Cynthia Lebeaupin, PhD was recently awarded the 2022 Fishman Fund Fellowship, a postdoctoral award unique to Sanford Burnham Prebys.
The award provides a boosted stipend to exceptional postdocs from the Institute who have a demonstrated research track record and whose work shows significant potential for future breakthroughs.
“It’s an honor to have been selected for such a prestigious award from the Institute, says Lebeaupin, who works in the lab of Randal J. Kaufman, PhD “The resources and people at Sanford Burnham Prebys are incredible and I’m happy to be able to continue my research here.”
Sanford Burnham Prebys introduced the Fishman Fund Awards in 2001 to honor of the Institute’s founders, Dr. William and Lillian Fishman. The fund was established by Reena Horowitz and the late Mary Bradley, longtime supporters of the Institute.
“The Fishmans created an Institute that fosters a collaborative, inspirational atmosphere for postdoc students,” said Horowitz at the 2021 Fishman Fund Awards. “The Fishmans understood that support for new science is a brilliant research investment.”
Lebeaupin has been at the Institute since 2018, and this is not her first honor from the Fishman Fund. In 2021, she was awarded a Fishman Fund Career Development Award, a smaller prize offered to several postdocs each year. She also completed an internship at the Institute’s former Lake Nona campus in 2014.
“I’ve had an affinity for Sanford Burnham Prebys for a long time,” says Lebeaupin. “I knew once I met Dr. Kaufman and everybody on campus that this was the best place to complete my postdoc.”
Lebeaupin’s research focuses on a growing and pressing problem in medicine – liver cancer. One of the major risk factors for developing liver cancer is fat accumulation in the liver, known as fatty liver disease. Increases in obesity rates over the last several decades have led to a dramatic increase in fatty liver disease.
Fatty liver disease is increasing at an alarming rate, and unfortunately, it’s here to stay,” says Lebeaupin. “My research is figuring out how fatty liver disease progresses to liver cancer, so we can use this knowledge to help prevent it.”
In particular, Lebeaupin is working on exploring how cells respond to fatty liver disease over time. She discovered that a molecule that helps liver cells protect themselves from short-term stress can promote cancer in the long-term. She has now moved into studying the system in human tissues.
“This research is exciting because we aim to translate our discoveries from the bench to the bedside,” says Lebeaupin. “What I hope to do in the future is use new technologies on liver samples from patients so we can identify what’s actually going on in liver diseases.”
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Facing cancer disparities head-on: An interview with Svasti Haricharan
Svasti Haricharan, PhD, and her lab are revealing why more Black women get breast cancer, and they’re also telling us what we can do about it.
Svasti Haricharan, PhD, an assistant professor at Sanford Burnham Prebys, is tackling one of the most pernicious problems facing cancer researchers today—why some people, particularly disenfranchised groups such as Black women, get cancer more frequently and more severely than others. For years, the answer has been explained away by differences in lifestyle or socioeconomic status, but Haricharan’s research, published in Therapeutic Advances in Medical Oncology, is demonstrating that the real answer is much more complicated.
What were your findings? We found differences between the breast cells of white and Black women that help explain why Black women experience higher mortality from ER+ breast cancer. These included differences in the expression of specific genes and consistent molecular differences in the cellular signals controlling how fast cells can grow. These differences were present in both healthy and cancerous cells.
Why is it important to study breast cancer disparities? Black and white women have about the same incidence of ER+ breast cancer, but Black women are 42% more likely to die from it. This is just one example of the type of glaring health disparity we see in Black people and other marginalized communities. Unfortunately, these issues have been severely neglected by the research community. Or worse still, they are attributed entirely to lifestyle factors, which often shift the blame to the patients themselves.
What do your findings mean for women with breast cancer? The immediate implication is that we can act on this information to improve diagnostics and treatment for Black women with breast cancer. Our results suggest that at least some Black women could benefit from being treated earlier with CDK inhibitors, which are drugs we already have and understand. In the bigger picture, we’re showing that there are internal factors at play in health disparities that develop based on people’s lived experiences. We’re going to have to really dive in and explore these factors if we want to make any real progress in precision medicine. Everybody deserves care that is tailored to their molecular makeup as closely as possible.
