoded by these genes,

There is an urgent need for new ideas for cancer drugs – especially pancreas cancer drugs. Kathleen Giacomini, PhD, of the UCSF School of Pharmacy has a new strategy that could lead to many new drugs for pancreas cancer and other cancers. Although she is not reinventing the wheel, before she is through, drugs may be rolling over cancer cells much more easily than before.

Funded through a UC Discovery Grant and working with col-laborators, Giacomini is doing some well-informed tweaking of standard chemotherapy drugs to make them more potent. The strategy is to get more of the drug dose into cancer cells. Giacomini is engaging in a kind of pharmaceutical jujitsu – using a cancer cell’s strength against it, and turning that strength into vulnerability.

Cancer cells divide rapidly. Because they grow so fast, they have a great need for chemical fuel and nutrients. Nutrients and other molecular cargo enter all cells through channels called membrane transporters. Different membrane transport-ers traffic in different molecules.

Cancer cells often make and use an abnormally large number of certain transporters, including the transporters that bring in nutrients. That’s an advantage, but Giacomini aims to turn this characteristic into a weakness by more efficiently deliver-ing cancer-fighting drugs into tumor cells through these same abundant transporters.

Giacomini is one of the world’s leading experts on these cell-membrane transporters. She is well versed in the ways in which these proteins enable or restrict the movement of mol-ecules into and out of cells, including cancer cells. Giacomini has studied the molecular structures, biochemical functions and genetic code of a large number of these proteins, which act like gatekeepers within cells’ outer membranes.

Before Giacomini starts changing the blueprint of a chemo-therapy drug, she probes the molecular interactions between molecules of the drug and the molecular parts of the trans-porter protein through which the drug molecules must pass to

enter or leave a cell. These studies provide clues about how to change the drug’s structure, so that it can more efficiently pass through a nutrient transporter, for instance.

“We have made several different chemical entities, modified from standard drugs,” Giacomini says. She has been testing the new chemicals to see how well they kill various strains of cancer cells grown in the lab. The best candidates will be tested later in mice.

One of the transporters that often appears in abnormal abun-dance on cancer cells is a vitamin transporter. Giacomini has modified methotrexate, an anti-cancer drug, and is testing it for efficacy in various cancers that have high levels of this transporter.

Giacomini has made pancreas cancer a priority. She has modified chemotherapies and made them more potent against different varieties of lab-grown pancreas tumor cells. “We would like a chemical that is about 10 times more potent than what we have now before we would begin to evaluate it as a drug candidate,” she says.

Giacomini also is an expert in pharmacogenetics. That means she studies how drugs act differently in different individuals because of genetic differences. She is investigating variant forms of genes for transporters in cancer patients and in a cross-section of the Bay Area population to identify variations that affect responses to chemotherapies and to the newer chemicals her research team is developing. Some common transporter variants might even merit their own targeted drug development efforts, but it’s too soon to tell, Giacomini says.

Kathleen Giacomini’s research is funded in part by gener-ous donations to the David J. Hasbun Pancreatic Cancer Research Fund.

basic research

new Drugs for special Delivery

KATHLEEN G IACOMINI

3

Giacomini is engaging in a kind of pharmaceutical

jujitsu – using a cancer cell’s strength against it, and

turning that strength into vulnerability.

some gene variations alter disease risk,

including risk for diseases that – like cancer –

arise most often later in life.

Even when tumors look the same, more often than not, they are genetically dif-ferent from one another. Scientists are discovering that the likelihood of patient death or survival is associated with par-ticular genetic abnormalities, or with tell-tale patterns of genetic abnormalities.

In normal cells, there are controls that limit cell division and cause the death of cells that become abnormal. All tumors escape these normal controls. However, the varying patterns of genetic abnor-malities within cancers often represent slightly different ways of doing so. These different routes of escape may best be blocked with different drugs.

In recent years, targeted therapies have been developed against specific genetic abnormalities that frequently arise within cancer cells to foster their continued growth and survival. In breast cancer, for instance, the drug Herceptin is targeted against the many breast tumors in which abnormal production of a protein called HER2 drives the tumor’s growth.

Unfortunately, in practice, Herceptin is effective against only a minority of breast cancers with this abnormality, despite the targeting.

Indeed, researchers are discovering that the effectiveness of specific cancer treatments may vary with the genetic fingerprints of tumors in ways that are not easily predicted.

Many drugs have been rejected as treat-ments for certain types of cancer, based on unimpressive overall results in treating patients – even when individual patients appear to benefit. Among available treat-ments, many potentially useful drugs or combinations of treatments have never been evaluated in common genetic subsets of tumors, says Joe Gray, PhD, director of the Life Sciences Division at the Lawrence Berkeley National Laboratory (LBL), head of the UCSF Breast Oncology Program and one of the world’s leading cancer genetics research-ers. As a consequence, it may be that good cancer treatments are being over-looked, Gray says.

