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CANCER CENTER

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CANCER RESEARCH AT SANFORD-BURNHAM Sanford-Burnham is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes.

National Cancer Institute-designated basic research cancer center since 1981.

$89,505,375

500+

scientists working in highly collaborative and interactive programs

59

full-time faculty members

in grant funding

20

4

shared scientific core facilities

research programs addressing different aspects of cancer: Tumor Development, Signal Transduction, Tumor Microenvironment, Apoptosis and Cell Death

300+

publications per year

13

adjunct faculty members

CANCER CENTER LEADERSHIP Kristiina Vuori, M.D., Ph.D.

PRESIDENT, SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE PROFESSOR AND DIRECTOR, CANCER CENTER PAULINE AND STANLEY FOSTER PRESIDENTIAL CHAIR JEANNE AND GARY HERBERGER LEADERSHIP CHAIR IN CANCER RESEARCH

Ze’ev Ronai, Ph.D.

Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla), California, and Orlando (Lake Nona), Florida.

ASSOCIATE DIRECTOR, CANCER CENTER PROFESSOR AND PROGRAM DIRECTOR, SIGNAL TRANSDUCTION

Craig Hauser, Ph.D.

VICE PRESIDENT FOR SCIENTIFIC RESOURCES ASSOCIATE DIRECTOR FOR SHARED RESOURCES, CANCER CENTER ADJUNCT ASSOCIATE PROFESSOR

Sara Courtneidge, Ph.D.

PROFESSOR AND PROGRAM DIRECTOR, TUMOR MICROENVIRONMENT DIRECTOR, ACADEMIC AFFAIRS

Robert Wechsler-Reya, Ph.D.

PROFESSOR AND PROGRAM DIRECTOR, TUMOR DEVELOPMENT

Guy Salvesen, Ph.D.

PROFESSOR AND PROGRAM DIRECTOR, APOPTOSIS AND CELL DEATH RESEARCH DEAN, GRADUATE SCHOOL OF BIOMEDICAL SCIENCES

sanfordburnham.org

Eveline Hernandez, M.B.A.

ASSOCIATE DIRECTOR, CANCER CENTER ADMINISTRATION

LETTER FROM THE DIRECTOR

bacterial and viral toxins has revealed new strategies to engineer those same toxins to selectively kill cancer cells. Understanding how cancer cells become resistant to chemo- and radiotherapies has provided new insights into protecting brain and heart cells from stroke and heart attack. Deciphering the mechanisms that cause uncontrolled cell growth in cancer has informed our thinking about neurodegeneration and the propagation of stem cells. Sanford-Burnham’s cancer research is motivated by the quest to discover new cancer-fighting tools. We take great pride in the fact that research in Sanford-Burnham’s Cancer Center is yielding tangible medical benefits, including diagnostic procedures and FDA-approved therapeutic agents. These efforts are supported in large part by cutting-edge technologies in our core facilities—shared resources such as cellular imaging and proteomics, which are available to all Sanford-Burnham researchers and to the entire scientific community. What’s more, robotic high-throughput drug screening platforms in Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics—technology rarely found outside large pharmaceutical companies—give our researchers the opportunity to rapidly move their laboratory discoveries into a sophisticated search for chemical compounds that could become the cancer drugs of tomorrow. Over the next decade, these resources will help us accelerate our work towards targeted cancer therapies that destroy or inhibit cancer cells while leaving healthy tissues untouched, and develop more personalized treatments aimed at molecular underpinnings in an individual patient’s tumor. This publication is intended to introduce you to our cancer research, highlight the progress we have made on the path to cancer cures, and give a glimpse of new directions we will be pursuing over the next few years as we realize our motto, From Research, the Power to Cure.

“We take great pride in the fact that research in Sanford-Burnham’s Cancer Center is yielding tangible medical benefits, including diagnostic procedures and FDA-approved therapeutic agents.” Sanford-Burnham Medical Research Institute is dedicated to finding new ways to fight cancer. Since our founding in 1976 as the La Jolla Cancer Research Foundation, our research has been guided by the belief that the most substantial breakthroughs come from studying the basic mechanisms of cells and the molecules that comprise them. In 1981, the National Cancer Institute (NCI) awarded us with a Cancer Center Support Grant. Today, we are one of just seven NCI-designated basic research cancer centers in the nation. We believe collaboration is the catalyst for success. Our researchers work together—merging the talents of biologists with those of physicians, chemists, biophysicists, engineers, and other scientists—to tackle the great unmet medical challenges of today. We have made great scientific advances by combining our cancer focus with our expertise in other areas. Removing the walls between disciplines encourages innovation. Studying

Kristiina Vuori, M.D., Ph.D.

