Pancreas Center FROM THE DIRECTOR Team Science One set of facts remains stark. Each year, 94 percent of the nearly 44,000 Americans who receive a diagnosis of pancreatic cancer will die from the disease within five years. We still lack reliable early detection or effective treatment – and pancreatic cancer remains on track to become the country’s second leading cancer killer, perhaps by as early as next year. Yet other facts give us reason for hope. More patients are living longer. Some novel treatments are showing promise. Our understanding of how the disease develops is growing fast. Perhaps our most powerful weapon for leveraging these developments is something called “team science.” It may sound like a description of a high school competition, but the concept reflects a mature realization that creative collaborations are our best hope for accelerating and refining our research efforts. At the UCSF Pancreas Center, the concept has already catalyzed some exciting projects and made clear, once again, the extraordinary value of a center like ours. Our independent fundraising can garner the powerful support of generous donors like Frank Stein, Paul S. May, and Stu Rickerson. Our organizational infrastructure enables the hiring of someone like Julie Sudduth- Klinger, who expertly manages Continued on next page Margaret Tempero News SPRING/SUMMER 2014 Continued inside Hard on the Trail of New Therapies O ncologists W. Michael Korn, MD, and Andrew Ko, MD, are driven to transform a rapidly expanding knowledge base about how pancreatic cancer develops into new treatment strategies for the devastating disease. Their research program focuses on combination therapy strategies that target signaling pathways important in the survival and growth of cancer cells. These include two pathways – MAPK and PI3K – located downstream of KRAS, an oncogene mutated in the majority of pancreatic cancers. While a number of drugs in development target either MAPK or PI3K, to date these drugs have demonstrated limited effectiveness in pancreatic cancer clinical trials. Anxious to understand why, Korn – who shares patients with Ko, but is the basic scientist in the partnership – used high throughput technology and complex methodologies to measure key indicators and detect patterns in cancer cells before and after treatment. The work led to the discovery that inhibiting the MAPK pathway sparked activation of the PI3K pathway through a feedback loop mediated by epidermal growth factor (EGF) receptors on a cell’s surface. “Our theory was that if we could block these receptors while simulta- neously inhibiting MAPK, we would cut off the ‘escape route’ and see enhanced therapeutic value with manageable toxicity,” says Korn. First, in experimental models and then in a clinical trial for patients with advanced pancreatic cancer, Korn and Ko saw promising results. “Unfortunately, only a subset of patients in the trial derived significant benefit,” says Ko, who is the partnership’s clinical trial expert. Recognizing that different molecular subtypes of pancreatic cancers may respond differently to therapy – and that several of the subtypes may live side by side in the same tumor – drove Korn back to the lab to try to identify the subtypes most likely to achieve the best response. The next steps will be to refine the combination therapies so they effectively target the most promising subtypes – and to Andrew Ko (left) and Michael Korn
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Pancreas CenterFROM THE DIRECTOR
Team ScienceOne set of facts remains stark.
Each year, 94 percent of the nearly 44,000 Americans who receive a diagnosis of pancreatic cancer will die from the disease within five years. We still lack
reliable early detection or effective treatment – and pancreatic cancer remains on track to become the country’s second leading cancer killer, perhaps by as early as next year.
Yet other facts give us reason for hope. More patients are living longer.
Some novel treatments are showing promise. Our understanding of how the disease develops is growing fast.
Perhaps our most powerful weapon for leveraging these developments is something called “team science.” It may sound like a description of a high school competition, but the concept reflects a mature realization that creative collaborations are our best hope for accelerating and refining our research efforts. At the UCSF Pancreas Center, the concept has already catalyzed some exciting projects and made clear, once again, the extraordinary value of a center like ours.
Our independent fundraising can garner the powerful support of generous donors like Frank Stein, Paul S. May, and Stu Rickerson. Our organizational infrastructure enables the hiring of someone like Julie Sudduth-Klinger, who expertly manages
Continued on next page
Margaret Tempero
News
SPRING/SUMMER 2014
Continued inside
Hard on the Trail of New Therapies
Oncologists W. Michael Korn, MD, and Andrew Ko, MD, are driven to transform a rapidly expanding
knowledge base about how pancreatic cancer develops into new treatment strategies for the devastating disease.