Gray is working with a team of scientists and clinical investigators from LBL and UCSF to correct this oversight. His team already has identified potentially useful treatment combinations and new experi-mental therapies that might prove effec-tive in treating breast tumors for which genetic profiling shows a poor prognosis with standard treatment. Now, working with UCSF oncologist Eric Collisson, MD, Gray also is exploring genetics and drug response in pancreas cancer.

Unfortunately, in pancreas cancer, virtu-ally every patient faces a poor prognosis. Only 5 percent of patients survive for five years after a diagnosis. But that does not mean pancreas tumors are all the same genetically. Collisson already has evidence to suggest that there is genetic variability among them, and that these differences matter.

Collisson examined tumor tissue from 29 patients with cancers that were confined to a small region of the pancreas at the

time of diagnosis – thus permitting surgi-cal removal. Historically, even among these patients that undergo surgery, only about one in five has no recurrence of cancer within three years. Collisson and collaborators identified a genetic pattern that predicts even worse-than-average outcomes following surgery.

Collisson seeks to build on this proof of principle – that genetic differences in pancreas cancer exist and do indeed matter. The goal is to use a tumor’s genetic fingerprints to guide patients to better treatments and better chances for survival.

“A lot of approved chemotherapies have been tried in pancreas cancer and failed,” Collisson says. “We want to revisit them to determine if there are genetically defined subsets of pancreas tumors that actually do respond to some of these drugs.”

To expand efforts to match tumor to treatment, Collisson and colleagues are working with 30 diverse varieties of pancreas cancer cells that can be grown in the lab. The researchers are collaborat-ing with UCSF pathologist Grace Kim, MD, to obtain additional tumor tissue for analysis.

Gray and Collisson also are using the same strategy to test new, experimental treatments targeted against specific biochemical pathways that are altered in cancer. They want to identify genetic characteristics that may make some tumors particularly vulnerable to these new drugs. Combined with preclinical animal studies, such an approach may lead to better patient selection for clinical trials – enriching participation among those patients who may be most likely to benefit.

Joe Gray and Eric Collisson’s research is supported in part by generous donations to the Noren Pancreatic Cancer Research Fund.

clinical research

tumors Meet their Genetic Match

In recent years,

targeted therapies

have been developed

against specific genetic

abnormalities that

frequently arise within

cancer cells to foster

their continued growth

and survival.

JOE GRAY

The long hours Kim McDermott spent as a graduate student examining the world of cancer at a molecular and cellular level in a lab at University of Nebraska Eppley Cancer Center never blinded her to the human cost of the disease she was studying – a fellow scientist there had been diagnosed with and succumbed to pancreas cancer at an unusually early age.

After completing her doctoral degree, McDermott, PhD, came to UCSF to investigate the cellular origins of breast cancer. Now, as part of a team led by Thea Tlsty, PhD, a UCSF expert on the cellular biology of tumors, McDermott is investigating whether the Tlsty lab’s recent success in identifying markers of early breast cancer can be repeated in pancreas cancer.

One goal is to identify early markers of pancreas cancer that can be detected reliably in fluid secreted by the pancreas – or better yet, in blood. The difficulty of detecting pancreas cancer early is a key reason the disease is among the deadliest cancers.

In breast tissue, the UCSF researchers believe they already have identified a molecular signature that will serve as the basis for a lab test to predict whether abnormal but not yet cancerous breast lumps are destined to develop into full-fledged cancer.

Tlsty has led successful efforts to identify cells in normal breast tissue – perhaps one in 10,000 cells – that are most likely to develop later into breast cancer. A tumor-suppressing gene called p16 is “silenced” in these cells – meaning the gene is switched off and its encoded protein is not produced.

McDermott explains that loss of p16 contributes to mistakes in how chromosomes are divvied up when daughter cells form during cell division. This allocation of chromosomes is governed by structures within cells called centrosomes. Centrosomes often form aberrantly in cells in which p16 is not functioning normally. The result is daughter cells with one or more unpaired chromosomes. This characteristic, called aneuploidy, may be one of the very earliest, most common and easily tracked changes in precancerous cells of the pancreas ducts. These ducts are where pancreas tumors most often develop.

To advance the research, painstakingly prepared, normal pancreas ductal cells – essentially an unwanted byproduct of diabetes research – are available from the UCSF Islet and Cellular Production Facility. In addition, UCSF pathologist Grace Kim, MD, provides living pancreas tissue from patients with pancreas diseases, including many with rarely identified, early-stage cancers. (See Pancreas Cancer News 2007 online at cancer.ucsf.edu/research/pancan2007.pdf.)