President, Sanford-Burnham Medical Research Institute Professor and Director, Cancer Center Pauline and Stanley Foster Presidential Chair Jeanne and Gary Herberger Leadership Chair in Cancer Research

Learn more about Sanford-Burnham’s NCI-designated Cancer Center at sanfordburnham.org/CancerCenter 1

FROM RESEARCH, TH CANCER CENTER PROGRAMS

Dr. Robert Wechsler-Reya Professor and Director, Tumor Development Program

Dr. Ze’ev Ronai Professor and Director, Signal Transduction Program

SOMETHING GOES WRONG IN A CELL

CANCER CELL GROWTH SPINS OUT OF CONTROL

Dr. Sara Courtneidge, Professor and Director, Tumor Microenvironment Program

Dr. Guy Salvesen, Professor and Director, Apoptosis and Cell Death Research Program

TUMORS INVADE AND METASTASIZE

CANCER CELLS REFUSE TO DIE

Scientists in the Tumor Development Program are working to better understand the molecular mechanisms that control proliferation, differentiation, and survival during normal human development and how tumors form when these processes malfunction. They’re also using this information to develop more effective cancer therapies.

Many health problems arise from malfunctioning signal transduction processes in particular cells or tissues. The Signal Transduction Program focuses on research questions related to the control of cell cycle progression, cell proliferation, DNA damage checkpoint function, stress response pathways, and cellular senescence.

Research in the Tumor Microenvironment Program aims to understand the molecular basis of cell-to-cell interactions, cell adhesion and cell migration, how these processes are controlled in normal physiology, how this control is subverted in disease, and how to restore normal control with chemical or biological inhibitors.

Scientists in the Apoptosis and Cell Death Research Program investigate the molecular mechanisms that control cell death and survival. Cell death is a natural process that regulates the number of cells in an organism. Disruptions in normal cell death contribute to the cell accumulation seen in tumors. 2

HE POWER TO CURE Sanford-Burnham researchers are working to uncover the fundamental mechanisms of cancer—at the molecular and cellular levels—to lay the foundation for next-generation diagnostics and therapeutics. Our cutting-edge drug discovery technology (page 9) and collaborative approach help deliver the most efficient and targeted treatments possible.

DRUG DISCOVERY PIPELINE Fundamental discoveries by our scientists have contributed to the basis of a number of anti-cancer detection and treatment strategies that are either FDA-approved or currently being tested in clinical trials. Here are a few examples: Agent

Aimed at

Phase I Phase II Phase III

Targretin®

cutaneous T-cell lymphoma

Epogen®

anemia caused by chemotherapy in people with certain types of cancer

Genasense®

advanced melanoma, leukemia, lymphoma, non-small cell lung cancer

Cilengitide

glioblastoma

NGR-hTNF

malignant pleural mesothelioma

Gossypol

leukemia, lymphoma, prostate, non-small cell lung cancer, B-cell malignancies, small cell lung cancer, glioma, esophageal cancer

Birinapant

solid tumors

ABT-263

lymphoma, leukemia, small cell lung cancer

PX-866

colorectal cancer, squamous cell cancer, glioblastoma, solid tumors, prostate cancer

GC-1008

renal cell carcinoma, malignant melanoma, malignant pleural mesothelioma

Retinoid X receptor agonist Epoetin alfa injection

Bcl-2 antisense

Integrin inhibitor av 3, av 5 Targeted TNF

Pan-Bcl-2 inhibitor IAP antagonist Bcl-2 inhibitor

PI-3K inhibitor TGF- 2 inhibitor

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FDA-approved

RESEARCH HIGHLIGHTS

In Sanford-Burnham’s NCI-designated Cancer Center, more than 500 scientists, including more than 70 full-time and adjunct faculty members, are working to pre-empt cancer before it develops, detect the disease at its earliest point, and eliminate its spread. Here are examples of current research from each of the Center’s four programs.