Their research program focuses on combination therapy strategies that target signaling pathways important in the survival and growth of cancer cells. These include two pathways – MAPK and PI3K – located downstream of KRAS, an oncogene mutated in the majority of pancreatic cancers. While a number of drugs in development target either MAPK or PI3K, to date these drugs have demonstrated limited effectiveness in pancreatic cancer clinical trials.
Anxious to understand why, Korn – who shares patients with Ko, but is the basic scientist in the partnership – used high throughput technology and complex methodologies to measure key indicators and detect patterns in cancer cells before and after treatment. The work led to the discovery that inhibiting the MAPK pathway sparked activation of the PI3K pathway
through a feedback loop mediated by epidermal growth factor (EGF) receptors on a cell’s surface.
“Our theory was that if we could block these receptors while simulta-neously inhibiting MAPK, we would cut off the ‘escape route’ and see enhanced therapeutic value with manageable toxicity,” says Korn. First, in experimental models and then in a clinical trial for patients with advanced pancreatic cancer, Korn and Ko saw promising results.
“Unfortunately, only a subset of patients in the trial derived significant benefit,” says Ko, who is the partnership’s clinical trial expert.
Recognizing that different molecular subtypes of pancreatic cancers may respond differently to therapy – and that several of the subtypes may live side by side in the same tumor – drove Korn back to the lab to try to identify the subtypes most likely to achieve the best response. The next steps will be to refine the combination therapies so they effectively target the most promising subtypes – and to
Andrew Ko (left) and Michael Korn
the application and implementation of clinical trials, so our scientists and clinicians can spend more of their time on what they do best.
And we can bring together a brilliant and driven group of people who truly understand the promise of combining their individual efforts. It is inspiring to see Michael Korn and Andrew Ko creating combination therapies to address something they found in the disease-treatment-resistance cycle; and Emily Bergsland and Michael German transforming a discovery about the growth of pancreatic neuroendocrine tumors into individualized therapy they hope will reverse those tumors; and Charles Craik and Kimberly Kirkwood devising an innovative technique for early detection.
Moreover, we can leverage this remarkable work by collaborating with colleagues across the country as we’ve done with our recently accepted “Dream Team” project, which will use a grant from the Stand Up to Cancer initiative to harness the immune system to promote tumor control and transform pancreatic ductal adenocarcinoma into a manageable disease.
In short, we believe team science has us on the verge of some exciting, if not miraculous, advances – and we are anxious to push the edges of the envelope, because all of this work begins with our clear understanding of the urgent need. We see patients every day. We know them. We know their families.
And we know it’s up to us to find some answers.
Sincerely,
Margaret Tempero, MDDirector, UCSF Pancreas CenterThe Rombauer Family Distinguished Professor in Pancreas Cancer Clinical and Translational Science
FROM THE DIRECTORContinued from front page
Find out more about the “Dream Team” at tiny.ucsf.edu/dreamteam – or scan this QR code with your smart phone.
When a loved one receives a pancreatic cancer diagnosis, the UCSF Pancreas Center can be an oasis of hope. One reason: it offers not just world-class expertise, but access to innovative clinical trials.
Making those trials available demands someone who can shepherd a brilliant idea through a maze of logistical, regulatory, and budget hurdles. Absent project management expertise, trials are delayed or never make it off the laboratory whiteboard.
In the case of pancreatic cancer, such expertise has never been more important. “Novel, investigative drugs are emerging with greater frequency. Patients are surviving longer with a better quality of life and that’s why it’s
incumbent on us to open more trials, more quickly,” says Julie Sudduth-Klinger, the clinical trial protocol project manager for the gastrointestinal and pancreatic cancer trials at the UCSF Helen Diller Family Comprehensive Cancer Center.
A scientist herself, Sudduth-Klinger began her career at UCSF, in viral immunology. In the heady, early days of the biotech industry, she shifted to Chiron to work first on HIV vaccines and then as a project manager for the development of targeted cancer therapies. After two decades learning the ins and outs of clinical research, she returned to UCSF in February 2012.
