SBP Pathways Winter 2016

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SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE

A SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE PUBLICATION | COMMEMORATIVE | WINTER 2016

10901 North Torrey Pines Road La Jolla, California 92037 SBPdiscovery.org

LET’S GET TO WORK. Fighting deadly cancer

Our work is made possible through the generous donations of people like you.

If you wish to support our research, please email giving@SBPdiscovery.org or call 1-877-454-5702.

COMMEMORATIVE ISSUE WINTER 2016 ON THE COVER Petrus de Jong, M.D., Ph.D., Brooke Emerling, Ph.D., and Ani Deshpande, Ph.D., are advancing cancer research.

See page 16.

IN MEMORIAM

Trustees

FOUNDERS Dr. William H. and Lillian Fishman* HONORARY TRUSTEES

Roberta and Malin Burnham Joseph C. Lewis T. Denny Sanford TRUSTEES AND OFFICERS

Henry L. Nordho° CHAIRMAN

James C. Blair, Ph.D. VICE CHAIRMAN

Perry Nisen, M.D., Ph.D. CHIEF EXECUTIVE OFFICER DONALD BREN CHIEF EXECUTIVE CHAIR

Kristiina Vuori, M.D., Ph.D. PRESIDENT PROFESSOR, NCI°DESIGNATED CANCER CENTER

Celebrating the life of Conrad Prebys In July, our Institute lost a great friend and supporter.

We dedicate this issue to Conrad Prebys, whose confidence in our work inspires us to continue making medical discoveries that improve human health. We are proud to carry on his legacy.

PAULINE AND STANLEY FOSTER PRESIDENTIAL CHAIR

Gary Chessum, ACMA, CGMA CHIEF FINANCIAL OFFICER

Knox Bell CORPORATE SECRETARY

Lorenzo M. Berho David W. Down Daniel J. Epstein M. Wainwright Fishburn, Jr. Carol G. Gallagher, Pharm.D. William Gerhart Alan A. Gleicher Donald L. Jernigan, Ph.D. James E Jardon II Gregory T. Lucier Papa Doug Manchester Douglas H. Obenshain Edward R. Schulak Stuart A. Tanz Luder G. Whitlock Jr.

*Deceased

10901 North Torrey Pines Road La Jolla, California 92037

SBPdiscovery.org

The research at Sanford Burnham Prebys Medical Discovery Institute is made possible in part by philanthropic support. For more information, please contact giving@SBPdiscovery.org or 1-877-454-5702.

FOLLOW US ON:

10901 North Torrey Pines Road La Jolla, California 92037

SBPdiscovery.org @SBPdiscovery Sanford Burnham Prebys Medical Discovery Institute is a 501(c)3 nonprofit organization.

Contents

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Conrad Prebys

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An Immunology Trail Leads to New Cancer Treatments

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The Trailblazer

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Top Guns

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Where Disco Meets Discovery

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Fishman Fund Awards for Promising Young Scientists

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David Whitmire Hearst Jr. Foundation Initiates Postdoctoral Scholar Program

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Preserving Eric’s Legacy

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A Philanthropist Who Made the World a Better Place

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A Graduate Student Gives Back

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Science Benefitin Patients

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Discovery Hub

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“We honor the life of Conrad Prebys, whose friendship, support and confidence we were privileged to have for more than a decade. He and former trustee Pauline Foster will be greatly missed.�

Kristiina Vuori, M.D., Ph.D. Perry Nisen, M.D., Ph.D.

White blood cells can be harnessed to attack cancer cells.

See page 8.

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LETTER

Science, Supporters and Studio 40—a Glimpse at the Life of Our Institute Perry Nisen, M.D., Ph.D., Conrad Prebys and Kristiina Vuori, M.D., Ph.D.

In this issue of PATHWAYS, we honor Conrad Prebys, whose friendship, support and confidence we wer privileged to have for more than a decade. Conrad’s remarkable spirit uplifted those around him, and his generosity will help ensure the health of generations to come. He and Pauline Foster, a trustee and active advisor who endowed the presidential chair six years ago, will be greatly missed.

Conrad died of cancer in July of this year, and we focus this issue exclusively on our efforts to fight th pervasive disease.

In An Immunology Trail Leads to New Cancer Treatments, Dr. Linda Bradley, a competitive horse jumper and cancer survivor, shares how her career in immunology has led to harnessing the immune system to fight cance .

Part of our Institute’s mission is to educate the next generation of scientists. Graduate student Marisa Sanchez, in A Graduate Student Gives Back, discusses her enthusiasm for completing her doctorate degree, while sharing her passion for science with elementary and high school students from San Diego schools.

A special thank you to those who attended the annual Gala event, Where Disco Meets Discovery, and to those who gave so generously. We hope you enjoy the photos.

As we continue to celebrate our Institute’s 40th anniversary, we thank you for your continued support.

We encourage you to invite others to learn about the great work we are doing.

You will meet Dr. Adam Godzik, The Trailblazer, who prefers to commute to work by mountain bike. Adam is an authority on the analysis of extremely large data sets—“big data”—to reveal mutations that cause cancer.

In Gunning for the Deadliest of Cancers, you’ll meet five of our early-career scientists who are taking ai at hard-to-treat cancers like pancreatic, liver, leukemia and certain breast cancers.

We also share Dr. Robert Wechsler-Reya’s collaboration with a pediatric neurologist from Rady Children’s Hospital to transform the treatment of a dangerous brain tumor in children. Brain Matters describes their search for more effectiv , tolerable treatments. We also introduce Makala May, age 6, a vibrant brain tumor survivor who completed treatment more than a year ago.

Perry Nisen, M.D., Ph.D. Chief Executive Offic Donald Bren Chief Executive Chair

Kristiina Vuori, M.D., Ph.D. President Pauline and Stanley Foster Presidential Chair Professor, NCI-designated Cancer Center

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Conrad Prebys The selfless giver

Conrad Prebys addresses donors, faculty and sta at the Institute in 2015.

“I check myself every so often, and it appears it’s the right thing for me to do, to share excess wealth.”

Conrad Prebys

In 1941, an 8-year-old boy was diagnosed with a heart condition. His doctors told him he would need to lead a sedentary life. His working-class parents provided piano lessons with the hope that, as an adult, he could make a living as a musician.

When that boy grew up, he found a differen route to fulfil his life, making a fortune and giving so much away that he became recognized as one of the most thoughtful philanthropists in the world.

That boy was Conrad Prebys, who lost his battle with cancer on July 24, 2016, at the age of 82.

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LEGACY

Real estate became the road to Conrad’s financial success. He started as a cofounder of Progress Construction Company, going on to own rental properties and ultimately landing on the Forbes billionaire list.

But that wasn’t the only list Conrad landed on. His gifts to organizations, including Scripps Health, San Diego State University, the San Diego Zoo, the San Diego Opera, the Boys and Girls Clubs of East County, the La Jolla Music Society, the Old Globe, the Salk Institute, San Diego Hospice and Sanford Burnham Prebys Medical Discovery Institute (SBP), recently put him on the Chronicle of Philanthropy list of America’s top 50 philanthropists.

In 2015, Conrad donated $100 million—his largest philanthropic gift ever—to SBP. “In honor of Conrad’s generous donation, we renamed our Institute, adding Prebys’ name, and held a celebration on campus,” says Kristiina Vuori, M.D., Ph.D., president of the Institute. “Conrad was truly a great friend to our Institute. His deep-seated loyalty is helping us tremendously by fueling our efforts to find ne treatments for challenging diseases. On his visits to our La Jolla campus, he would often say to the sta , ‘Life is a bowl of cherries,’ spreading his optimism, appreciation and positive attitude throughout our campus.”

At the ceremony, T. Denny Sanford, honorary trustee, said he was “super ecstatic about what Conrad’s gift is going to do for the organization. The work he has done so far and the donations he has made and contributions to the medical area are fantastic.” Fellow honorary trustee Malin Burnham added, “In philanthropy, he seeks out opportunities. And he doesn’t make up his mind until his gut tells him it’s the thing to do.”