TUMOR DEVELOPMENT PROGRAM Targeting Childhood Brain Cancer

Dr. Robert Wechsler-Reya Professor and Program Director

Cerebellar Stem Cells

Dr. Robert Wechsler-Reya’s group studies the relationship between normal human development and cancer. They’re interested in how normal stem cells make decisions like when to divide, when to specialize into other cell types, and what tissues to become. They’re also interested in how those decisions go wrong in cancer. The Wechsler-Reya lab was the first to identify a new type of stem cell that, when functioning normally, develops into many different cell types in the cerebellum. But if this cell acquires certain mutations, it can also give rise to medulloblastoma, the most common malignant brain cancer in children. While medulloblastomas are often treatable with surgery, radiation, and chemotherapy, these treatments can also dramatically reduce cognitive function and overall quality of life. Dr. Wechsler-Reya’s team is now trying to understand what is driving the growth of the tumor so they can inhibit it in a much more specific way than radiation. To do this, they are creating stem cell-based models of medulloblastoma that can be used to test new drugs that target the disease. Over the next few years, they hope to use this information to develop more effective therapies for children suffering from medulloblastoma.

Converting Tumors into Benign Tissue What if the best way to stop a tumor is not to kill it, but to turn it into something else? That’s the idea behind differentiation therapy, a novel concept that targets cancer stem cells. Dr. Robert Oshima, in collaboration with Dr. Masanobu Komatsu and others, led a study that provides strong evidence in favor of differentiation therapy. In the study, an aggressive mouse model of breast cancer was treated with bosutinib (SKI-606), a drug currently being developed to treat advanced malignant tumors. As expected, the drug prevented the appearance of tumors in more than half of the treated mice and reduced tumor growth in older animals with preexisting tumors. However, the surprise came from how these tumors were diminished. Bosutinib treatment was successful not because it directly killed cancer cells, but because it induced their differentiation into normal, functioning tissue not seen in the untreated mice. Differentiation therapy is an attractive alternative to chemotherapy and radiation, which kill any cell whether cancerous or not. Dr. Oshima and his team are now searching for other drugs that might induce cancer stem cell differentiation in order to stop tumors at their earliest stages.

Dr. Robert Oshima Professor

Visit our blog to read more about these studies and many others: beaker.sanfordburnham.org 4

RESEARCH HIGHLIGHTS

SIGNAL TRANSDUCTION PROGRAM Rooting Out Melanoma

Dr. Ze’ev Ronai Professor and Program Director

Over the past two decades, Dr. Ze’ev Ronai’s laboratory has studied protein kinases such as JNK, AKT, and PDK1. These enzymes are important components of pathways that are commonly deregulated in melanoma and therefore serve as potential targets for new treatments. Dr. Ronai’s team also studies a protein called Activating Transcription Factor 2 (ATF2), which is associated with poor prognosis in melanoma. ATF2 can regulate a vast array of genes important for cellular function. The Ronai laboratory identified a protein kinase named PKC as the component that makes ATF2 oncogenic (cancer-causing) in melanoma. In normal tissues, PKC is not as active and allows ATF2 to protect against tumor formation. Using this information, Dr. Ronai’s team, in collaboration with Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics (page 9), is searching for small molecules that would confer the antioncogenic function of ATF2, thereby resuming ATF2’s ability to protect from tumor development. This approach could offer new therapeutic options for melanoma, and possibly other tumors where PKC promotes ATF2’s oncogenic function.

Sending Medicine Where it’s Needed Most For many years, Dr. Elena Pasquale has studied the interplay between Eph cell surface receptors and ephrin proteins. Eph receptors are like antennae protruding from the surface of a cell. They foster cell communication by binding to ephrin proteins on the surfaces of neighboring cells. Eph receptors also appear more often in cancer cells than normal ones. Dr. Pasquale is now exploiting her deep knowledge of Eph/ ephrin interactions to create peptides that attach selectively to Eph. Collaborator Dr. Maurizio Pellecchia has developed methods to combine one of these compounds with chemotherapeutic agents—creating a guided missile with a potent anti-cancer payload. Other investigators have attached imaging agents to another Ephtargeting peptide developed by Dr. Pasquale and successfully

Dr. Ze’ev Ronai Professor and Director, Signal Transduction Program

Dr. Elena Pasquale Professor

imaged tumors in mice. These approaches might give physicians the ability to use MRI or PET scans for early tumor detection or to locate a peptide-attached drug in the body, ensuring that it’s

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congregating in the tumor. New approaches like this will one day send chemotherapy treatments directly to the cancer, making them more effective while greatly reducing side effects.