“I was interested in gastrointestinal oncology, because of my work at Chiron and because when my father was diagnosed with colon cancer, I took him to Dr. [Alan] Venook,” she says. Venook also cared for Sudduth-Klinger’s best friend, who had metastatic colorectal cancer and lived many years beyond the average for people with that disease. “I have a profound emotional and biomedical respect
for the doctors at UCSF that’s only been strengthened over time. They are so dedicated to our patients, so emotionally involved.”
That emotional attachment drives an institution-wide effort to speed clinical trial development, which typically can take six months to a year from the time an investigator has an idea. In addition to needing to secure grants, write protocols, enlist collaborators, and create budgets, proposals must undergo review by a variety of bodies both within and outside UCSF. Review boards vet everything from scientific integrity and medical need to patient safety and feasibility.
Once a trial is open, keeping it running smoothly and reducing costs and time spent for patients present new challenges. Sudduth-Klinger might spend one day seeking ways to minimize patients’ long drives to UCSF, another making sure procedures fit what insurers consider standard of care so patients don’t have to pay out of pocket.
Despite the challenges, Sudduth-Klinger is bent on accelerating the process. She’s driven, she says, by the very real needs of very real people.
clinical careA Passion for Bringing New Clinical Trials to Patients
“I want to push, push and do the little I can to help. I want to get studies open so we create more options for patients.”– Julie Sudduth-Klinger
individualized therapy
Pancreatic neuroendocrine tumors (PNETs) comprise a rare form of pancreatic cancer that is
notoriously hard to treat. “Treatment has only been individualized to the extent we choose therapies based on rate of growth and extent of the tumor – and current targeted agents can delay progression, but eventually, all tumors become resistant to therapy,” says oncologist Emily Bergsland, MD.
So when a recent study identified the most commonly mutated genes in PNETs – which it turns out are distinct from those in the more common pancreatic ductal adenocarcinoma – Bergsland says a door opened to potentially more effective, individualized therapy based on the molecular features of the tumor.
In particular, researchers now know mutations in the multiple endocrine neoplasia 1(MEN1) gene – which encodes the tumor suppressing protein called menin – not only clearly correlate with the inherited form of PNET, but that MEN1 is also the most commonly mutated gene in patients with nonhereditary PNET, with mutations documented in 44 percent of those cases.
“We’re hopeful that if we can better understand the role of MEN1 in
Opportunities Emerge to Individualize PNET Treatment
Emily Bergsland
Michael German
PNET progression and target that role therapeutically, we can create a new, tailored therapy for close to half of all patients with PNETs,” says Bergsland.
Such a therapy could emerge from her long clinical and research relationship with cell biologist and
endocrinologist Michael German, MD, whose lab explores the growth and production of beta cells in the endocrine cells of the pancreas. While pursuing that work, German discovered unique information about how growth changes when endocrine cells form tumors – a surprising discovery that had direct application to PNETs.
“While menin normally functions to inhibit cell division in menin-dependent neuroendocrine cells…the loss of MEN1 function results in unrestrained cell growth,” he says. Moreover, these now cancerous cells become extremely dependent on the MAPK signaling pathway – which meant they died when German’s lab blocked the signaling.
“That was the point when we contacted Emily and started working on applying this information to PNETs,” he says.
The pair’s working hypothesis is that optimal treatment for tumors associated with the MEN1 mutation will arise from a targeted MAPK pathway inhibition. Bergsland and German will test the hypothesis in mouse models, with the hope they can move quickly to a Phase 2 clinical trial in humans.
“This is a relatively rare disease and it’s not possible to test all drugs in all combinations in the clinic,” says Bergsland. “That’s why it’s so important for people to come together with different areas of expertise.” Combining German’s pre-clinical models, which can be used to identify new targets and predict mechanisms of action, with Bergsland’s clinical research program can optimize the chances of success in the clinic.
“We are hopeful that this is an important step toward more precise, individualized therapies for patients with pancreatic neuroendocrine tumors.” – Emily Bergsland
NEW THERAPIES Continued from front page
Seeking the Answer to Early Diagnosis
Charles Craik, PhD, and Kimberly Kirkwood, MD, believe their chance meeting two years ago
could be the type of happy coincidence that catalyzes years of hard work into a substantial leap forward for early diagnosis of pancreatic cancer.