What are some of the challenges still facing researchers working on health disparities? The simplest answer is getting the money to do the research. We’re fortunate that we’ve found something here that’s quickly actionable, but it’s not always going to work out like that. This isn’t about just a few more studies. The types of differences we’ve found here are likely present in other types of cancer and in other groups. The more we look, the more we’re going to find. Funders and researchers alike need to be willing to prioritize this type of research going forward, or we’ll never see real change.
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Padres Pedal the Cause 2022: Team Sanford Burnham Prebys raises more than $21,000 for cancer research
Each year a team from Sanford Burnham Prebys hits the pavement as part of Padres Pedal the Cause, an annual event that invites participants to cycle, spin, run or walk to support local cancer research. This year’s team was small but mighty, raising more than $21,000 to fund collaborative cancer research projects in the San Diego area.
Including the money raised by the Sanford Burnham Prebys team, Padres Pedal the Cause has raised more than $2.8 million this year so far. These funds will be distributed as grants to support collaborations between six participating research organizations: the Salk Institute, Scripps Research, Rady Children’s Hospital, UC San Diego, the La Jolla Institute, as well as Sanford Burnham Prebys.
“This is more than just a fundraising event; it’s also a chance to connect with the cancer community and reflect on the importance of teamwork in cancer research,” says rider Ze’ev Ronai, PhD, director of the Institute’s NCI-designated Cancer Center. “I’ve done the race for four years, and every year it makes me proud to be on team Sanford Burnham Prebys.”
Besides Ronai, notable Institute names on the team this year included Thomas Chung, PhD, director of Translational Programs Outreach at the Conrad Prebys Center for Chemical Genomics; and Scott Tocher, general counsel and vice president of Communications. In addition to the riders, event volunteers from Sanford Burnham Prebys included Michaela Andrews, Araceli Ambert, Mariela Castanares, David Scott, Susan Goho and Katherine Kling.
“We don’t have a huge team, but we always have a great one,” says team captain Adrienne Crown, JD, director of Administration at the Cancer Center and director of Compliance and Operations for the Institute, “I’m so proud that just a few people are able to help make such a big impact.”
The top fundraiser on this year’s team was not an employee of the Institute but is still very much a friend of Sanford Burnham Prebys. Kim McKewon is a longtime donor to the Institute and has been participating in Padres Pedal the Cause since its inception in 2013. This year she raised more than $6,000; and to date, she has raised more than $30,000. In her website bio, she writes that she pedals for her husband, Ray, who is in remission from leukemia.
“Kim is one of the superstars of our team, and we are so thrilled that she was able to ride with us again this year,” adds James Short, Crown’s co-captain and director of Digital Design at the Institute.
And although the event itself is over, the ride is not. The deadline for fundraising is May 9, and 100% of every dollar raised goes toward lifesaving cancer research. Help team Sanford Burnham Prebys create a world without cancer.
Researchers from Sanford Burnham Prebys have collaborated the University of Pittsburgh Cancer Institute to reveal a new approach to enhance the effects of immunotherapy in glioblastoma, one of the most aggressive and treatment-resistant forms of brain cancer.
The study, published recently in Cancer Discovery, describes a novel method to ‘turn off’ cancer stem cells—the malignant cells that self-renew and sustain tumors—enabling the body’s own defense system to take charge and destroy tumors.
“Tumors are more than just masses of cells—each one is a complex system that relies on a vast network of chemical signals, proteins and different cell types to grow,” says senior author Charles Spruck, PhD, an assistant professor at Sanford Burnham Prebys. “This is part of why cancer is so difficult to treat, but it also presents us with opportunities to develop treatment strategies that target the machinery powering tumor cells rather than trying to destroy them outright.”
Glioblastoma is an extremely aggressive form of cancer that affects the brain and the spinal cord. Occurring more often in older adults and forming about half of all malignant brain tumors, glioblastoma causes worsening headaches, seizures and nausea. And unfortunately for the thousands of people who receive this diagnosis each year, glioblastoma is most often fatal.
“We haven’t been able to cure glioblastoma with existing treatment methods because it’s just too aggressive,” says Spruck. “Most therapies are palliative, more about reducing suffering than destroying the cancer. This is something we hope our work will change.”
Immune checkpoint inhibitors—which help prevent cancer cells from hiding from the immune system—can be effective for certain forms of cancer in the brain, but their results in glioblastoma have been disappointing. The researchers sought a way to improve the effects of these medications.