But it’s up to McDermott to extract from normal tissue the rare cells that have silenced p16 and coax them to grow in the petri dish – with whatever growth serum does the trick. She already has made significant progress.

McDermott’s early achievements and future promise have been recognized through a rare Pathway to Independence Award from the National Institutes of Health. The grant helps postdoctoral fellows make a smooth transition to research careers as university faculty.

“We’ve learned a lot from the mammary system,” she says. “Now we have been able to quickly begin to apply what we have learned about mammary cells to the study of cells that we think may be playing a similarly important role in the development of pancreas cancer.”

Kim McDermott’s research is funded in part by generous donations to the David J. Hasbun Pancreatic Cancer Research Fund.

young investigator

cells that seed tumors

5

KIM McDERMOTT

one goal is to identify

early markers of pancreas

cancer that can be

detected reliably in fluid

secreted by the pancreas –

or better yet, in blood.

the difficulty of detecting

pancreas cancer early is

a key reason the

disease is among the

deadliest cancers.

Kim McDermott is developing techniques to grow human pancreas cells in the lab,

to learn more about the earliest stages of pancreas cancer.

Pancreas cancer is an uncommon disease. Even so, there are some unfortunate families in which two or more people have been diagnosed. In many instances, the pattern of pancreas cancer in these families may signal that an inherited gene is largely to blame. In fact, as with breast cancer, up to 10 percent of pancreas cancer occurs in families at an elevated genetic risk for the disease.

In some cases, faulty genes more famous for contributing to other types of familial cancer – such as breast, colon or skin cancer – also increase the gene carrier’s risk for pancreas cancer.

It was not until 2006 that researchers first identified a cancer risk gene specifically for a familial form of pancreas cancer. It is not yet clear whether mutations in this gene, identified in a single family, will prove to be common in other families with multiple cases of pancreas cancer. There still is no genetic test for pan-creas cancer susceptibility unrelated to other known hereditary cancer syndromes.

Genetic counselor Helps Families with troubling Heritage

clinical care

6

AMIE BLANCO

“We’re clinical detectives. We sort out

family histories in great detail to determine

if we suspect a hereditary cause.”

The search for inherited genes that may influence risks for both sporadic and familial forms of pancreas cancer is ongoing at UCSF and other academic medical centers. (See page 2.) As members of affected families try to gain a better understanding and to keep abreast of the latest discoveries, they often benefit by consulting with a genetic counselor like UCSF’s Amie Blanco.

Working with UCSF gastroenterologist Jonathan Terdiman, MD, Blanco, a genetic counselor for the UCSF Cancer Risk Program, helps concerned families affected by a variety of cancers. Blanco gathers information to gauge whether chance, inheritance or unusual exposures to environmental hazards are the strongest contributors to a family’s patterns of cancer.

“We’re clinical detectives,” she says. “We sort out family histo-ries in great detail to determine if we suspect a hereditary cause. Some of the things we look for are young ages at cancer diag-nosis, multiple primary cancers in a single individual, cancers in

at least two successive generations and types of cancer seen in known cancer predisposition syndromes.”

Blanco counsels individual family members on genetics, diet and lifestyle, and develops recommendations and follow-up plans. When it’s available, Blanco and her counseling colleagues offer genetic testing for individuals who might be affected by a faulty gene responsible for a family’s misfortune.

Educating family members on pancreas cancer genetics and risk can go a long way to reduce uncertainty and anxiety among individual family members.

Blanco reminds family members that they are still unlikely to get pancreas cancer. Having a fourfold, or even an eightfold, higher-than-average risk for a rare disease does not turn a rare occur-rence into an inevitable one. Blanco advises individuals at risk to limit exposures to known pancreas cancer risks, such as smoking.

Clinical trials are now underway to determine how best to use ultrasound and other screening methods to prevent premature pancreas cancer death. Blanco often refers high-risk family members to these screening clinical studies. In addition, Blanco helps families get involved in research studies. The UCSF Cancer Risk Program banks blood and DNA samples.

Blanco offers to enroll patients in a familial pancreas cancer reg-istry. The hope is that new scientific discoveries will lead to valu-able tests for better gauging risk and possibly even better ways to diagnose cancer early. Blanco expects in the future to have much more to offer family members who visit her today.

“Our biggest recommendation is that they keep in touch with us,” she says.