Born and raised in South Bend, Indiana, Conrad was inspired by a high school drama teacher to further his education, and became the first of five brothe to graduate from Indiana University. He came to San Diego in 1965 and began a love affair with the cit that now has a reputation for excellence in music, art, education and medical research—causes to which he would generously donate.

Wealth wasn’t handed to him. Conrad described the circumstances of his arrival in San Diego to the San Diego Union-Tribune in 2015. “I had $500, no job, and no prospects. I looked out at that ocean and said, ‘If I could just make a buck.’”

Both agree that Conrad’s passing is a tremendous loss to the San Diego community. “He was an invaluable trustee to SBP and a discriminating philanthropist with incredible insight and unwavering energy,” says Sanford. “Prebys only supported well-run organizations that he believed could make a difference to humankind. There are so many institutions, especially in San Diego, that have been able to grow by leaps and bounds with Conrad’s contributions,” adds Burnham.

“Conrad was an extraordinarily generous man and we are privileged to have been a recipient of his thoughtful and giving spirit, which touched all parts of San Diego,” says Perry Nisen, M.D., Ph.D., CEO of SBP. “Conrad just loved being here. He was so engaged with the scientists at our Institute.”

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From left: T. Denny Sanford, Conrad Prebys and Malin Burnham in 2015.

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Conrad Prebys – A life of living and giving

1933 Prebys was born in South Bend, Indiana, as the son of a tool-and-die maker.

1941 At age 8, he developed a heart condition that left him bedridden for more than a year.

Embracing a less physical lifestyle, he learned to play the piano and develop an appreciation for the arts.

1950s He graduated with an economics degree from Indiana University and managed a pizzeria and a steel mill.

1965 With $500 in his pocket, Prebys moved to San Diego. He cofounded Progress Construction and Management Company when the city was experiencing a building boom.

1980 After buying out his business partner, Prebys expanded from the construction business into building ownership. He owned at least 81 properties, totaling 7,099 units in greater San Diego.

2006 Conrad Prebys Emergency and Trauma Center at Scripps Mercy Hospital was founded.

2007 Prebys began contributing to the San Diego Zoo, including the habitats for polar bears and elephants.

2008 With a $10 million gift from Prebys, the Conrad Prebys Center for Chemical Genomics was founded at our Institute. The Center screens millions of chemical compounds to fin the few that are starting points for new medicines.

2009 Located in San Diego’s Balboa Park, the Conrad Prebys Theatre Center at the Old Globe was completed.

2011 Prebys Cardiovascular Institute was founded at Scripps Memorial Hospital.

2014 Plans began for the Conrad Prebys Performing Arts Center, known as The Conrad. It will be the new permanent home for the La Jolla Music Society, opening in 2018.

2015 With a $100 million donation from Prebys, our Institute was renamed Sanford Burnham Prebys Medical Discovery Institute in honor of his generous support.

July 24, 2016 Prebys passed away from cancer at the age of 82 at Scripps Mercy Hospital. He is survived by his partner, Debbie Turner.

Conrad Prebys and Debbie Turner on vacation in Egypt.

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Linda Bradley, Ph.D., a skilled horsewoman, harnesses the immune system to fight diseas .

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FACULTY

An Immunology Trail Leads to New Cancer Treatments Dr. Linda Bradley is finding ways to harness the immune system to fight cancer “There is something about the outside of a horse that is good for the inside of a man,” says Linda Bradley, Ph.D., professor in the Infectious and Inflammatory Disease Cente . “Although Winston Churchill said it first, I embrace the concept and live by the code.”

Bradley finds regular rejuvenation on the back of her Saddlebred mare, Tippy. Whether competing in the show ring—where the accomplished duo has garnered many championships—or ambling along the trails in Rancho Santa Fe, the athletic immunologist finds horses incredibly healing ONE ON ONE WITH CANCER Equine therapy was especially helpful 10 years ago when Bradley was diagnosed with breast cancer and traveled that harrowing journey from the shock of diagnosis and the uncertain prospects of treatment through the feeling of never really knowing if you’re “cured” or not. And again, six years later, equine therapy helped when her husband, a pediatrician, was diagnosed and treated for colon cancer.

“With horses, like science, there is a process of exploring and gaining intimacy with your work—even if it doesn’t go as planned—it helps the creative process.”

Linda Bradley, Ph.D.

“My bond with Tippy has helped me through some of life’s most challenging times,” says Bradley, who spends her days seeking new treatments for harmful diseases.

A START IN IMMUNOLOGY “At UCLA, I was fortunate to study with Dr. Eli Sercarz, one of the world’s most respected immunologists, and the field just clic ed with me,” Bradley explains. “Maybe it’s because I’d once considered becoming a doctor and immunology is so closely tied with medicine. Eventually immunology led me to melanoma research, one of the cancers where immunology research has had the most impact.”

The immune system’s potential for battling melanoma made headlines last year when former president Jimmy Carter, diagnosed with the deadly disease, was treated with immunotherapy and subsequently declared cancer-free. According to Bradley, “While immunotherapy’s potential was recognized a decade ago, the first successful drugs cam in the form of immune checkpoint inhibitors— drugs that unleash the immune system to fight cancer—and now the field has br en wide open.”

RELEASING THE BRAKES TO TREAT CANCER It’s that very path—using the body’s own immune system to fight cancer—that le Bradley and her team to their recent discovery of another weapon for bolstering the immune system. Their new research, led by postdoctoral scholar Roberto Tinoco, Ph.D., identified protein called PSGL-1 that’s required to increase levels of immune checkpoints.

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“Immune checkpoints are molecules in the body that control the strength of an immune response,” says Bradley. “They can turn the response up or down, and tumors have a unique way of controlling checkpoints to turn the immune response down so that tumors can thrive.

Linda Bradley, Ph.D., leads a team of scientists exploring the intersection of immunology and cancer.

“PSGL-1 limits the immune system’s ability to battle cancer by increasing levels of checkpoints. We found that when PSGL-1 is missing in mouse models of melanoma, the immune brakes are o , and the system is fired up to respond to cance . It’s possible

that PSGL-1 inhibitors could improve cancer outcomes. We’re already in discussions with pharmaceutical companies to advance this discovery,” adds Bradley.

YOUR TUMOR, YOUR TREATMENT According to Bradley, the future of cancer therapeutics lies in personalized medicine.

“Every tumor is unique,” she says. “There’s a program now to map the mutations within a specific tumor so you can find its Achill ’ heel and develop an immunotherapy to target that weakness. Ideally each patient will have their own specific treatment ”

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But a challenge faced by all cancer patients, especially those with aggressive tumors, is the time it takes to develop an effectiv yet safe drug. “Right now,” she says, “I’m working with UC San Diego Moores Cancer Center, and they’re ready to begin clinical trials. But they have over 30 drugs to explore.”

To help select drugs for specifi patients, Bradley and her team are developing unique mouse models. They’re taking fragments of a tumor from a patient, planting them in immune-deficien mice, then adding that patient’s own T cells. This provides an in vivo

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model for determining which drugs, or which combination of drugs, might work best for that particular patient.

“I’m super excited to be part of the science that’s truly improving the survival of cancer patients,” she says. “We never thought there’d be a cure for melanoma, but now we can absolutely cure some patients. Hopefully we are still at the beginning of harnessing the immune system to combat the many types of cancer for which better treatments are needed.”

What Are Immune Checkpoints?

ACTIVATED T-CELL

T-CELL

T-CELL

Antigen receptor

T-CELL

ACTIVATED ACTIVATED T-CELL T-CELL

DEACTIVATED T-CELL

Antigen

Antigen

have co-stimulator proteins on their surface, they begin to hunt down and kill cells covered with the same antigen.

ACTIVATED ACTIVATED T-CELL T-CELL

DEACTIVATED DEACTIVATED T-CELL T-CELL

Antigen Co-stimulator Co-stimulator receptor

Immune checkpoint

Antigen

ANTIGEN PRESENTING ANTIGEN PRESENTING CELL CELL

CANCER CELL

CANCER CELL

Cancer cells avoid destruction by flippin switches on T cells called immune checkpoints to shut down the immune response.