“Modern cancer treatment rarely relies on just one strategy at a time,” says Spruck. “Sometimes you have to mix and match, using treatments to complement one another.”
The researchers used genomic sequencing to investigate glioblastoma stem cells. These cells are the source of the rapid and consistent regeneration of glioblastoma tumors that make them so difficult to treat.
The team successfully identified a protein complex called YY1-CDK9 as essential to the cells’ ability to express genes and produce proteins. By modifying the activity of this protein complex in the lab, the team was able to improve the effectiveness of immune checkpoint inhibitors in these cells.
“Knocking out this transcription machinery makes it much more difficult for the cells to multiply” says Spruck. “They start to respond to chemical signals from the immune system that they would otherwise evade, giving immunotherapy a chance to take effect.”
While the approach will need to be tested in clinical settings, the researchers are optimistic that it may provide a way to improve treatment outcomes for people with glioblastoma.
“What our results tell us is that these cells are targetable by drugs we already have, so for patients, improving their treatment may just be a matter of adding another medication,” adds Spruck. “For a cancer as treatment-resistant as glioblastoma, this is a great step forward.”
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How a breast cancer advocate shapes research at Sanford Burnham Prebys
An end goal of all biomedical research is improving outcomes for patients living with illness, but far too often, patient’s voices are not heard in the process. Advocacy programs, such as those offered by the Susan G. Komen Breast Cancer Foundation, help give individuals battling illness a voice in the lab. They also provide critical insights for the researchers doing the science.
To learn more about the role of patient advocates in cancer research, we spoke with Svasti Haricharan, PhD, an assistant professor at Sanford Burnham Prebys, and Karen McDonald, a patient advocate working with Haricharan’s team. Karen, a retired computer applications professor, has been working with Svasti’s group since 2020 and has battled three forms of cancer in her life, including her current fight with metastatic breast cancer, which began in 2020.
Today, she is helping in the broader fight against cancer by bringing her unique perspective to the lab, both as a retired scholar and as a woman living with cancer.
What do patient advocates bring to the lab and why are they so important?
Karen: I was a neurology technician many years ago, so I have some science background, but I’m not an expert in the type of science that Svasti and her team do. I look at things from a patient’s point of view – not as a scientist or a doctor. I ask questions most patients would ask—but not necessarily questions scientists think about.
One of the things I’ve learned is that I need to have research presentations ahead of time—before a lab meeting—so I can figure out the technical terms. Once I’ve done that, I can bring a real-life perspective to the research—because the scientists aren’t treating patients. Svasti and her team thankfully welcome my input.
Svasti: I agree completely. Having an advocate really helps me and everybody else on the team see things in a completely different way. I think the experience also helps humanize scientists, because it’s easy, especially in biomedical research, to become so focused on the next paper or the next grant that we forget we came into research not to publish papers, but to do amazing science and help people. And having Karen’s perspective does influence what we do.
For example, there was a project on nutraceutical research, or using food as medicine, which a lot of funders don’t want to support because some people think it’s just made up. I was ready to give up on the project because it wasn’t getting support, but Karen brought up the point that patients would love to see this transitioned into the clinic because it’s less toxic with fewer side effects. I went to the top at Sanford Burnham Prebys and actually got funding to develop a drug to mimic the nutraceutical’s effects. I’m not sure this would have happened without Karen’s input—and now we are hopeful for the results.
How far have we come toward giving patients their due voice, and what are some hurdles we need to overcome?
Karen: As times have changed, physicians have stopped being thought of as gods and have started to be more human. They make mistakes. And women in particular have become more active in their healthcare because we were ignored for so long. When women started to speak up, doctors started to listen. I think is why patient advocacy started with breast cancer. Women are communicators and take an integral role in their family’s healthcare. But we still have a long way to go in terms of giving advocates’ voices full consideration.
Svasti: Karen brings up a great point here that women are more used to having to fight to have their voices heard, and that’s why breast cancer helped start the patient advocacy movement through organizations like Susan Komen. It’s beginning to spread beyond breast cancer as more funding agencies are including advocates as grant reviewers, because these are the people who are going to benefit directly from the research.
I think one thing that’s still a problem is not taking an advocate’s input seriously enough. I often see grant applications where the advocate says that a project is very significant, but other reviewers find some nitpicky aspect of the research strategy they don’t like, and the grant doesn’t get funded. There must be a better way for patient advocates’ voices to be included, as opposed to just having them on a review panel to check a box.