As a cancer surgeon, Kirkwood constantly faces difficult decisions about whether or not to remove patients’ pancreatic cysts. The cysts are common and some will develop into pancreatic cancer, but there is no definitive way to distinguish between those that are benign and those that are malignant.
“Current guidelines depend on consensus criteria that use size and cyst appearance on imaging. Unfortunately, these criteria fail to provide accurate prognostic information,” says Kirkwood. Sometimes surgeons aspirate the cysts and test the fluid for precancerous activity, but even these tests only correctly predict one in three cancers, resulting in too many missed cancers as well as unnecessary surgeries.
Kirkwood and her colleagues know that the malignant cysts – called mucinous neoplasms – contain active proteases, which are a family of enzymes that play an important role in many biological processes, and which normally the body knows how
to turn on and off. In cancer, however, the proteases become unregulated. Kirkwood had spent years struggling to identify markers of those active proteases, believing that doing so might make it possible to detect cancer before conventional imaging can reveal a mass.
Then, two years ago, one of Kirkwood’s residents attended a talk by Anthony O’Donoghue from Craik’s lab and told Kirkwood: “You have to hear these guys.”
explore ways to manipulate subtypes less sensitive to the treatment in such a way that they become responsive.
“As cancer doctors, we build this work in a patient-centric way,” says Korn. “When we talk about trial design, we are constantly thinking about things like: Where in the treatment sequence would a new drug combination fit best? Which biopsies should we do and when should we do them?”
“One of the challenges is patient selection,” says Ko. “Who is most likely to benefit from a particular treatment strategy and who should we avoid treating with a certain drug or drug combination because it could potentially be ineffective or even toxic? Of course, we hope not to deprive anyone, unless we’re convinced there’s a complete lack of benefit because, for us, this is always about helping as many patients as possible.”
Image at right: Gene expression profiles identify cells sensitive to new combination therapy.
“The paper Anthony presented showed that we had a technology that could monitor the activity of multiple proteases in a complex biological sample,” says Craik. “We had a hammer; we were looking for a nail.” The pancreas, which is full of proteases whose activity changes as disease progresses, fit the bill.
Using cyst fluid samples that clinicians routinely aspirate during the evaluation of Kirkwood’s patients, preliminary work indicates that Craik’s tool can use protease activity as a biomarker to effectively distinguish between benign and aggressive cysts. If the preliminary findings are validated, surgeons and oncologists would have a tool to match the right therapy to the right patient at the right time.
“There is the potential to detect cysts destined to become cancers one step before they become malignant; at this stage, they can nearly always be cured,” says Kirkwood.
Craik and Kirkwood have also developed a novel, non-invasive approach to identifying the protease activity that could avoid the need to do fine needle aspiration. “It could have a transformative effect on the diagnosis, prognosis, and treatment of pancreatic cancer,” says Craik. They hope someday the work could lead to a simple blood test for early detection.
cyst sleuths
Charles Craik
“Ours is the perfect storm of UCSF collaboration. Together we achieve a synergy you really can’t find if you’re only working with the folks you usually rub elbows with.”– Kimberly Kirkwood
Creating Opportunities to Honor Patient Care Staff
Beating the odds by surviving pancreatic cancer – at six percent it’s the only major cancer in America with a five- year survival rate in single digits – Stuart Rickerson has
become a powerful advocate for the UCSF Pancreas Center. In addition to giving generously, Stuart has appeared with the Center’s director, Margaret Tempero, MD, on billboards and in a moving video about why he and his wife, Nancy, chose UCSF for his treatment despite living in San Diego, 500 miles away.
The see their latest gift – a five-year $100,000 pledge to support education, professional development, and training for the Pancreas Center’s nurses and other clinical staff – as a way to show their enormous gratitude for the exceptional care they received from the Center’s dedicated staff. It will establish The Rickerson Family Endowment for UCSF Pancreas Center Patient Care Support.
Stuart Rickerson needed to fly up to San Francisco weekly for his chemotherapy and with the couple’s six-year-old daughter at home, Nancy couldn’t travel with him after the first trip. She took comfort in knowing who was caring for him. “Dr. Tempero is the most amazing person. We appreciate her so much. But we also developed a very strong relationship with the nurses and all of the clinical staff. I always knew Stu was in great hands.”