Immune checkpoint

CANCER ANTIGEN When T cells encounter antigensCELL PRESENTING presented by specialized cells that also CELL

Checkpoint inhibitors Antigen receptor

CANCER CELL

ANTIGEN PRESENTING Antigen CELL

Co-stimulator

Each T cell has claw-like antigen receptors on its surface that recognize and lock onto foreign or abnormal molecules on the surface of infected or cancerous cells.

T-CELL

ACTIVATED T-CELL Co-stimulator

Antigen receptor

DEACTIVATED T-CELL

Checkpoint inhibitors

Immune checkpoint

CANCER CELL

CANCER CELL

Checkpoint inhibitors are drugs that physically block the checkpoint, preventing cancer cells from deactivating T cells, each one of which can kill thousands of cancer cells.

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FACULTY

The Trailblazer

Dr. Adam Godzik uses “big data” to reveal mutations that cause cancer

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Adam Godzik, Ph.D.

“I didn’t know much about San Diego before coming here in 1990,” says Adam Godzik, Ph.D., professor and director of the Bioinformatics and Structural Biology Program.

But that didn’t stop the born mathematician from relocating and starting a career path that led to his now groundbreaking work to fin undiscovered cancer drivers—genes that cause cancer when altered.

Godzik was a trailblazer even as a young boy. His father, a plant pathologist, would take him on long hikes in local mountains near Silesia, Poland, where he was born and raised. They looked for damaged vegetation caused by the local, flourishin coal-mining industry. “I was hiking as soon as I could walk,” says Godzik. “And today it’s my passion.”

After teaching himself English and getting a doctoral degree in physics, he found himself in a crowded fiel of young, ambitious students, all wanting to make a mark in the field When Godzik saw an ad asking, “Interested in biology?” he jumped at the opportunity to enter a world that combined his passion for precision with the somewhat untidy world of cancer biology.

Adam Godzik, Ph.D., an avid cyclist, and his son, Mikolaj (Nick), in the backcountry in San Diego.

WHEN PHYSICS AND BIOLOGY COLLIDE “Physicists are trained to look at complex systems and simplify them,” says Godzik. “We use theories and apply math to make predictions. We divide the world into sharply delineated unchanging categories, and reduce matter to its basic components. In contrast, biologists tease out the smallest details and create vast amounts of data. They also have to deal with the element of chance—the random mutation that is unpredictable,” he adds.

“Molecular biology and the era of genomics have led to too much data, and physicists, used to reducing complex systems to basic principles, are helping make sense of it all,” says Godzik.

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“Increasingly, it looks like tumors develop when the immune system fails to recognize cancer cells as harmful.”

Adam Godzik, Ph.D.

Godzik’s bioinformatics team (from left to right): Mayya Sedova, Zhanwen Li, Andrew LeBlanc, Piotr Cieplak, Ph.D., Adam Godzik, Ph.D., Kai Post, Thomas Hrabe, Ph.D.

BREAKING BOUNDARIES Godzik moved to San Diego to start making sense of “big data” by analyzing large-scale genomic, clinical and molecular data to better explain and predict cancer patient outcomes and fin new drugs to prevent, treat and potentially cure cancer.

“If I could have hiked to work every day, I would,” says Godzik.

“But it was just too far from my home.” So he bought a bicycle at Target, found a dirt path through the Los Peñasquitos Canyon and rode to work. Today, he rides his Intense cycle—

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the mountain bike of choice among experienced cyclists—to our La Jolla campus as many days as his schedule permits. The other days he drives with the masses. “I’m a hybrid,” says Godzik.

Now an established and recognized authority in the fiel of bioinformatics and systems biology, he leads a group of more than a dozen like-minded researchers that have developed e-DRIVER, a proprietary computer algorithm that has identifie more than 100 new cancer drivers.

“Interestingly, we are now findin cancer drivers that seem to be regulating the immune system,” he says.

“With the growing appreciation of the importance of the immune system in cancer progression, the immunity genes we fin are providing new insights on the pathology of cancer.”

COMBING THE CANCER GENOME Using databases such as The Cancer Genome Atlas (TCGA), Dr. Godzik has found more than 100 mutations in immune system genes that correlate with cancer. Understanding genetic changes linked to cancer helps speed up and expand opportunities for personalized medicine.

What is The Cancer Genome Atlas?

TCGA is one of the world’s largest collections of cancer genome data available. Established by the National Cancer Institute and National Human Genome Research Institute, it is available on a web-based platform to qualifie researchers to improve prevention, diagnosis and treatment of cancer.

TCGA holds 2.5 PETABYTES OF DATA – the equivalent of 50 TRILLION pages of standard printed text.

It allows scientists to search, download and analyze information from 33 cancer types collected from more than 11,000 patients from 20 institutions across the United States and Canada.

Source: National Institutes of Health

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RESEARCH

Top Guns

SBP scientists seek new tactics to fight deadly cancers.

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Cancer isn’t one disease—it’s thousands of diseases. A single tumor may comprise many types of cancer cells, and worse, tumors can change. How do you outmaneuver an enemy that morphs?

Some cancers—pancreatic cancer, liver cancer, specific forms of breast cancer and leu emia— are more deadly than others. They may be harder to detect, like pancreatic cancer, which often isn’t detected until an advanced stage.

With the odds stacked against them, these scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP), like Top Gun fighter pilots, are relentless in their dogged pursuit to find a breakthrough and win the war against cancer.

TAKING AIM AT PANCREATIC CANCER Pancreatic cancer has a five-year survival rate of 8 percent, a prognosis that has not much improved in 20 years. This unfortunate fact drives Cosimo Commisso, Ph.D., an assistant professor, and Petrus de Jong, M.D., Ph.D., a postdoctoral researcher, to find new ways to attack this aggressive cancer.

Commisso’s lab is focused on understanding how some pancreatic cancers hijack normal cell functions to survive. Because pancreatic tumors are so dense, they get very few nutrients from blood, so they have to acquire a different way to get fuel. Commisso is studying a key tumor survival strategy—macropinocytosis, or “drinking” the surrounding fluid, which contains proteins. The breakdown products of engulfed proteins can be burned for energy or used as building blocks for new cancer cells, feeding the tumor’s unregulated growth.

Commisso sees two ways to harness this feeding mechanism. “We can either starve the tumor by blocking the process, or take advantage of macropinocytosis to deliver nanoscale therapeutics that kill the tumor cells,” he says. Commisso found that using a chemical to block macropinocytosis stopped the growth of, and sometimes even shrank, pancreatic tumors in mice.

Macropinocytosis is driven by mutations in a signaling protein called Ras, found in more than 90 percent of pancreatic cancers. Oncogenic Ras drives pancreatic tumor progression in

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other ways, too, so it would seem like an ideal target for drugs. However, according to de Jong, to date, Ras has proven undruggable. “So targeted therapy hasn’t worked,” he says.

protect cancer cells from stressful conditions. She is currently searching for drugs that inhibit these cancer-friendly enzymes with a goal to help more breast cancer patients survive cancer-free.

Worse, de Jong says, Ras-driven tumors don’t respond to chemotherapy or immunotherapy. “By 2020, unless we find new treatments, pancreati cancer will be the second leading cause of cancer deaths.”

RESTORING LEUKEMIA CELLS TO NORMAL “For many childhood leukemias, treatments can have long-lasting, debilitating side effects ” says Assistant Professor Ani Deshpande, Ph.D. “The main interest of my lab is a subtype of leukemia called mixed lineage leukemia, which accounts for a large proportion of pediatric and especially infant leukemias. There are no specific therapy options for these leukemias, and they are often associated with a poor prognosis. My goal is to change this.”

De Jong’s research focuses on tumor-stromal interactions. In normal tissue, the stroma provides structure by building the fibrous networks that give the pancreas shape. In cancer, the stroma is coopted to provide nutrients. De Jong is examining exactly how that happens, as he considers future therapies that block these interactions to offer new chances of survival.

FIGHTING AGAINST TRIPLE-NEGATIVE BREAST CANCER Brooke Emerling, Ph.D., is an assistant professor and one of our newest faculty members working on another challenging problem in cancer research.

She is researching an aggressive and recurrent form of breast cancer called triple-negative breast cancer (TNBC) that has a mortality rate three times higher than other types of breast cancer.