RESEARCH HIGHLIGHTS

TUMOR MICROENVIRONMENT PROGRAM

Dr. Jorge Moscat and Dr. Maria Diaz-Meco Professors

Dr. Minoru Fukuda Professor

Fueling Tumor Growth

Aiming for Cancer’s Sweet Spot

Drs. Jorge Moscat and Maria Diaz-Meco have been working together for more than 20 years to understand the mechanisms that allow cancer cells to grow so rapidly. Their investigations have led to a network of proteins that all have one thing in common—a region called the PB1 domain. These proteins control inflammation, how cells communicate with each other, and how they sense nutrients—all key drivers of cancer growth. For example, the PB1-containing protein p62 regulates an enzyme called PKCZ, which is often missing in human cancers. PKCZ is a tumor suppressor that prevents inflammation and ensures that cells remain sensitive to nutrient levels. Cells without PKCZ get reprogrammed to endure food scarcity. Dr. Moscat hopes that learning more about PKCZ, and other proteins regulated through PB1 domain interactions, will help him find new ways to fix these malfunctioning processes and slow tumor growth. Dr. Diaz-Meco is also trying to understand proteins regulated by PB1, particularly those missing in prostate cancer. She and her group are studying the tumor suppressors PTEN and Par-4, proteins that are commonly lost in prostate cancer.

Carbohydrates on a cell’s surface influence many cellular functions and their misplacement or malfunction can contribute to tumor development. Mucin-type O-glycans (core 3 O-glycans) are one type of carbohydrate that is found in abnormally low levels in cancer cells. Dr. Minoru Fukuda and his laboratory found that core 3 O-glycans suppress tumor formation and metastasis. When core 3 O-glycans are artificially expressed on human prostate cancer cell lines, these cells produce much smaller tumors and almost no metastasis. By contrast, the parent cancer cells, which do not express core 3 O-glycans, produce robust primary and metastatic tumors. Going a step further, Dr. Fukuda determined that the expression of core 3 O-glycans decreases formation of integrin complexes (receptors that mediate cell adhesion), therefore diminishing cancer cell migration. This study indicates that certain carbohydrates on normal cells, such as core 3 O-glycans, and enzymes that synthesize them, can function as tumor suppressors. Interventions that boost those key enzymes may become a novel way to treat cancer.

Visit our blog to read more about these studies and many others: beaker.sanfordburnham.org 6

RESEARCH HIGHLIGHTS

APOPTOSIS AND CELL DEATH RESEARCH PROGRAM

Dr. Stefan Riedl Associate Professor

Viewing Cancer Proteins in 3D When members of two protein families called Cas and NSP get together, they help a cell migrate or invade surrounding tissues— processes that can allow cancer

cells to metastasize. While biologists have made significant strides in understanding these proteins and their functions, questions remained about how the proteins actually get together to do the work they do. Structural biologist Dr. Stefan Riedl and his team answered several of the most perplexing questions about the 3D shape of NSP and Cas proteins and their interactions. They solved the costructure of one NSP-Cas pairing, the duo NSP3 and p130Cas, as well as the structure of another NSP by itself. This accomplishment revealed a big surprise about NSP protein function—it doesn’t actually do what scientists had long assumed it does. Sequence information showed that the “business-end”

of NSP proteins looks like an enzyme that helps turn cellular communication proteins on or off. However, Dr. Riedl’s 3D structures revealed that this function is impossible—the business end is folded over in a “closed” position. Instead, this closed position is what lets NSP carry out its true function—binding p130Cas. Structural studies like these help answer important biological questions—and reveal new targets for anti-cancer drug development.

NSP-p130Cas

Using Cancer’s Chemistry Scientists in Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics (page 9) screen hundreds of thousands of small molecule compounds against biological material to find a handful of hits— molecules that can alter a protein’s function and perhaps form the basis for new therapeutic drugs. But that’s only the beginning of the story. Medicinal chemists, like Dr. Nicholas Cosford and his group, take those molecules and improve, or optimize, them to bind target proteins tighter, improve their effectiveness, and reduce unwanted side effects. To accelerate molecular redesign, Dr. Cosford is pioneering a new technology called microfluidics, a multidisciplinary approach combining engineering, chemistry, and biology. Dr. Cosford is also collaborating with fellow Sanford-Burnham researchers by bringing an expert chemist’s viewpoint to highly relevant biological problems. These collaborations involve studies on GPCRs, a class of cellular proteins, as well as kinases and hydrolases, which are important enzymes involved in cellular signalling. These targets are the focus of current and future therapeutic efforts in cancer. Dr. Cosford and his team work to develop compounds with excellent drug-like properties that would merit further testing, possibly leading to preclinical and clinical evaluation. Their efforts could provide tools to understand essential details about cancer biology, and ultimately lead to new cancer treatments. 7