What’s something you’d want to tell people who may not know much about cancer research or patient advocacy?
Karen: People need to take it upon themselves to learn more about how research is done. There is such a big divide between scientists and patients, and that’s part of why patients go unheard. Even when you ask your physician about the latest research, they don’t always know.
It’s great that we have the internet now to help. I have a friend with lymphoma and that’s what we spend our time doing – researching the latest science, because we want to make sure we’re in charge of driving our own bus, not letting others have full control.
We need an environment of open-mindedness and willingness to learn. And that goes for physicians as well. We need bridges to connect cancer researchers with the oncologists who are actually going to implement their work and help humanity.
Svasti: That’s such an important idea because just like patient advocates, working with clinicians is sometimes a check box for researchers as well. It’s essential that we have meaningful collaborations—between science and medicine—that can advance research breakthroughs and improve patient outcomes.
I once spoke at a conference that had both patient advocates and researchers, and an advocate came up to me after my talk and asked, “Well what are you doing about this? If your research is real and important, why aren’t you bringing this to clinicians to get this into a clinic to help me?” That really blew my mind, because even though my role is to study cancer in the lab, she was right. Just like we need patient advocates in the lab, scientists need to advocate for research that will help patients the most.
Saying Goodbye to Dawn Dunsmore: A reflection from Josh Baxt
In September 2021, we lost Dawn Dunsmore to breast cancer, a disease she fought for a decade. Dawn was one of Sanford Burnham Prebys’ many committed administrators, most recently in Carl Ware’s lab, before stepping down to pursue treatment. She was a mom, an adventurer, an animal lover, a stubborn fighter and a friend to many, myself included.
Dawn had the bad luck of developing triple-negative breast cancer—one of the deadliest—and the good luck of being surrounded by people who loved her. She had been working for Carl for about two years when she told him about the lump in her chest. She was quickly diagnosed and treated, but the tumor soon returned.
“Dawn was approaching the end very quickly,” says Bobbie Larraga, Community Relations Manager and one of Dawn’s closest friends. “She was having seizures and difficulty breathing, and we were starting to make end-of-life plans.”
In the background, Carl, a world-renowned immunologist, helped Dawn get into a Moores Cancer Center clinical trial for an immunotherapy (PD-1 inhibitor) that takes the brakes off T cells, allowing them to attack tumors. PD-1 inhibitors work for about a third of patients and, fortunately, Dawn was one of them.
“It’s even crazier because breast cancer is not one that typically responds well to checkpoint inhibitors,” says Carl, who directs the Infectious and Inflammatory Disease Center at Sanford Burnham Prebys. “She was lucky to have that response.”
When they work, immunotherapies are like a little miracle, and Dawn did not take that lightly. She’d been given a reprieve and had things to do.
“She was just crazy for travel,” says Bobbie. “She went with her daughter to Spain. Italy, Indonesia, India, Central America. She went skydiving and was able to really check off things on her bucket list.”
But the cancer never quite went away. There were more treatments and surgeries and at 51, she finally ran out of options. Even in September, when the hospital would not release her, she was planning a trip to Yosemite.
Thinking Forward
There are so many stories. Bobbie shared how Dawn interviewed her when she first applied at Sanford Burnham Prebys (then the Burnham Institute); how they had an instant connection. Carl described the incredible work they accomplished, and how her support helped him keep it together when his wife was dying of Alzheimer’s.
I don’t usually insert myself into the articles I write – it’s just not appropriate – but Carl asked if I would, and that got me thinking. I joined Sanford Burnham Prebys in 2008, and the first piece I wrote here was a news release for the faculty member Dawn was working for. I was pretty green and Dawn helped me through, the first time of many. She was a generous soul.
Dawn was one of our own and it hurts that she’s gone. Like many at our Institute, she worked long hours to shepherd papers and grants through and helped manage the labs where she worked. She didn’t complain, even when she had the right.
Her experience underscores Sanford Burnham Prebys’ important work. Immunotherapies were first tested in academic labs, much like ours. It also brings home that the statistics we read so often, five-year survival rates or whatever, are representations of real people. The long hours, the stress of so many deadlines, the weekends in the lab, there’s a reason for those. And it’s a good one.