“Many breast cancers can be treated with targeted therapies—drugs that block the receptors on cancer cells that help fuel their growth,” Emerling says. “TNBC lacks these receptors, so patients are treated with surgery, standard chemotherapy and radiation, but this doesn’t always work.”

Emerling is hoping her research will lead to new treatments for TNBC that selectively kill the tumor, leaving healthy cells alone. She has identified a promising new target for TNBC called PI5P4Ks. According to her studies, PI5P4Ks normally help Ani Deshpande, Ph.D.

In mixed lineage leukemia, a gene on chromosome 11 called MLL (named after mixed lineage leukemia) is broken and gets attached to a gene on a completely different chromosom , leading to the production of an abnormal fusion gene. That is a catastrophic event, because protein made from the fusion gene has the potential to turn a completely normal blood cell progenitor into a limitlessly dividing leukemia cell.

The MLL-fusion protein works by modifying our “epigenome,” which is the set of chemical tags on our DNA that determine which genes are turned on and o . Deshpande’s research aims to restore altered chemical tags on the DNA of cancer cells to their normal state, thus reverting the leukemia cells to normalcy.

This idea—reprogramming cancer cells rather than killing them—is an emerging area in cancer research. “It’s exciting and new,” Deshpande says.

“We might be able to target cancer cells in ways that have not previously been imagined. This is what makes this one of the hottest areas of research right now.”

Cosimo Commisso, Ph.D., (left) and Yotaro Kudo, M.D., Ph.D. (right)

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A FOCUS ON LIVER CANCER As a practicing hepatologist in Tokyo, Yotaro Kudo, M.D., Ph.D., saw patients with hepatocellular carcinoma (HCC)—the most common type of liver cancer—sufferin despite receiving top-level care.

He wanted to move to the lab bench to create new therapeutics to improve patient outcomes.

For patients with early-stage disease, surgery and radiofrequency ablation provide a favorable outcome. However, the treatment options for patients with advanced-stage disease are limited and those patients have a very poor prognosis.

“We desperately need effectiv treatment options for patients with advanced HCC,” he says.

Although the favored strategy for treating cancer is targeted therapy, that doesn’t work for HCC. “Liver tumors are heterogeneous and become genetically more diverse as the disease progresses. So, a single targeted therapy is unlikely to be successful across the board,” he says.

Instead, Kudo, a postdoctoral researcher in the lab of Jorge Moscat, Ph.D., is focusing on changes in stromal cells—the cells that surround liver cancer cells. HCC results from chronic liver injury, whether from viral infections such as hepatitis C virus, excess alcohol consumption, or accumulation of lipid in the liver due to obesity. Liver injury leads to inflammation and inflammatio can lead to cancer.

Inflammatio also causes stromal cells to take on tumor-supporting features.

Kudo is therefore looking for ways to interfere with the cancer-supporting functions of stromal cells.

“Our lab has recently reported a novel role of stromal cells in HCC, and I’m looking for more,” he explains.

Petrus de Jong, M.D., Ph.D.

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ARE WE LOSING THE WAR ON CANCER? Ask any of our scientifi Top Guns and you’ll get the same response: “Not on Our Watch.”

Q: What sparked your interest in research?

Deshpande: My sister, a research scientist, and the antibody and vaccine revolution got me excited.

De Jong: I was influence by a pediatric rheumatologist who said, “Whatever you do has to go back to patients.”

Q: How did you decide to focus on cancer?

Commisso: Connecting with patients, hearing their stories made me work on pancreatic cancer.

Emerling: Years ago, I worked at UC San Francisco as a technician for a pediatric oncologist, who said I should become a scientist. I’m the firs scientist in my family.

Q: Why did you choose to do your research at SBP? Kudo: I came to this institution because of Drs. Moscat and Diaz-Meco, who are passionate and dedicated to science. I have a lot to learn from them, and I am enthusiastic about SBP and spending time investigating liver cancer.

De Jong: I heard Garth Powis, D. Phil., professor and director of SBP’s Cancer Center, give a presentation at UC San Diego and knew I wanted to study with him.

Q: What keeps you up at night?

Emerling: I love asking scientifi questions and solving them like puzzles. It’s the one question that keeps me up at night that makes this challenging and fun.

Commisso: There are very few survivors of pancreatic cancer— and it’s hard to detect. There’s also a lack of people to herald the cause.

Q: Who influenced your career path, or whom do you most admire?

Kudo: My grandfather, a medical doctor who lived to be more than 90 years old. Every time I saw him he was studying something new.

Deshpande: The patients with leukemia.

Brooke Emerling, Ph.D.

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EVENTS

Where Disco Meets Discovery If vibrant music, fab bell-bottoms and energetic dances characterized the ‘70s, Sanford Burnham Prebys Medical Discovery Institute’s 2016 fundraising gala exuded disco fever. “Studio 40: Where Disco Meets Discovery” was the theme of the event, held on November 5 at the Estancia Hotel in La Jolla, celebrating 40 years of scientifi discoveries since our Institute’s founding in 1976.

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There’s no discovery without disco—and no SBP without each of our donors, who had an evening of fun and funky flashbacks

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KNEE-HIGH BOOTS AND LEISURE SUITS SBP supporters electrifie the evening by dressing in full disco attire, including honorary gala co-chairs Greg Lucier, Chairman and CEO of NuVasive, Inc., a member of our Institute’s Board of Trustees Executive Committee and his wife, Marilena, SBP’s CEO Perry Nisen, M.D., Ph.D., and his wife, Amy. As guests entered the ballroom beneath the spinning disco-ball lights, professional dancers did the Hustle to the four-on-thefloo beat of disco favorites like “Stayin’ Alive.”

On two screens, a montage of the Institute’s achievements and pop culture over the last 40 years rotated out of a gold disco ball. And that was just the beginning!

David and Gabrielle Dorne.

Alan

Nisen welcomed guests and introduced Lucier, who explained why he’s involved with our Institute: Investing in SBP “gives great intrinsic return in terms of making a real differenc to humanity.”

A commemorative video highlighted our Institute’s evolution in interviews with scientists, T. Denny Sanford, and the late Conrad Prebys.

Malin Burnham, honorary trustee, shared that collaboration has been in the DNA of this place from its inception, thanks to founders William Fishman, Ph.D., and his wife, Lillian.

Sam and Reena Horowitz, Jeanne Jones and Don Breitenberg.

One of SBP’s firs scientists who subsequently became president of our Institute, Erkki Ruoslahti, M.D., Ph.D., distinguished professor, reflecte on how his 37 years at our Institute allowed him to follow his passions from cell biology to nanomedicine. T. Denny Sanford, honorary trustee, said our organization has more potential to do great things than any other institution. From diagnosing 200 children with rare genetic diseases to a Prebys Center drug advancing to clinical trials next year, our Institute is reaching the potential the late Conrad Prebys always believed it would.

Jud

Perry and Amy Nisen, Debbie Turner, Malin Burnham, Kristiina Vuori, Marilena and Greg Lucier.

William Gerhart and Melissa Seipel, Zuhre Tutuncu, Mell and Kieran Gallahue, Ahmet Tutuncu.

Alan and Marleigh Gleicher, Lorenzo and Rocio Berho.

Peter and Olivia Farrell, T. Denny Sanford and Sue Prelozni, Phyllis and Daniel Epstein.

Judy White and Brad Benter.

Cindy and Steve Aselage, Beth Aselage, Steve Rodems, Amy Benton, Bill and Lana Benvenuto, Neil McFarlane, Jean and Nils Olsson.

Claudia Dunaway, Hudson Freeze, Nina Fishman, Alan Attridge, José Luis Millán and Theresa Millán.

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EVENTS

Fishman Fund Awards for Promising Young Scientists For the 15th consecutive year, postdoctoral researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) were recognized at the Fishman Fund annual awards ceremony, held on September 15, at the Sanford Consortium in La Jolla.

The annual awards included two $10,000 Career Development Awards. In honor of our Institute’s 40th anniversary, a new award, the Fishman Fund Fellowship, was added.

This fellowship funds the winner’s salary for two years and provides a $5,000 careerdevelopment award.