Dr. Nicholas Cosford Associate Professor

SHARED RESOURCES, SHARED SUCCESSES 20

From the start, Sanford-Burnham recognized that investigators would need the Institute’s help accessing state-of-the-art instrumentation and facilities that no individual lab could afford on its own. Today, Sanford-Burnham’s NCI Cancer Center Support Grant allows the Institute to purchase and maintain instrumentation and to subsidize the operation of 20 of the Institute’s 34 core facilities, each offering valuable technology, resources, and expertise. Most facilities also provide services to non-profit and for-profit investigators outside the Institute. Here are just a few examples.

Dr. Craig Hauser Associate Director, Shared Resources

Animal Resources

Cell Analysis and Histopathology

Structural Biology

Sanford-Burnham’s AAALACaccredited animal facility allows investigators to better understand the factors involved in cancer susceptibility, growth, and spread, and to test experimental treatments to defeat cancer.

In the cellular imaging facility, access to a wide variety of microscopes, including fluorescence and confocal systems and a transmission electron microscope, allows researchers to observe cancer on a cellular level.

The structural biology facility allows researchers to probe protein structures to better understand how their activities might help or hinder cancer and how they may be targeted by more specific cancer therapies.

Genomics

Proteomics

Bioinformatics

Experts in our genomics facilities can analyze the status of nearly every gene in a cell, helping investigators address the roles genes play in keeping cancer at bay and how those genes can malfunction.

Researchers use our proteomics facilities to measure which proteins are being expressed within cells. A protein that is overexpressed in a cancer cell may be a marker, allowing earlier diagnosis, or a target for a new treatment.

Our bioinformatics facilities help make sense of the vast amounts of data produced by highthroughput experiments, using sophisticated tools to better understand the biological and medical significance.

shared scientific core facilities

Access the full list at sanfordburnham.org/SharedResources 8

WHERE DO NEW MEDICINES COME FROM?

Far Left: Robotic arms in the Prebys Center help scientists search for chemical compounds that alter cellular behavior—compounds that could be precursors to new medicines. Top Right: Dr. Sara Courtneidge, Professor and Program Director Bottom Right: Cells with invadopodia, shown here as bright red spots (image by Begoña Díaz)

Spotlight on the

Conrad Prebys Center for Chemical Genomics

One of the first steps in discovering and developing a new cancer treatment involves screening small chemical compounds to determine how they affect cellular behavior. Scientists in Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics (Prebys Center)—another one of Sanford-Burnham’s valuable shared resources—use robotic technology to sift through chemical compounds by the millions to find the few that could potentially be developed into new medicines. Dr. Sara Courtneidge, professor and director of the Tumor Microenvironment Program, is working with Prebys Center staff to find compounds that might help put a stop to tumor metastasis, the most common reason that cancer treatments fail. To metastasize, some types of cancer cells rely on invadopodia, cellular projections that act like feet, helping them “walk” away from the primary tumor and invade surrounding tissues. To determine how cells control

invadopodia formation, Dr. Courtneidge and the team screened a collection of compounds to identify those that either promote or inhibit the process. Two major findings came out of their initial research. First, the screen revealed compounds that inhibit invadopodia formation without causing toxicity. Several of these invadopodia inhibitors targeted a family of enzymes called cyclin-dependent kinases (Cdks), revealing a previously unrecognized role for Cdks in invadopodia formation. Secondly, the search also turned up other compounds that increased the number of invadopodia. One of these pro-invadopodia compounds was the chemotherapeutic agent paclitaxel—a finding that might have implications for the drug’s current use in treating cancer. Using the Prebys Center’s chemical biology and drug discovery resources, this study suggests that identifying invadopodia regulators might also lead to new strategies for controlling cancer metastasis.

