The October Science Connect Series event was themed around Breast Cancer Awareness Month and featured two cancer research experts.
The Sanford Burnham Prebys Wellness Ambassadors hosted a Science Connect event on Wednesday, October 30, 2024, featuring two faculty experts discussing their breast cancer research and its implications.
The Science Connect Series provides a forum for Sanford Burnham Prebys principal investigators to share their research with administrative personnel. Faculty members gain experience in communicating their science to a lay audience, and administrators gain a better understanding of research conducted at the institute so they can become better advocates and ambassadors of the shared mission to translate science into health.
Kelly Kersten, PhD, an assistant professor in the Cancer Metabolism and Microenvironment Program, opened the event by focusing on the importance of finding new treatments —such as immunotherapies — for the one-third of breast cancer patients that are diagnosed after the early stages of the disease when surgery is less effective.
The immune system is one of the main defenses of the human body to fend off harmful pathogens and invasive cells, such as cancer. Among all white blood cells, a particular cell type, called a T cell, can directly kill cancer cells and therefore plays an essential role in building anti-tumor immune responses.
Many types of cancer are confronted and infiltrated by T cells, only to be suppressed by the local tumor environment.
“While immunotherapies that boost the immune system have revolutionized the way we treat cancer, many patients do not respond to the treatments, and the mechanisms of resistance remain largely unclear,” said Kersten.
Kersten’s goal is to understand why T cells enter a state known as exhaustion and lose their tumor-killing capacity. This knowledge will help her team find potential future therapies that could prevent T-cell exhaustion and improve immunotherapies for cancer patients.
Kevin Tharp, PhD, also an assistant professor in the Cancer Metabolism and Microenvironment Program, shared that his lab’s focus is on how cancer cells adapt their metabolism to generate the energy needed to spread to other tissues through metastasis. He presented his team’s work with the Kersten lab on another aspect of potential resistance to immunotherapy in breast cancer.
Tharp and Kersten are studying the hypothesis that part of the reason why these therapies fail is due to tumor-associated fibrosis, the creation of a thick layer of fibrous collagen (like scar tissue) that acts as a barrier against the anti-tumor immune response. They published a paper on June 3, 2024, in Nature Cancer, discussing how tumor-associated macrophages, a type of immune cell found abundantly in the tumor microenvironment, respond to the physical properties of fibrosis.
By synthesizing injury-associated collagens that facilitate wound closure, TAMs experience metabolic changes and generate metabolic byproducts that suppress the anti-tumor function of immune cells.
“The metabolic changes in the microenvironment present more of a challenge to anti-tumor responses than the physical barrier,” said Tharp. “Our study provides an alternative explanation for why anti-tumor immunity is impaired in fibrotic solid tumors.”
To follow up on these results, Tharp is collaborating with Sarah Blair, MD, a professor of surgery at the University of California San Diego, to fund and initiate a clinical trial testing the potential of dietary supplements to counteract the suppressive effects of TAM metabolic byproducts as an adjunct therapy to surgery.
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Two Sanford Burnham Prebys scientists selected for American Cancer Society postdoctoral fellowships
Alicia Llorente Lope, PhD, is a postdoctoral associate in the lab of Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. Ambroise Manceau, PhD, is a postdoctoral associate in the lab of Cosimo Commisso, PhD, interim director and deputy director of the institute’s NCI-Designated Cancer Center.
Funds will support Alicia Llorente Lope and Ambroise Manceau who study breast and pancreatic cancer
Alicia Llorente Lope, PhD, and Ambroise Manceau, PhD, were awarded 2024 Postdoctoral Fellowships from the American Cancer Society (ACS). These prestigious awards provide more than $65,000 per year for up to three years to support early career scientists studying cancer.
“I was so excited when I heard the news,” said Llorente. “It is a privilege to have this award, and it feels very validating to know that someone saw enough potential in my research to deem it worthy of funding.”
Tackling treatment-resistant breast cancer
Llorente joined the lab of Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, nearly three years ago after beginning her breast cancer research career as a doctoral student.
“I was first interested in breast cancer because my grandmother died of the disease, and I wanted to contribute to finding new therapeutic opportunities for cancer patients,” said Llorente. Llorente’s ACS-funded research project focuses on HER2-positive (HER2+) breast cancer.