Established in 2001 by Reena Horowitz and Mary Bradley in honor of Institute founders Dr. William and Lillian Fishman, The Fishman Fund recognizes the remarkable achievements of young scientists at our Institute. The competition is open to all SBP postdoctoral researchers.

Co-founder Horowitz, Jeanne Jones, the co-founder designee, Armi Williams and Perry Nisen, CEO, presented the awards. Nina Fishman, daughter of founders Dr. William and Lillian Fishman, read an excerpt from her father’s notes: “Each scientist is encouraged to develop original ideas, which can be tested experimentally and subsequently qualify for grant support.”

2016 Fishman Fund Award winners (from left to right) Jia (Zack) Shen, Ph.D., Joana Borlido, Ph.D., and Bernhard Lechtenberg, Ph.D.

Fishman Fund Fellowship Awardee:

Fishman Fund Career Development Awardee: Bernhard Lechtenberg, Ph.D.

Fishman Fund Career Development Awardee: Jia (Zack) Shen, Ph.D.

Borlido explores the role of specialized channels in cells and how they affect the immune system. Her work will help elucidate the molecular Joana Borlido and husband, basis for the onset Stephen Sakuma and development of leukemia and may identify new targets to treat the disease.

Lechtenberg studies the body’s molecular machines using X-ray crystallography. His research may lead to novel treatments for cancer and ALS (Lou Gehrig’s disease).

Shen develops functional screens for drugs that inhibit ubiquitin ligases (enzymes that tag proteins with a small Jia (Zack) Shen and his protein called wife, Jian-Mei (Molly), and ubiquitin). Such daughter, Olivia drugs, alone and in combination with current chemotherapies, are considered promising therapies for breast cancer.

Joana Borlido, Ph.D.

Bernhard Lechtenberg and wife, Anne Hempel

s,

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DONORS Mark Goldberg, Ph.D. and Charles Spruck, Ph.D.

David Whitmire Hearst, Jr. Foundation Initiates Postdoctoral Scholar Program Dr. Charles Spruck’s laboratory receives first award to fight aggressive breast cancer

TNBC represents about 20 percent of all breast cancers.

The David Whitmire Hearst, Jr. Foundation is funding a postdoctoral researcher for two years at Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla, California.

Mark Goldberg, who completed his Ph.D. in biology at the University of California, Riverside, has started his fellowship in Charles Spruck’s lab, and together they are working to advance research for potential treatments of an aggressive form of breast cancer called “triple-negative.”

“I’m honored to host the first recipient of th David Whitmire Hearst, Jr. Foundation Scholar Award,” says Spruck, an assistant professor at SBP’s National Cancer Institute-designated Cancer Center. “The Foundation awards funds to causes that benefit the community an bringing Mark on board helps broaden our efforts in San Diego to help cure cance .”

IT’S JUST THE BEGINNING Goldberg explains, “It’s hard for young scientists like myself to get their foot in the door. With the David Whitmire Hearst, Jr. Scholar opportunity, I can work in the lab of successful scientists like Spruck right here in Southern California. Many postdocs have to move to a new city to pursue their research interests. With the help of Mr. Hearst, I can stay here in southern California and contribute to pioneering research,” says Goldberg.

TRIPLE-NEGATIVE BREAST CANCER In Spruck’s lab, scientists study a very aggressive form of breast cancer known as triple-negative breast cancer (TNBC).

These tumors lack three receptors known to fuel most breast cancer growth: estrogen, progesterone and HER2. Since the most successful treatments for breast cancer target these receptors, the treatment options for these patients are limited.

Spruck is looking for ways to to prevent the metastasis of breast cancer cells by blocking specific pathways they use to spread. An initial study identified a novel target, and now they will validate the target and look for drugs that can induce the desired response.

“In spite of significant treatment advances, more than 40,000 women will die from breast cancer this year in the U.S.” Charles Spruck, Ph.D.

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LEGACY

Preserving Eric’s legacy The Eric Dudl Scholarship Fund will help Dr. Roberto Tinoco pursue immunotherapies for cancer At 33 years old, Eric Dudl, Ph.D., was well on his way to a successful career as a cancer researcher at Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla. Tragically, his life was cut short by lung cancer, and he passed away on August 30, 2006.

To help postdoctoral researchers like Eric continue their commitment to cancer research, his family established the Eric Dudl Scholarship Fund. Eric left his entire life savings to our Institute, a place that inspired him to never miss a day of work, even while he was recovering from hospitalizations and debilitating lung clots. For the ninth year since Eric’s passing, the Eric Dudl Scholarship Award has provided a boost to a postdoctoral researcher’s career.

Left to right: Guy Salvesen. Ph.D., Dean, Graduate School of Biomedical Sciences, Roberto Tinoco, Ph.D., and Jim Dudl

Roberto Tinoco, Ph.D., is the recipient of this year’s award. He’ll receive $2,000 to further his education and career development. “With the Eric Dudl Scholarship Fund, I’ll have the opportunity to attend the Annual International Cancer Immunotherapy Symposium in New York City,” he says.

“There I’ll learn about the latest immunotherapies in the pipeline, like chronic viruses and how cancers thwart immune responses in humans by making T cells dysfunctional. We need to learn how to restore immune function and boost T cells to fight cance ,” adds Tinoco.

In a statement, the Dudl family said, “We’re ecstatic that Eric can help postdocs like Roberto continue their important work. We saw firsthand how Eric suffered his lung cancer took a toll on his immune system and his body. However, his indomitable spirit lives on by funding cancer researchers like Roberto to advance our understanding of cancer immunotherapy.”

Eric Dudl Ph.D.

A W

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LEGACY

A Philanthropist Who Made the World a Better Place “Pauline Foster was dedicated to making the world a better place,” says Kristiina Vuori, M.D., Ph.D., professor and president of Sanford Burnham Prebys Medical Discovery Institute (SBP). “She took every opportunity to do that, through both financial givin and service.”

Vuori holds the Pauline and Stanley Foster Presidential Chair, which was established in 2010 with Foster’s generous gift. Foster, who died in July, had supported our Institute for the last 10 years, serving as a trustee and governance committee member. Her contributions to SBP will continue to help us find new ways to prevent, diagnos , treat and potentially cure human disease.

“Pauline believed strongly in our work,” says Perry Nisen, M.D., Ph.D., CEO of SBP. “She was an active, committed advisor, and she generously raised her paddle at our annual gala almost every year.”

Foster was more than a philanthropist, though she did give widely to the Museum of Contemporary Art San Diego, UC San Diego (especially the Jacobs Medical Center), the La Jolla Playhouse and the San Diego Central Library, among other institutions. She also served the community, volunteering and helping direct several organizations, including the United Way, United Jewish Federation and the Jewish Community Foundation. This work earned her considerable recognition, including the United Way’s Alexis De Tocqueville Award.

Perhaps the strongest evidence of Foster’s love of giving back is that she passed it on to her daughters, Karen Silberman and Marcia Hazan, who live in San Diego, and Lisa Foster, who lives in Washington D.C.

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EDUCATION

A Graduate Student Gives Back

She’s also one of our Institute’s most enthusiastic volunteers, sharing her passion for science with San Diego’s disadvantaged students. No matter if they’re 8 or 18 years old, “seeing young people of any age get excited about science is empowering,” she says.

Marisa Sanchez is achieving her educational goals while helping others do the same

At 26, she is busy preparing her Ph.D. thesis in the lab of Dieter Wolf, Ph.D., director of the NCI-designated Cancer Center Proteomics Facility, and she has an overwhelming desire to carve out time for the community.

For graduate student Marisa Sanchez, mentoring young people is in her blood.

As the first in her family to earn a college degree, she’s shepherded her brother and all seven of her cousins into college.

NEVER TOO YOUNG Once a week, Sanchez represents Sanford Burnham Prebys Medical Discovery Institute (SBP) by leading interactive science experiments with third-graders at Lafayette Elementary School in San Diego to show them how cool science is. The program, part of the UC San Diego BioCircuits Institute, is inspiring a new generation of critical thinkers by appealing to their natural curiosity.

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Students from the Preuss School (from right to left) Bao Lam, Luan Nguyen, Daniel Macaraeg, Jennifer Vazquez-Gonzalez, Gizelle Avitia, Julieta Ornelas, (seated) Thuy-An Hoang, America Sanchez Radilla.