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Advocates for our Cancer Center ensure patient perspective is understood in the lab
Helen Eckmann and Ruth Claire Black share a common history with breast cancer and a drive to serve their community.
Ruth Claire Black and Helen Eckmann are sisters from different parents. They both have doctorates, work as professors and volunteer for Sanford Burnham Prebys’ Cancer Advisory Board (CAB).
Black and Eckman are incurable optimists and are both thriving after breast cancer. They want other cancer survivors to feel the same way.
“One of the messages we like to deliver is that you can live an amazing, vibrant, positive, productive, fully engaged-in-your-community life,” says Black, “even after fully metastasized, stage 4 breast cancer.”
Parallel journeys
Black knew all along that she was going to face breast cancer. Both her grandmother and mother died from the disease when they were in their 50s. That shoe dropped for her, as expected, around her 50th birthday.
“I got my diagnosis on a Thursday before a long Memorial Day weekend,” says Black. “I kept calling in, getting the switchboard and becoming increasingly anxious. But I was lucky. I had people I could call to talk me off the ledge.”
One of her impromptu counselors was Helen Eckmann.
Eckmann was initially diagnosed when she was 42, the first of three bouts with the disease. Following an inconclusive mammogram, Eckmann was instructed to come back in six months, but a sudden epiphany brought her back sooner.
“I was putting on a pair of shoes, and I think God spoke to me and said, ‘Go now!’” says Eckmann. “I told the doctor I wanted a needle biopsy to figure out whether it was actually cancer. They told me not to worry about it, to wait the full six months, but I insisted. At that point, the cancer had already moved into my lymph system.”
That was just the beginning of her long journey, including multiple rounds of chemotherapy and surgery. “About six years ago, I was going up the stairs, and my right femur broke,” says Eckmann. “The cancer had gone to my bones.”
From Experience to Advocacy
Eckmann and Black were knocked down repeatedly by breast cancer, but they kept getting back up. During these treatment odysseys, each developed a profound ability to see the disconnects in the system: the oncologists who wouldn’t take their intuition seriously (but soon learned better); the insurance companies that seemed to make random coverage decisions; the difficulty finding timely, accurate information.
“I’m a lawyer, a professor and I’ve worked a lot as a consultant,” says Black. “But even with that background, I didn’t know what I needed to know to successfully move through treatment. I think that’s a common theme.”
Both wanted to find productive ways to give back. Eckmann was one of the earliest members of the Sanford Burnham Prebys’ NCI-designated Cancer Center’s Community Advisory Board, which includes cancer survivors and family members who’ve supported a loved one through treatment. She recalls her conversation, many years ago, with President Kristiina Vuori, MD, PhD, who was the Cancer Center director at the time.
“I told her I wanted to help, and she leaned across the desk and practically hugged me,” said Eckmann. “She said she was going to put me to work, and she did.”
Black joined a few years later. Together with seven fellow CAB members, they organize public events to educate the community about cancer research, teach scientists how to communicate their work to lay audiences and help principal investigators with their grant applications.
“Part of the Department of Defense’s (DOD’s) Breast Cancer Research Program grant assessment process is measuring community support for the research,” says Black. “We act as advocates, providing support letters and making sure the patient experience is understood in the lab.”
This is no small piece. Dedicated lab scientists spend much of their time conducting research. And while this often gives them great insights into cancer biology, and possible interventions, it can also create blind spots.
“One time I was at a lab meeting, and they were talking about an experiment that would require patients to give blood samples every month or so,” says Black. “But that’s a high burden to place on people who may not have an extra two hours in their schedule. The lab’s focus was on how to collect these biomarkers sequentially over time, but they hadn’t really thought about the patients. This was a new perspective for them, and they were really open to it.”
Both Eckmann and Black have steadily elevated their game and are now part of the DOD’s Consumer Review Program, in which they rate grant proposals for their potential impact on patients. Eckmann has also joined NCI Cancer Center accreditation visits, and Black is on the Food & Drug Administration’s National Mammography Quality Assurance Advisory Committee.
All these efforts are driven by their concerns for fellow cancer patients and survivors. They clearly remember those early days, soon after diagnosis, when they didn’t understand their roles as patients, insisted on working and keeping their normal hectic schedules and tried to pretend that nothing was wrong.