Visit the Conrad Prebys Center for Chemical Genomics at sanfordburnham.org/ScreeningCenter 9

THERAPIES TO WATCH iRGD: Making Cancer Treatments Better

Dr. Erkki Ruoslahti Distinguished Professor

One of the many challenges of creating effective cancer treatments is getting enough medicine to the tumor to kill it, without harming healthy tissues. To overcome this hurdle, Dr. Erkki Ruoslahti and colleagues Drs. Kazuki Sugahara and Tambet Teesalu developed a peptide (a short protein) called iRGD that helps co-administered drugs penetrate deeply into tumor tissue. The peptide improves treatment efficacy against human breast, prostate, and pancreatic cancers in mice, achieving the same therapeutic effect as a normal dose with one-third as much of the drug.

Dr. Ruoslahti and his team believe the results of this study may have far-reaching implications for drug delivery and cancer treatment. Because they can co-administer iRGD, there is no need to modify existing drugs, which means existing treatments can be mixed with the peptide and tested right away. The iRGD technology was licensed to biotechnology company CendR Therapeutics, Inc. The company secured NCI grant funding and is now working with collaborators at a major hospital to begin testing the peptide in humans.

Sabutoclax: Helping Tumors Die Sanford-Burnham partnered with biotechnology company Oncothyreon, Inc. to develop sabutoclax, a chemical discovered as a result of research in the laboratories of Dr. Maurizio Pellecchia and Dr. John Reed, into a potential new anti-cancer drug. Sabutoclax inhibits a family of proteins called Bcl-2, which helps cells avoid self-destructing in a process known as apoptosis. By tempering Bcl-2, sabutoclax shows great promise in blocking cancer cell growth. One or more members of the Bcl-2 family of proteins are over-produced in most human cancers. This overexpression prevents apoptosis, making cells resistant to many frequently used cancer treatments. By blocking Bcl-2 protein function, sabutoclax induces apoptosis in tumor

cells and increases the activity of chemotherapy. Sabutoclax inhibits all of the Bcl-2 protein family members, which may prove advantageous when compared with other compounds directed at these targets.

Dr. Maurizio Pellecchia Professor

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Bcl-2

Dr. John Reed Professor and CEO

PARTNERING FOR CURES

Collaborating with pharmaceutical and clinical partners helps Sanford-Burnham scientists translate their research into patient benefit—ensuring that promising early-stage discoveries don’t languish, but instead move into new treatments and innovations.

Clinical Collaborations Tackle Cancer from Every Angle Sanford-Burnham has partnered with several clinical medical centers, including Scripps Health, Cedars-Sinai, Sanford Health, Florida Hospital, and Moffitt Cancer Center. These joint translational medicine efforts combine the discovery research and laboratory science at Sanford-Burnham with clinical science and networks of physicians and patients at these partner hospitals. These collaborations—and hopefully more like them in the near future—will catalyze the discovery and development of innovative new therapies and diagnostics for cancer.

Standing up to Melanoma One in 51 people born today will be diagnosed with melanoma at some point in their lifetimes. To tackle this powerful threat, bi-coastal teams of Sanford-Burnham researchers are studying the root causes of melanoma and exploring personalized medicine—the idea that a person’s unique genetic makeup can impact his or her response to medical treatments. For example, Dr. Ze’ev Ronai studies cellular stress in the context of melanoma, work that has led to the discovery of several new targets for treating the disease (page 5). In addition, Dr. Ranjan Perera and his team are using advanced DNA sequencing technologies to study the genomes and epigenomes—chemical modifications that can alter the genome’s structure—of melanoma cells and normal skin cells. They hope this work will reveal molecular signatures that will allow them to divide melanoma into distinct subtypes. This re-classification might then allow physicians to personalize treatments to each specific subtype of melanoma, potentially improving outcomes for patients in the future.

As further evidence of Sanford-Burnham’s collaborative nature and dedication to melanoma research, Dr. Kristiina Vuori, Sanford-Burnham’s president and Cancer Center director, is part of a “Dream Team” working to find innovative new ways to fight melanoma. With funding from Stand Up To Cancer and the Melanoma Research Alliance, the multi-institute team is exploring a personalized medicine approach to treating metastatic melanoma—work that may also lay the groundwork for fighting many other tumor and disease types. Stand Up To Cancer is a program of the Entertainment Industry Foundation, a charitable organization that has raised more than $100 million for cancer research. The Dream Team—one of just six and the first to target melanoma—is led by researchers at the Translational Genomics Research Institute (Phoenix, Ariz.) and the Barbara Ann Karmanos Cancer Institute (Detroit, Mich.) and brings together members from several other U.S. research institutions.