Third-graders at Lafayette Elementary School in San Diego having fun with Marisa Sanchez’s science experiment.

The school has a special-education program accommodating hearing-impaired children, and some of the children Sanchez teaches have hearing impairments, which adds to the challenge of teaching science.

More than half the students qualify for free school lunches. “These kids don’t have a lot of privileges, like a lot of other kids these days,” explains Sanchez.

In the summer, she mentors high school students from The Preuss School, one of the highest-ranked schools in California.

To be eligible for the school, students must come from low-income families and strive to be the firs in their family to go to college. Sanchez says the students are academically driven while overcoming challenges that many teenagers don’t usually face.

“I can relate to the Preuss students— that’s why I want to help propel them to a successful future,” she says. To finis her

own degree at UC San Diego, she took out all the financial-ai loans she could.

RAISED TO LEARN Both her mom and dad were forced to drop out of college to take care of their own families. “My mom is from Italy, and my dad is from Mexico. They started working at young ages,” she says. Sanchez grew up listening to both Italian and Spanish, giving her linguistic skills that she says help her in her volunteer work.

While growing up, she says her parents stressed that education is really important.

They always said, “No matter what, no one can take that away from you.”

Now that she’s well on her way toward completing her doctorate, Sanchez loves the idea that SBP’s research “makes a differenc to patients. Translating research to patient treatment is so important here,” she says.

“Science is the root of everything.

It’s an important part of society. The more people are interested in it and stick with it, the better our future will look.”

Marisa Sanchez

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SCIENCE BENEFITING PATIENTS

Brain Matters A dedicated researcher joins forces with a pediatric neurologist to transform the treatment of a dangerous brain tumor.

Sixteen years ago, as a postdoctoral fellow at Stanford University, Robert Wechsler-Reya, Ph.D., met a young boy with a love for soccer, a talent for math and an aggressive form of medulloblastoma, the most common malignant brain tumor in children. The boy’s prognosis was poor.

“It had a profound impact on me,” Wechsler-Reya recalls. “I suddenly felt an urgency in studying the disease, a need to really make progress and fin better treatments.”

That urgency has remained throughout his career, and today, as director of the Tumor Initiation and Maintenance Program at Sanford Burnham Prebys Medical Discovery Institute (SBP), he’s leading innovative research aimed at the most aggressive medulloblastoma tumors.

He’s found a kindred spirit in the clinical world in John Crawford, M.D., director of Pediatric Neuro-Oncology at Rady Children’s Hospital-San Diego.

Together, they’re on a mission to transform medulloblastoma treatment— and the first clinical trial from their collaboration is close at hand.

A DEADLY CANCER Medulloblastoma—a fast-growing cancer that arises in the cerebellum in the lower, rear portion of the brain—is hardly a household word. When most people think of childhood cancers, they think of leukemia, a cancer of the blood and bone marrow. But while leukemia is more common in children, brain tumors are deadlier.

Pre- and postoperative MRI of 8-year-old boy with medulloblastoma Image courtesy of Oncolex.

One reason for that is the so-called blood-brain barrier. Blood vessels in the brain are wrapped in a particular way that insulates them from the rest of the bloodstream. Only certain compounds— like glucose—are allowed entry.

“A drug in the bloodstream will get to leukemia,” Wechsler-Reya notes. “But a lot of chemotherapy drugs can’t get to a brain tumor.”

In medulloblastoma, five-year survival rates are roughly 75 percent, but those rates progressively decline over time.

For the highest-risk tumors, called Group 3, five-year survival is less than 50 percent.

Moreover, because treatment is so aggressive—consisting of surgery, radiation and high-dose chemotherapy— survivors often experience significan long-term side effects, including cognitive deficits, developmental disabilities an increased susceptibility to other cancers.

“We not only need more effective treatments for patients who aren’t surviving,” he says, “but we need safer and less-toxic treatments for the ones who are.”

Robert Wechsler-Reya, Ph.D. (left), director of the Institute’s Tumor Initiation and Maintenance Program, and John Crawford, M.D. (right), director of Pediatric Neuro-Oncology at Rady Children’s Hospital.

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“We not only need more effective treatments for patients who aren’t surviving, but we need safer and less-toxic treatments for the ones who are.”

Robert Wechsler-Reya, Ph.D.

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Mikayla May, a patient (center), meets with John Crawford, M.D.,(right) and Robert Wechsler-Reya, Ph.D. (left).

LIKE-MINDED PARTNERS In the lab, Wechsler-Reya’s group examines the role stem cells play in the development of medulloblastoma, aiming to deepen the understanding of how these tumors form—and develop novel approaches to treat them.

To help develop these approaches and ultimately move research to human clinical trials, Wechsler-Reya reached out to Crawford at Rady Children’s six years ago. He found a willing and eager partner.

Brain cancer now surpasses leukemia as the leading cause of cancer deaths in children.

Source: National Center for Health Statistics

“Basic science research serves as the backbone of our fundamental understanding of the drivers of these tumors,” Crawford says. “Our goal is to change the standard of care for medulloblastoma.”

The pair regularly exchange ideas and collaborate on grants. Most important, Crawford and Michael Levy, M.D., Ph.D., head of Pediatric Neurosurgery at Rady Children’s, arrange (with parental consent) to share patients’ tumor tissue with Wechsler-Reya after surgery.

Wechsler-Reya’s team extensively studies that tissue, conducting genetic profilin and high-throughput drug screening, a specialized automated process that tests the tumor against thousands of drugs and chemical compounds.

They also inject patient tissue into the brain of a mouse. Called a patient-derived xenograft, or PDX, this innovative model allows researchers to study the tumor real-time in a mouse, not just a culture dish.

“As soon as you put tumor cells in a dish, they change—they either die or they acquire new mutations,” Wechsler-Reya says. “But in the mouse, the tumor retains a lot of the properties it had in the patient.”

Their effort are already yielding promising results, including identifying a combination of drugs that potently inhibit growth of Group 3 medulloblastoma with minimal toxicity to normal cells. A clinical trial based on these finding is planned for the near future.

“It’s an ongoing process. Some discoveries will go into clinical trials very soon, but others will take longer,” Wechsler-Reya says. Clinical studies will be run by national consortia, with Crawford and Rady Children’s participating.

SBP is the ideal environment for conducting translational research. “I feel unleashed here,” Wechsler-Reya says. “We do basic science, but everyone is committed to moving research forward to the clinic. The goal is to impact patients.”

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Makayla’s story

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SCIENCE BENEFITING PATIENTS

It was a Saturday morning in late spring 2014, and 4-year-old Makayla May was throwing up—again.

Over the previous two weeks, the San Diego preschooler had thrown up four times and had some coordination issues. Suspecting a stomach virus, her mom, Stephanie May, took her to the pediatrician’s offi . Even after the nurse practitioner directed them to Rady Children’s Hospital-San Diego for a CT scan of Makayla’s brain, the mother of three wasn’t overly worried.

“She seemed fin ,” Stephanie remembers.

“She was joking around and being silly and trying to steal the doctor’s stethoscope.”

Unfortunately, the scan revealed a frightening diagnosis: Makayla had a brain tumor. Surgeons at Rady Children’s soon removed the plum-sized mass from her brain, but she would also need radiation and chemotherapy. That regimen comes with long-term risks—including cognitive deficits endocrine issues and increased susceptibility to other tumors.

Stephanie and her husband, Michael, faced some wrenching decisions.

“It’s horrible enough when your kid gets this kind of thing,” she explains. “But as a parent, it’s almost harder to choose a treatment.

Because you’re choosing to do something that you know is going to harm your child.”

Under the care of John Crawford, M.D., director of Pediatric Neuro-Oncology at Rady Children’s, the Mays sent Makayla’s tumor tissue for special genetic testing to help determine how aggressive her treatment should be.

That testing is far from a perfect science, but it helped the Mays make their decisions.

Today, Makayla—who finishe treatment in March 2015—has no evidence of disease and is a silly, sassy and funny first-grade who loves music, arts and crafts and reading.