Over time, they learned that cancer treatment is a marathon, and that it’s easy for people to waste tremendous energy on issues beyond their control until they have nothing left in the tank. However, they also want their peers to know that, yes, a cancer diagnosis is horrific, but it will help people find resilience they never knew they had.
“The journey will make you stronger for sure, whether you want to be stronger or not.”
Ruth Claire Black
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Conrad Prebys Foundation provides $3 million for pediatric brain cancer research
Conrad Prebys was an extraordinary man and a passionate philanthropist. Today, his generosity extends beyond his life through the Conrad Prebys Foundation.
This year, the Foundation provided $3 million to Robert Wechsler-Reya, PhD, and his team of researchers to advance a potential drug to treat medulloblastoma—the most common malignant brain tumor in children.
Children with medulloblastoma often receive aggressive treatment (surgery, radiation and chemotherapy), but many still die of their disease, and survivors suffer long-term effects from therapy. Safer and more effective therapies are desperately needed.
Wechsler-Reya recently combined forces with Michael Jackson, PhD, senior vice president of Drug Discovery and Development, to find a drug(s) that would inhibit the growth of Group 3 medulloblastoma, the most aggressive form of the disease. Using high-throughput screening technology, they identified a compound that reduces levels of a protein called MYC, which is found at exceptionally high levels in Group 3 medulloblastoma, as well as in cancers of the blood, breast, lung and prostate.
“An effective MYC inhibitor could have a major impact on the survival and quality of life of patients with medulloblastoma,” says Wechsler-Reya. “We identified a compound that reduces levels of MYC in medulloblastoma cells, but now we need to learn how it works to optimize it as an anti-cancer drug and advance studies toward the clinic.
“Historically, pharmaceutical companies and funding agencies have under-invested in childhood cancers, and the majority of drugs currently used to treat these cancers were originally developed for adult cancer,” adds Wechsler-Reya. “We believe that effective drugs for pediatric brain tumors must be developed—and this award from the Foundation will help us achieve this goal.”
“We are profoundly grateful to Conrad for his generosity over the years,” says President Kristiina Vuori, MD, PhD “He has a special legacy at our Institute, which was renamed Sanford Burnham Prebys in 2015 to honor him. We are now thankful to his Foundation for including us in their inaugural grant cycle, and for supporting the critical work we do to benefit children and others suffering from cancer.”
The Conrad Prebys Foundation allocated $78 million in its inaugural grant cycle to fund 121 projects. The awards reflect areas of personal interest to Conrad Prebys—including visual and performing arts, higher education, health care, youth development and animal conservation.
Sanford Burnham Prebys joins a long list of recipients, which included other prominent San Diego institutions such as Rady Children’s Hospital, KPBS, San Diego State University, Scripps Research, Museum of Contemporary Art San Diego and the La Jolla Music Society.
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Scientists design potential drug for triple-negative breast cancer
Drug candidate blocks autophagy, a cellular recycling process that cancer cells hijack as a way to resist treatment
Scientists at Sanford Burnham Prebys Medical Discovery Institute have designed a next-generation drug, called SBP-7455, which holds promise as a treatment for triple-negative breast cancer—an aggressive cancer with limited treatment options. The drug blocks a cellular recycling process called autophagy, which cancer cells hijack as a way to resist treatment. The proof-of-concept study was published in the Journal of Medicinal Chemistry.
“Scientists are now learning that autophagy is one of the main ways that cancer cells are able to survive, even in the presence of growth-blocking treatments,” says Huiyu Ren, a graduate student in the laboratory of Nicholas Cosford, PhD, at Sanford Burnham Prebys, and first author of the study. “If all goes well, we hope this compound will stop cancer cells from turning on autophagy and allow people with triple-negative breast cancer to benefit from their treatment for as long as possible.”
Cells normally use autophagy as a way to recycle waste products. However, when cancer cells’ survival is threatened by a growth-blocking treatment, this process is often “revved up” so the cancer cell can continue to receive nutrients and keep growing. Certain cancers are more likely to rely on the autophagy process for survival, including breast, pancreatic, prostate and lung cancers.
“While this study focused on triple-negative breast cancer, an area of great unmet need, we are actively testing this drug’s potential against more cancer types,” says Cosford, professor and deputy director in the National Cancer Institute (NCI)-designated Cancer Center at Sanford Burnham Prebys and senior author of the study. “An autophagy-inhibiting drug that stops treatment resistance from taking hold would be a great addition to an oncologist’s toolbox.”