Visit our blog to read more about Sanford-Burnham’s translational research and clinical collaborations: beaker.sanfordburnham.org 11

TRAINING THE NEXT GENERATION OF SCIENTISTS

Postdoctoral researchers and graduate students conduct the majority of the hands-on science at Sanford-Burnham. While faculty members illuminate the paths research should take, it’s usually the postdocs and students who implement that vision. In return for their labor and insights, these young scientists learn by doing and receive critical insights from senior investigators. The experience they acquire will guide their future research.

Meet a Young Scientist Meet Dr. Aman Mann, a postdoctoral researcher in Dr. Erkki Ruoslahti’s laboratory, co-chair of Sanford-Burnham’s postdoc and graduate student association, and Fishman Fund Award recipient. What inspired you to pursue cancer research? My passion for cancer research stems from the fact that there is so much suffering from this disease. The gratification from the fact that my work in the lab can potentially have a positive impact on cancer patients led me to pursue a career in translational cancer research. And my focus and persistence in what I do is constantly revitalized due to the ongoing battle that my own family has waged against this disease. What do you do? Our research group seeks to identify methods to improve drug delivery to tumor cells. In particular, my project is to identify Dr. Aman Mann and target a drug-resistant population made up of “tumor-initiating cells” Postdoctoral Researcher that play a key role in metastasis or tumor relapse. We believe that therapies that specifically target these cells, combined with the conventional therapies already being used in the clinic, will more effectively eliminate the tumor and reduce chances of relapse in breast cancer patients. What would you do if you had unlimited research funds? Recent cuts in funding have forced many researchers to give up on bold new ideas for curing cancer. With extra funding, I would focus on early detection of tumors by a collaborative effort, bringing together scientists from multiple disciplines to work on highly innovative strategies, such as newer imaging modalities. Better tools to diagnose cancer early enough for treatment can greatly improve the therapeutic outcome and make cancer a curable disease.

Sanford-Burnham’s Graduate School of Biomedical Sciences Graduate students have always played an important role at Sanford-Burnham. In the past, our grad students were officially enrolled at other universities and carried out their research in a Sanford-Burnham laboratory because of its particular expertise. Although this type of arrangement still continues, the situation changed in 2006 when the Institute founded its own graduate training program designed to confer Ph.D. degrees. The Graduate School of Biomedical Sciences at SanfordBurnham was recently recognized by the Western Association of Schools and Colleges as a Candidate for Accreditation. According to the dean of the program, Dr. Guy Salvesen, “Our eventual goal of full accreditation will serve as proof of what we already know—namely, that a Ph.D. degree from Sanford-Burnham is a rigorous one of high quality that stacks up well against a degree from any other outstanding institution.” For Sanford-Burnham graduate student Judith Scheliga, the choice of a mentor was a key factor in applying to graduate

Dr. Guy Salvesen and graduate program coordinator Stacy Devlin (center), with a few of Sanford-Burnham’s graduate students

school. “For me, the big advantage of the program has been the way the required classes and the specialized tutorials have contributed to my success in the lab,” says Judith. “In particular, the one-on-one nature of the tutorials with Institute professors has provided very practical guidance for my thesis work, and has also opened the door to some productive collaborations with other labs.”

Learn more at sanfordburnham.org/Training 12

SANFORD-BURNHAM’S NCI-DESIGNATED CANCER CENTER FACULTY Kristiina Vuori, M.D., Ph.D.

SANFORD-BURNHAM PRESIDENT AND CANCER CENTER DIRECTOR

TUMOR DEVELOPMENT PROGRAM

TUMOR MICROENVIRONMENT PROGRAM

SIGNAL TRANSDUCTION PROGRAM

APOPTOSIS & CELL DEATH RESEARCH PROGRAM

DIRECTOR

DIRECTOR

DIRECTOR

DIRECTOR

PRIMARY APPOINTMENTS

PRIMARY APPOINTMENTS

PRIMARY APPOINTMENTS

PRIMARY APPOINTMENTS

Robert Wechsler-Reya, Ph.D. Marcia Dawson, Ph.D. Rati Fotedar, Ph.D. Robert Margolis, Ph.D. Robert Oshima, Ph.D. Xiao-kun Zhang, Ph.D.