The integral work of our cancer genetic counselors is supported in part by generous donors, including Dr. and Mrs. Gordon E. Moore.

hen Dick Klein died of pancreas cancer five years ago, Diane Klein lost a hus-band, Jeffrey and Jennifer Klein lost a father, and Tom Klein lost a brother. It is difficult to glimpse a silver lining in the dark cloud of a family’s pancreas cancer diagnosis. For the Kleins, a small consolation was that they did not have to travel far for pancreas cancer care and treatment that ranks among the very best anywhere. After visits to UCSF, Dick Klein and his family could cross the Bay Bridge and return home the same day.

Diane Klein was moved by the care Dick received from oncologist Margaret Tempero, MD, nurse Elizabeth Dito and the other members of the medical team at UCSF. Her experience with pancreas cancer motivated her to try to make a difference and to advance understanding of ways to improve outcomes for patients.

“For me, it is a gift to be able to offer support for the cause,” Diane Klein says. “This can-cer does not get a lot of attention. The mortality rate is very high because it is detected so late. There are no easy methods to diagnose it, and the symptoms are very similar to symptoms of common diseases. I think pancreas cancer is probably the worst cancer that one can have – although I know that every cancer patient feels the same way about their cancer.”

“I was shocked to learn how fatal pancreas cancer is,” says Tom Klein, a San Francisco resident and proprietor of Rodney Strong Vineyards. He also wanted to do something to change the fate of those with pancreas cancer. “A cancer diagnosis is never good news, but for other cancers, there are more ways to fight the disease,” he says. “We just want to move the ball forward – to help give families ways to fight harder and pancreas cancer patients better chances to survive.”

After being introduced to UCSF developmental biologist Matthias Hebrok, PhD, and hearing about his research studies, Diane Klein knew she had found someone whose work the family would be pleased to support. Hebrok studies specific molecules that communicate signals within the developing embryo. The signaling that Hebrok is focus-ing on guides the formation of a functioning pancreas.

These signals appear to be abnormally activated in pancreas cancer. Hebrok is explor-ing whether the signals can be interfered with or otherwise manipulated to prevent the growth of pancreas tumors.

Knowledge gleaned from basic biological investigations, including Hebrok’s, often has broad implications. Hebrok’s research is relevant not only for pancreas cancer, but also for type 1 diabetes, in which beta cells of the pancreas are lost. Hebrok is manipulating the same signals in an effort to generate insulin-producing cells to treat type 1 diabetes.

“I hope the research will help others diagnosed with this deadly cancer, as well as those – like my son – who are diagnosed with type 1 diabetes,” Diane Klein says.

W

Rombauer Vineyards is once again hosting the Joy of Wine Fundraiser. The 2007 event was a big success, with more than $100,000 raised for the UCSF Rombauer Cancer Research Fund for Pancreas Cancer and for Hospice of Napa Valley. The next event will be held on July 26, 2008. For more information, contact Sheana Rombauer at 800/622-2206.

Rombauer Vineyards

The Richard G. Klein Research Fund

7

how to help

UCSF Helen Diller Family Comprehensive Cancer CenterUniversity of California San FranciscoBox 0248San Francisco, CA 94143

Pancreas Cancer News Volume 3, Number 1 May 2008

Pancreas Cancer News is published by the Pancreas Cancer Program at the University of California, San Francisco

Co-Leaders: Margaret Tempero, MD Martin McMahon, PhD

Writer/Editor: Jeffrey Norris Designer: UCSF Public Affairs Photography: Grace Kim, cover; Kaz Tsuruta, cover; Chris T. Anderson, p. 2; Majed, p. 3; Roy Kaltschmidt, p. 4; Elisabeth Fall, p. 5; Susan Merrell, p. 6

Cover Photo: The image shows cells growing abnormally within an intralobular duct of the pancreas – an early stage in the development of pancreas cancer.

© 2008 The Regents of the University of California

Produced by University Publications/Public Affairs, PR710

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

Nonprofit Org.

US Postage

P A I D

San Francisco, CA

Permit No. 8285

(continued from p. 1)­­

working with experimental geneticist Allan Balmain, PhD, to identify more gene variants that affect risk. (See page 2.)

UCSF scientists are working toward a future in which early pancreas cancer detection may be achieved by tracking certain genes – or, more likely, the proteins produced from these genetic blueprints. Leading cancer biologist Thea Tlsty, PhD, has teamed with talented young postdoctoral fellow Kim McDermott, PhD (see page 5), and pathologist Grace Kim, MD, to identify proteins that may be shed by abnormally growing pancreas tissue into the bloodstream, before tumors are visible.

With support from the National Institutes of Health and from donors, we have made new strides, and have officially incorporated the Pancreas Cancer Program as part of the UCSF Helen Diller Family Comprehensive Cancer Center. With additional support, we aim to bring the Pancreas Cancer Program to the next level.

pancreas cancer news