About 15% to 20% of all breast cancers are triple negative, which means they do not respond to hormonal therapy or targeted treatments. The cancer is currently treated with surgery, chemotherapy and radiation, and is deadlier than other breast cancer types. If the tumor returns, other treatments such as PARP inhibitors or immunotherapy are considered. People under the age of 50 are more likely to have triple-negative breast cancer, as well as women who are Black, Hispanic, and/or have an inherited BRCA mutation.
An optimized drug
In this study, the scientists optimized a first-generation drug they created in 2015. The result is a compound called SBP-7455 that blocks two autophagy proteins, ULK1 and ULK2. SBP-7455 exhibits promising bioavailability in mice and reduces autophagy levels in triple-negative breast cancer cells, resulting in cell death. Importantly, combining the drug with PARP inhibitors, which are currently used to treat people with recurrent triple-negative breast cancer, makes the drug even more effective.
“We are hopeful that we have found a new potential therapy for people living with triple-negative breast cancer,” says Reuben Shaw, PhD, a study author and professor in the Molecular and Cell Biology Laboratory and director of the NCI-designated Cancer Center at the Salk Institute. “We envision this drug being used in combination with targeted therapies, such as PARP inhibitors, to prevent cancer cells from becoming treatment resistant.”
Next, the scientists plan to test the drug in mouse models of triple-negative breast cancer to confirm that the compound can stop tumor growth in an animal model. In parallel, they will continue optimization efforts to ensure the drug has the greatest chance of clinical success.
“Triple-negative breast cancer is one of the hardest cancers to treat today,” says Ren. “I hope that our research marks the start of a path to successful treatment that helps more people survive this aggressive cancer.”
Additional study authors include Nicole A. Bakas, Mitchell Vamos, Allison S. Limpert, Carina D. Wimer, Lester J. Lambert, Lutz Tautz, Maria Celeridad and Douglas J. Sheffler of Sanford Burnham Prebys; Apirat Chaikuad and Stefan Knapp of the Buchmann Institute for Molecular Life Sciences and Goethe-University Frankfurt; and Sonja N. Brun of the Salk Institute.
This work was supported by the National Institutes of Health (P30CA030199, T32CA211036), Epstein Family Foundation, Larry L. Hillblom Foundation (2019-A-005-NET), Pancreatic Cancer Action Network (19-65-COSF), SGC—a registered charity that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking (875510), Janssen, Merck KGaA, Merck & Co, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and Wellcome.
Hope’s research aims to help cancer immunotherapy work for more people
It’s not an overstatement to say that immunotherapy—an approach that uses our own immune system to kill a tumor—has revolutionized the treatment of cancer. Doctors continue to report incredible results, including tough-to-treat tumors seemingly melting away. However, the treatment doesn’t work for everyone, and even if it does work initially, it often stops working as time goes on.
Jennifer Hope, PhD, a postdoctoral researcher in the Bradley lab at Sanford Burnham Prebys, is working to find ways to make cancer immunotherapy work for more people. We caught up with her as she prepared to take the virtual stage at the Diversity and Science Lecture Series at UC San Diego (DASL) to learn more about what she wishes people knew about science and whom she admires.
Did you always know you wanted to be a scientist? I always had an interest in science, but at first I wanted to go a totally different route. I was an athlete in high school and college—I played tennis—and really wanted to go into sports medicine. Then I had my first real experience being in a lab in college, and I was hooked. I liked how hands-on it was and how I could keep asking questions. As my family knows, I’ve always been one to ask a lot of questions and always ask why. I found that being in the lab that was my opportunity to keep coming up with new questions, and finding answers that will impact people’s lives.
What do you research, and what is your greatest hope for your work? I’m trying to understand why the immune system—specifically, T cells—seems to turn a “blind eye” to tumors, which it doesn’t do to other foreign invaders like viruses. My ultimate hope is that we use this information to create better cancer immunotherapies, particularly for skin cancer, which is still really deadly.
What do you wish people knew about science? That it can be a lot of fun! Most people have this perception of science as being very boring. You see X and you do Y. That part can be true. But there’s a lot of opportunity for creativity and to come up with different ways to ask the same question. Some of the best scientists are incredibly creative people.
How would your coworkers describe you? Motivated and always willing to try new things.