SECONDARY APPOINTMENTS

Rolf Bodmer, Ph.D. Gregg Duester, Ph.D. Fred Levine, M.D., Ph.D. Mark Mercola, Ph.D. José Luis Millán, Ph.D. Ranjan Perera, Ph.D. Pier Lorenzo Puri, M.D., Ph.D. Tariq Rana, Ph.D. Evan Snyder, M.D., Ph.D. Alexey Terskikh, Ph.D. Jing Crystal Zhao, Ph.D. Rui Zhou, Ph.D. ADJUNCT PRIMARY APPOINTMENTS

Robert Cardiff, M.D., Ph.D. Eva Engvall, Ph.D. Craig Hauser, Ph.D. William Muller, Ph.D. Manuel Perucho, Ph.D. Tannishtha Reya, Ph.D.

Ze’ev Ronai, Ph.D.

Sara Courtneidge, Ph.D.

Elena Pasquale, Ph.D. Matthew Petroski, Ph.D. Charles Spruck, Ph.D. Dieter Wolf, M.D.

Maria Diaz-Meco, Ph.D. Michiko Fukuda, Ph.D. Minoru Fukuda, Ph.D. Masanobu Komatsu, Ph.D. Sunyoung Lee, Ph.D. Jamey Marth, Ph.D. Jorge Moscat, Ph.D. Barbara Ranscht, Ph.D. Erkki Ruoslahti, M.D., Ph.D. Jeffrey Smith, Ph.D. William Stallcup, Ph.D. Kristiina Vuori, M.D., Ph.D.

SECONDARY APPOINTMENTS

Sumit Chanda, Ph.D. Malene Hansen, Ph.D. Randal Kaufman, Ph.D. Andrei Osterman, Ph.D. Robert Rickert, Ph.D. Greg Roth, Ph.D. ADJUNCT PRIMARY APPOINTMENTS

SECONDARY APPOINTMENTS

Hudson Freeze, Ph.D. Dorit Hanein, Ph.D. Robert Liddington, Ph.D. Alex Strongin, Ph.D. Niels Volkmann, Ph.D. Yu Yamaguchi, M.D., Ph.D.

Robert Abraham, Ph.D. Yong Cang, Ph.D. Jeffrey Price, M.D., Ph.D. Zhuohua Zhang, Ph.D. ADJUNCT SECONDARY APPOINTMENTS

Tomas Mustelin, M.D., Ph.D.

Guy Salvesen, Ph.D. Nicholas Cosford, Ph.D. Francesca Marassi, Ph.D. John Reed, M.D., Ph.D. Stefan Riedl, Ph.D. SECONDARY APPOINTMENTS

Adam Godzik, Ph.D. Huaxi Xu, Ph.D. Stuart Lipton, M.D., Ph.D. Maurizio Pellecchia, Ph.D. Arnold Satterthwait, Ph.D. Carl Ware, Ph.D. ADJUNCT PRIMARY APPOINTMENTS

Giovanni Paternostro, M.D., Ph.D.

ADJUNCT PRIMARY APPOINTMENTS

Peter Seeberger, Ph.D.

SCIENTIFIC ADVISORY BOARD

COMMUNITY ADVISORY BOARD

William S. Dalton, M.D., Ph.D.

Linden Blue Mary Beth Burnham Judge Robert Coates Helen Eckmann, Ph.D. Dani Grady Alan Hunter Robert Kyle

CEO, M2GEN DIRECTOR, PERSONALIZED MEDICINE INSTITUTE AT MOFFITT CANCER CENTER

Tony Hunter, Ph.D. DIRECTOR, CANCER CENTER RENATO DULBECCO PROFESSOR, MOLECULAR AND CELL BIOLOGY LABORATORY SALK INSTITUTE FOR BIOLOGICAL STUDIES

Harold L. Moses, M.D. HORTENSE B. INGRAM PROFESSOR, MOLECULAR ONCOLOGY PROFESSOR AND ACTING CHAIR, CANCER BIOLOGY, MEDICINE, AND PATHOLOGY, MICROBIOLOGY AND IMMUNOLOGY DIRECTOR EMERITUS, VANDERBILT-INGRAM COMPREHENSIVE CANCER CENTER VANDERBILT UNIVERSITY MEDICAL CENTER

Jean Y. J. Wang, Ph.D. DISTINGUISHED PROFESSOR AND ASSOCIATE DIRECTOR OF BASIC RESEARCH MOORES CANCER CENTER, UC SAN DIEGO

Homer L. Pearce, Ph.D. DISTINGUISHED RESEARCH FELLOW (RETIRED) ELI LILLY AND COMPANY

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Sanford-Burnham Cancer Center