Her parents hope that today’s research— such as the collaboration between Drs. Wechsler-Reya and Crawford—will lead to a day when more precise molecular information is generated about each tumor shortly after diagnosis to help families make the best, safest treatment decisions for their children.

“There’s no ‘Eureka’ moment yet—it takes a lot of incremental steps to get there,” Stephanie says. “But I’m really passionate about this research. I feel strongly that parents need the best information early enough to make the best choice for their child.”

Makayla May, who loves music, arts and crafts and reading, completed treatment in March 2015 and has no evidence of disease.

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SCIENCE BENEFITING PATIENTS

The Patient-Scientist Dr. Nicholas Cosford fights cancer personally and professionally

FACTS ABOUT PROSTATE CANCER • 1 of 7 men will be diagnosed with prostate cancer in their lifetimes. early 3 million men are • N living with prostate cancer in the U.S. • I n the U.S., more than 25,000 men will die from prostate cancer in 2016 rostate cancer is the • P second-leading cause of male cancer death behind lung cancer.

Source: American Cancer Society

Nicholas Cosford, Ph.D., researches prostate cancer—while he experiences it. “Yes, I’ve got a real connection to cancer and cancer patients,” he says. “When you go for radiation treatment 39 straight days, you talk to a lot of cancer patients and become part of a unique community.”

Cosford, a professor and associate director of Translational Research in our NCI-designated Cancer Center, was first diagnosed with prostate cancer in 2009 and treated with surgery. “I was fortunate,” he says. “Although screening for prostate cancer generally begins at age 50, my primary physician began monitoring my PSA (prostate-specific antigen) levels at age 40. I was 46 when the cancer was found.”

The PSA test measures blood levels of a protein produced by the prostate.

In general, the higher a man’s PSA level, the more likely it is that he has prostate cancer.

After the surgery, Cosford was essentially cancer-free, until he wasn’t. “Earlier this year, they saw a slight increase in my PSA, which meant that the cancer was still present.” Radiation targeted the areas immediately adjacent to where the tumor had been. “The treatments are incredibly precise,” he explains, “and I experienced few side effects, other than fatigu .”

A FAMILY AFFAIR Two rounds with cancer haven’t dampened his active lifestyle. He and his wife, Rebecca, an analytical chemist, and their two teens are avid hikers and campers. Since 2009, the family has backpacked 800 miles, climbed Mt. Whitney and rafted whitewater rivers.

Cosford says their adventures have created strong, resilient human beings.

“My family adventures have occasionally left us in some precarious situations.

Nicholas Cosford, Ph.D.

When you’re somewhere that you can’t be rescued,” he says, “you have to rely on yourself—and if you’re lucky, you have a team. In my personal life my family is my team, but as I work to confront cancer on a professional level, I rely on my research team.”

A commitment to teamwork and a real understanding of what cancer patients experience make Nicholas Cosford a particularly tenacious researcher. His lab is targeting autophagy, a cellular process of degrading old, damaged cell membranes and proteins that tumor cells use to generate nutrients to grow and survive.

“Cancer cells are on a mission to proliferate rapidly, and that takes energy,” says Cosford. “By blocking autophagy with inhibitors, we can promote tumor cell death. There are a number of autophagy inhibitors in preclinical and ongoing clinical studies, and we are looking at these types of drugs to enhance chemosensitivity and tumor regression.”

A “ P w S o r to a a w a e ty a

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A PROMISING DISCOVERY “In a partnership with Reuben Shaw, Ph.D., professor at the Salk Institute, we have developed a prototype drug, SBI-0206965, that blocks the firs step of autophagy, effectivel cutting o the recycled nutrients that cancer cells need to live,” he adds. “SBI-0206965 targets an enzyme called ULK1 that kick-starts autophagy, and we have shown that it works in human and mouse lung cancer and human brain cancer cells. We are expanding the research into other cancer types with a particular focus on prostate and pancreatic tumors.”

At the same time, his team is digging more deeply into currently approved drugs—“those that could be realistically used tomorrow”—looking for untried combinations that might prove effectiv for individual patients. More acutely than many, Cosford understands that men with prostate cancer need effectiv new therapies now. “Great advances have been made and will continue to be made,” he predicts. Taking into consideration the personal motivation and tenacity of this patient-scientist, progress is in sight.

Nicholas Cosford, Ph.D. (far right), after 10 days in the wilderness hiking through Philmont Scout Ranch in Cimarron, New Mexico, with his family—from left to right, his son, Rayph, his daughter, Lydia, and his wife, Rebecca.

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DISCOVERY HUB

Erkki Ruoslahti, M.D., Ph.D., distinguished professor in SBP’s NCI-designated Cancer Center.

Delivering Drugs to Treat Brain Injuries

About

2.5 MILLION people in the U.S. sustain traumatic brain injuries each year

A new study from the laboratory of Erkki Ruoslahti, M.D., Ph.D., distinguished professor in SBP’s NCI-designated Cancer Center, describes a technology that could lead to new therapeutics for traumatic brain injuries. The discovery, published in Nature Communications, provides a means of delivering drugs or nanoparticles specifi ally to injured areas of the brain.

Brain injuries usually happen as a result of car crashes, falls or violence. While the initial injury may not be repairable, the damaging effect of breaking open brain cells and blood vessels that ensue over the following hours and days may be minimized.

“We have found a peptide sequence of four amino acids: cysteine, alanine, glutamine, and lysine (CAQK), that recognizes injured brain tissue,” says Ruoslahti. “This peptide could be used to deliver treatments that limit the extent of damage.”

The peptide selectively sticks to injured brain tissue (highlighted in pink on this MRI).

“Current interventions for acute brain injury are aimed at stabilizing the patient by reducing intracranial pressure and maintaining blood flo , but there are no approved drugs to stop the cascade of events that cause secondary injury,” says Aman Mann, Ph.D., co-firs author of the study with Pablo Scodeller, Ph.D., both postdoctoral researchers in Ruoslahti’s lab.

“Our goal was to fin an alternative to directly injecting therapeutics into the brain, which is

Source: Centers for Disease Control

invasive and can add complications,” explains Ruoslahti. “Using this peptide to deliver drugs means they could be administered intravenously, but still reach the site of injury in sufficie quantities to have an effect “Not only did we show that CAQK carries drug-sized molecules and nanoparticles to damaged areas in mouse models of acute brain injury, we also tested peptide binding to injured human brain samples and found the same selectivity,” adds Ruoslahti.

This promising technology has been licensed by a startup company, AivoCode, which was recently awarded a Small Business Innovation Research (SBIR) grant from the National Science Foundation for further development and commercialization.

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DISCOVERY HUB

Garth Powis, D.Phil., professor and director of SBP’s NCI-designated Cancer Center.

How Tumors Survive without Oxygen May Point to a New Drug Target One of the reasons tumors can grow out of control is that they survive harsh conditions that normal cells can’t. For example, cancer cells can thrive even when supplies of oxygen are low, which happens when tumor growth outpaces the formation of oxygensupplying blood vessels.

O2 Lack of oxygen in tumors correlates with poor survival in many types of cancer.

Tumor spheroid showing adaptation to low oxygen in the core (red).

Garth Powis, D.Phil., professor and director of SBP’s NCI-designated Cancer Center, has been studying how tumors adapt to this condition, called hypoxia, in hopes of findin ways to block it, which would kill certain cancers.

“Our finding suggest that HIF-1 and glycolysis are a self-perpetuating cycle,” comments Petrus R. de Jong, M.D., Ph.D., postdoctoral associate in Powis’ lab and co-lead author of the study.

Surviving hypoxia requires a protein called hypoxia inducible factor-1 (HIF-1), which controls genes involved in switching tumor metabolism to oxygen-independent pathways and promotes the growth of new blood vessels. Though blocking HIF-1 would kill hypoxic tumors, findin drugs that achieve this has so far proven difficul

“Turning o aldolase A breaks the cycle, decreasing both glycolysis and HIF-1 activity,” Geoffre Grandjean, Ph.D., co-firs author, explains. “This treatment strategy is a double whammy—it keeps tumors from generating energy without oxygen, and it keeps them from becoming better vascularized to get more oxygen.”

A new study from the Powis lab published in Cancer Research may have found another way to overcome cancers’ hypoxia resistance.