When you aren’t working, where can you be found? Reading a book. My family started a book club to stay connected during the pandemic. We just read The Food Explorer by Daniel Evan Stone, which was fascinating. It’s about a botanist who is responsible for transforming what food looked like in the U.S. at the turn of the century. I don’t want to give too much away, but it’s because of him that we have cherry blossoms in Washington D.C., and regulations on importing seeds.
Whom do you admire, and why? My parents. It sounds cliché, but it’s true. They have always been the biggest supporters of my dreams, whether career or personal.
One example that pops into my head is when I was getting my PhD, and my PI moved from Philadelphia to the Netherlands. I had the opportunity to move, too, if I wished. This was obviously a huge step, and I called my parents to talk it through. Immediately, the conversation was about how this would benefit me—the risks and the advantages—and they said they would support me if I wanted to go or not. That meant, and means, the world to me. Ultimately, I did go, and it was an incredible opportunity that I don’t regret at all.
What do you wish people knew about Sanford Burnham Prebys? That everyone is willing to help each other. You don’t see that everywhere. It is proof that you can do science at an exceptional level without competing with each other.
Institute News
Mining “junk DNA” reveals a new way to kill cancer cells
Scientists unearth a previously unknown vulnerability for cancer and a promising drug candidate that leverages the approach
Scientists at Sanford Burnham Prebys have uncovered a drug candidate, called F5446, that exposes ancient viruses buried in “junk DNA” to selectively kill cancer cells. Published in the journal Cell, the proof-of-concept study reveals a previously unknown Achilles’ heel for cancer that could lead to treatments for deadly breast, brain, colon and lung cancers.
“We found within ‘junk DNA’ a mechanism to stimulate an immune response to cancer cells, while also causing tumor-specific DNA damage and cell death,” says Charles Spruck, PhD, assistant professor in the National Cancer Institute (NCI)-designated Cancer Center and senior author of the study. “This is a very new field of research, with only a handful of papers published, but this has the potential to be a game-changer in terms of how we treat cancer.”
Since the human genome was fully sequenced in 2003, scientists have learned that our DNA is filled with some very strange stuff—including mysterious, noncoding regions dubbed “junk DNA.” These regions are silenced for a reason—they contain the genomes of ancient viruses and other destabilizing elements. An emerging area of cancer research called “viral mimicry” aims to activate these noncoding regions and expose the ancient viruses to make it appear that a cancer cell is infected. The hypothesis is that the immune system will then be triggered to destroy the tumor.
A one-two punch to cancer
In the study, Spruck and his team set out to find the molecular machinery that silences “junk DNA” in cancer cells. Using sophisticated molecular biology techniques, they found that a protein called FBXO44 is key to this process. Blocking this protein caused the noncoding sections of DNA to unwind—but not for long.
“When we revealed noncoding regions, which aren’t meant to be expressed, this caused DNA breakage. This told the cell that something is deeply wrong, and it committed suicide,” explains Spruck. “At the same time, the DNA of the ancient virus was exposed, so the immune system was recruited to the area and caused more cell death. So, we really delivered a one-two punch to cancer.”
The scientists then showed that a drug that targets the FBXO44 pathway, called F5446, shrank tumors in mice with breast cancer. The drug also improved the survival of mice with breast cancer that were resistant to anti-PD-1 treatment, an immunotherapy that is highly effective but often stops working over time. Additional studies in cells grown in a lab dish showed that the drug stops the growth of other tumors, including brain, colon and lung cancers.
The scientists also conducted many experiments to show that this silencing mechanism only occurs in cancer cells, not regular cells. Analysis of patient tumor databases confirmed that FBXO44 is overproduced in many cancers and correlated with worse outcomes—further indicating that a drug that inhibits this protein would be beneficial.
Moving the research toward people
As a next step, the scientists are working with the Conrad Prebys Center for Chemical Genomics to design an FBXO44 pathway-inhibiting drug that is more potent and selective than F5446. This state-of-the-art drug discovery facility is located at Sanford Burnham Prebys.
“Now that we have a compound that works, medicinal chemists can make modifications to the drug so we have a greater chance of success when we test it in people,” says Jia Zack Shen, PhD, staff scientist at Sanford Burnham Prebys and co-first author of the study. “Our greatest hope is that this approach will be a safe and effective pan-cancer drug, which maybe one day could even replace toxic chemotherapy.”