“Everybody – the receptionist, the people who helped with insurance billing, the infusion clinicians, the nurses – was so warm and embracing that it made this difficult period more tolerable,” agrees Stuart Rickerson. “With this gift, nine years after that first trip to UCSF, Nancy and I hope to encourage others who share in our sentiments, to partner with us and grow support for the Center’s amazing, compassionate, and caring staff.”
Frank Stein and his partner Paul S. May met as young men in New York, while beginning careers in a well-known department store. Those careers
quickly grew to major leadership positions until, after years of hard work, they decided to strike out on their own in the hotel and motel supply business.
“Many people in similar positions thought we were out of our minds,” says Stein.
They moved to San Francisco and began by selling up and down the west coast from the backs of their cars. The business became successful beyond their wildest expectations, while the extremely devoted couple worked together, lived together, and spent nearly all of their time together.
Tragedy, however, tempered the joy of those years, when both Stein’s mother and sister developed pancreatic cancer. “They suffered so,” says Stein. “And Paul had pancreatic cancer in his family as well.”
Philanthropy seemed like a way to help others avert some of that pain. “We realized life had been good to us, so we decided to do whatever we could for charity,” says Stein. Their generous gifts have gone to many organizations, including the UCSF Pancreas Center. In addition to making a major gift to the Center in 2006, they also committed to including the Center in their individual estate plans.
Then, on September 12, 2013, after a long illness, Paul May passed away. “He was in the hospital five-and-a-half months, and I was there every day,” says Stein.
May’s bequest and Stein’s pledged bequest generously support the Paul S. May and Frank Stein Pancreatic Cancer Fund and will be used primarily for research into cancer of the pancreas and liver.
Stein’s sadness and sense of loss following his partner’s death is palpable but, perhaps, he can take comfort in knowing that the generosity nurtured by their remarkable relationship continues to advance the fight against this terrible disease.
Lifelong Love Nurtures Business Success and Generous Support
donor snapshots
Stuart and Nancy Rickerson (above) have generously offered to match other gifts to The Rickerson Family Fund dollar for dollar. For more information, please contact Kathleen Jose at [email protected] or 415/476-5863.
Many thanks to our fundraisers for their time, support, and dedication!
To support the UCSF Pancreas Center, please contact Kathleen Jose at [email protected] or 415/476-5863.
Walk 4 Pancreatic CancerFor the past five years, Arlene Mariani has organized the Walk 4 Pancreatic Cancer around the beautiful Santa Clara University campus. The 5k walk/run event has helped raise more than $100,000 for pancreatic cancer research at UCSF. Thank you to Arlene (now enjoying a well-deserved retirement), the Mariani family, Santa Clara University, and everyone who took part in the events.
Bocce Ball TournamentThanks to sponsor Steve Hearst and all the supporters of John Legnitto’s Bocce Ball Tournament Fundraiser 4 Pancreatic Cancer Research last November. The event raised nearly $25,000 to benefit the UCSF Pancreas Center.
It is with immense sadness we learned that John Legnitto passed away on April 26, 2014. Our thoughts and sympathy go out to his family and friends.
Don Ritchie 5K Run/WalkOrganized by Jane Ritchie and Dave Ripp, the Memorial Day 5K run/walk at College of Marin in Kentfield is held in memory of Jane’s husband, Don, who died of pancreatic cancer in 2009. Thanks to Jane, Dave and all the people who take part in this event, which supports pancreatic cancer research at UCSF. For more information, go to www.marinraces.com.At left: Don Ritchie’s granddaughter, 2013
Titan’s Cage and the Correa FamilyAppreciation also to Titan’s Cage and the Correa family who have raised over $5,000 for the UCSF Pancreas Center at Mixed Martial Arts events throughout Northern California. Zeny Correa lost her mother, Cora Claro, to pancreatic cancer in 2013; her family is dedicated to increasing awareness and raising funds to fight this devastating disease.Above: Margaret Tempero with Zeny, Kiana and Shawn Correa