To show that aldolase A can be blocked by a drug, Powis teamed with medicinal chemists at the University of Texas at Austin to develop an inhibitor that slowed proliferation in cultured cancer cells.

The research team found that eliminating or blocking an enzyme called aldolase A lowers the activity of HIF-1 and inhibits the growth of breast cancer tumors in mice. Aldolase A is also responsible for one of the steps in glycolysis, a metabolic process crucial for tumor survival, as cancer cells use it to generate energy more than normal cells.

“The inhibitor we used hasn’t been optimized for use as an anticancer drug,” de Jong says.

“However, it could inform future drug design— aldolase A is a very promising target.”

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DISCOVERY HUB Cancer stem cells form less than

3%

of a tumor, but have all the information they need to regrow a new tumor.

Source: National Cancer Institute

Promising New Target to Eliminate Cancer Stem Cells Stem cells play an important role in healing and regeneration by replacing tissue lost to disease or injury. But stem cells can also give rise to tumors.

Cancer stem cells are rare immortal cells found within tumors that self-renew, helping form and sustain tumors. Targeting these cells is an emerging approach to treat cancer, but their resistance to most anticancer therapies has made this di cult.

Now, SBP scientists may have figure out how to eliminate cancer stem cells. The laboratory of Dieter Wolf, M.D., professor in our NCIdesignated Cancer Center, has identifie two proteins abundant in tumors that are required for cancer stem cells to generate energy and survive. The findings published in Cell Reports, suggest that blocking the two proteins may kill cancer stem cells.

Cancer stem cells are immortal—they proliferate indefinitel , while other cancer cells have limited capacity to divide.

“Our finding suggest that the proteins, called eukaryotic initiation factors (eIFs) 3d and 3e, are novel targets for anticancer drugs,” says Wolf, the study’s senior investigator. “If we could fin a way to inhibit these proteins, we could starve cancer stem cells to death.”

Wolf’s team identifie eIF3d and eIF3e by comparing all proteins made in normal cells to cells that lack the proteins. They found that eIF3d/e-deficien cells have much lower amounts of the proteins that make energy in

Dieter Wolf, M.D., director, NCI-designated Cancer Center Proteomics Facility.

Cancer stem cells help form and sustain tumors.

mitochondria (the energy factories of cells), indicating that the higher levels found in cancer stem cells are boosting mitochondria energy production.

“Cancer stem cells, unlike most tumor cells, rely on mitochondrial metabolism for energy,” Wolf explains. “Since these tumor cells have much higher levels of eIF3d/e than normal cells, inhibiting these proteins would preferentially obstruct metabolism in cancer stem cells.

“We’re now examining how eIF3d/e affec cancer metabolism overall to see if these proteins might be relevant to more than just cancer stem cells,” adds Wolf. “We also hope to move this research closer to the clinic, so we’re designing screens to identify drugs that inhibitor eIF3d/e.”

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DISCOVERY HUB p62 may serve as a biomarker of severity in hepatocellular carcinoma.

High Levels of Protein p62 Predict Liver Cancer Recurrence New research shows that high levels of the protein p62 in human liver samples are strongly associated with cancer recurrence and reduced patient survival. The protein was also found to be required for liver cancer to form in mice. This discovery suggests that p62 could be used as a prognostic marker and potential therapeutic target for liver cancer.

The 1-year survival rate for people with liver cancer is

44% Source: American Society of Clinical Oncology

Jorge Moscat, Ph.D., deputy director of SBP’s NCI-designated Cancer Center, was co-senior author on the study, published in Cancer Cell, to which Maria Diaz-Meco, Ph.D., professor, also contributed. Moscat and Diaz-Meco were the firs to discover p62 and have since led effort to fully understand its role in cancer initiation and progression.

By definin factors that allow liver cells to progress from pre-cancer to cancer, the scientists were able to fin one—p62—that can also be used to predict a liver cancer patient’s outcome following full removal of a liver tumor.

In this collaborative study with Michael Karin, Ph.D., distinguished professor of Pharmacology and Pathology at UC San Diego School of Medicine, the team looked at noncancerous liver samples collected from people who had undergone previous treatment to completely destroy their liver cancers. They found that people with higher levels of p62-positive aggregates were

Jorge Moscat, Ph.D., deputy director of SBP’s NCI-designated Cancer Center and Maria DiazMeco, Ph.D., professor.

significantl more likely to see their cancer return and less likely to survive cancer-free than people with low or no p62.

The specifi type of liver cancer analyzed in this study was hepatocellular carcinoma, the most common form of adult liver cancer.

While years of further testing are necessary before doctors might be able to use p62 information to make treatment decisions, new liver cancer detection and prevention methods are sorely needed.

“Our new study illustrates that p62 is necessary and sufficie to induce liver cancer in mice and that its high expression level in liver tissue surrounding a tumor predicts recurrence of the disease after tumors are removed,” says Moscat. “We believe that small molecules that interfere with p62 may be useful for preventing the progression of chronic liver disease to liver cancer.”

40

PATHWAYS

“We express our gratitude to all of our generous donors and volunteers who have supported our Institute over the past 40 years.”

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

OUR MISSION Sanford Burnham Prebys Medical Discovery Institute (SBP) conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. e educate the next generation of scientists to continue our work in improving human health.

OUR STORY • SBP is people—scientists, postdoctoral candidates, graduate students and support staff—who work collaboratively for the benefit of patients • A s an independent, nonprofit institution, we focus on conducting research in cancer, neuroscience, immunity and disorders of metabolism.

• S BP is home to one of the most comprehensive nonprofit drug discovery platforms, is dedicated to research in childhood diseases, and pioneers advances in molecular stem cell research.

• O ur innovation drives our strategic partnerships with the biotech and pharmaceutical industry.

• W e care about and cultivate the next wave of innovative scientists through our graduate program and the breadth of our scientific labs SBP conducts biomedical research funded primarily by grants from agencies of the federal government and private philanthropic support.

SBP is a California not-for-profit public benefit corporation unde Section 501 © (3) of the Internal Revenue Code.

Check out our new website at SBPdiscovery.org

COMMEMORATIVE ISSUE WINTER 2016 ON THE COVER Petrus de Jong, M.D., Ph.D., Brooke Emerling, Ph.D., and Ani Deshpande, Ph.D., are advancing cancer research.

See page 16.

IN MEMORIAM

Trustees

FOUNDERS Dr. William H. and Lillian Fishman* HONORARY TRUSTEES

Roberta and Malin Burnham Joseph C. Lewis T. Denny Sanford TRUSTEES AND OFFICERS

Henry L. Nordho° CHAIRMAN

James C. Blair, Ph.D. VICE CHAIRMAN

Perry Nisen, M.D., Ph.D. CHIEF EXECUTIVE OFFICER DONALD BREN CHIEF EXECUTIVE CHAIR

Kristiina Vuori, M.D., Ph.D. PRESIDENT PROFESSOR, NCI°DESIGNATED CANCER CENTER

Celebrating the life of Conrad Prebys In July, our Institute lost a great friend and supporter.

We dedicate this issue to Conrad Prebys, whose confidence in our work inspires us to continue making medical discoveries that improve human health. We are proud to carry on his legacy.

PAULINE AND STANLEY FOSTER PRESIDENTIAL CHAIR

Gary Chessum, ACMA, CGMA CHIEF FINANCIAL OFFICER

Knox Bell CORPORATE SECRETARY

Lorenzo M. Berho David W. Down Daniel J. Epstein M. Wainwright Fishburn, Jr. Carol G. Gallagher, Pharm.D. William Gerhart Alan A. Gleicher Donald L. Jernigan, Ph.D. James E Jardon II Gregory T. Lucier Papa Doug Manchester Douglas H. Obenshain Edward R. Schulak Stuart A. Tanz Luder G. Whitlock Jr.

*Deceased

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The research at Sanford Burnham Prebys Medical Discovery Institute is made possible in part by philanthropic support. For more information, please contact giving@SBPdiscovery.org or 1-877-454-5702.

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A SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE PUBLICATION | COMMEMORATIVE | WINTER 2016

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If you wish to support our research, please email giving@SBPdiscovery.org or call 1-877-454-5702.