Roughly one in five breast cancer tumors have elevated levels of the HER2 protein. While these tumors tend to grow quickly, drugs targeting the HER2 protein are usually effective at first. However, HER2+ tumors often are able to adapt and develop resistance to these drugs over time, leaving patients with few if any remaining treatments options.
Llorente has found evidence that a form of the protein phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) plays a role in breast cancer tumors becoming resistant to HER2 drugs.
Brooke Emerling, PhD
“We’ve revealed a strong connection between elevated levels of PI5P4K gamma and reduced survival rates in patients with HER2+ breast cancer,” explained Llorente. “I plan to explore whether targeting both HER2 and PI5P4K gamma in breast cancer cells may provide a path to overcoming treatment resistance.” Llorente also will study the functions of PI5P4K gamma in breast cancer cells to see why these cells cease to respond to HER2-targeting drugs.
“I am incredibly proud of Alicia for spearheading this groundbreaking project targeting the lipid kinase PI5P4K gamma,” said Emerling. “Her insightful analysis of breast cancer datasets, which uncovered a correlation between elevated expression of PI5P4K gamma and worse outcomes in HER2+ patients, has set the stage for vital research aimed at overcoming the significant challenge of resistance to targeted therapies in HER2+ tumors.”
Cosimo Commisso, PhD
Powering down pancreatic cancer
Manceau is in the second year of his postdoctoral training in the lab of Cosimo Commisso, PhD, interim director and deputy director of the institute’s NCI-Designated Cancer Center. During his doctoral program, Manceau studied how abnormal cells die in a programmed series of steps called apoptosis, a process known to go awry in cancer and neurodegenerative diseases.
“It began as a basic science project about the molecular processes around cell death, and over time it led to possible therapeutic implications,” said Manceau. “I learned that I like to study fundamental biology and then try to find an application for it, and I saw in the Commisso lab an opportunity to do just that in pancreatic cancer.”
Manceau’s fellowship project focuses on pancreatic ductal adenocarcinoma (PDAC) — the most common form of pancreatic cancer with only a 13% five-year survival rate — and its ravenous pursuit of energy. Because of PDAC cells’ constant need for fuel to sustain their rampant growth, they adapt by reshaping the surface of their cells to snatch extra nutrients from the jelly-like substance between cells.
Commisso and others have shown that cutting off the extra power supplied by this process — known as macropinocytosis — reduces tumor growth. Manceau has studied the contents taken by contorted pancreatic cell surfaces in pockets called macropinosomes. By analyzing every single protein in this scooped goop, he found that calcium transporter proteins present in macropinosomes also are required for macropinocytosis.
“During the fellowship, I will work to understand how these transporter proteins affect macropinocytosis,” said Manceau. “These proteins have never been targeted before in pancreatic cancer, so our long-term goal is to use this strategy to cut the nutrient supply to tumors and see if we can inhibit tumor growth.”
“By disrupting the cancer cells’ ability to feed themselves through macropinocytosis, we can potentially starve tumors and inhibit their growth,” added Commisso. “Ambroise’s research aims to target key proteins involved in this process, opening up new possibilities for treatments that could significantly improve outcomes for patients battling pancreatic cancer.”
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Svasti Haricharan joins the very first Stop & Talk podcast
Svasti Haricharan, PhD, was the first guest on Stop & Talk—a new podcast offered by The Conrad Prebys Foundation. In the broadcast, Svasti shares how she came to be a research leader in therapy-resistant breast cancer and how race affects clinical outcomes.
Early in her career, Svasti would have to present her research over IPA beers in the UK. (She learned to love beer as she connected with her scientific community.) While completing her postdoctoral training in Texas, her boss asked her to help him write a grant application on cancer disparities and how race affects cancer outcomes. At the time, she had no idea that this was an issue because no one had ever brought it up in her 12 years of training. Since then, she’s taken a deep dive into who gets studied, why, and how to ensure that we help more people in the general population living with cancer.
Join Svasti and Grant Oliphant, the CEO of The Conrad Prebys Foundation, for this important conversation about diversity, science, changing the world, and what it means to be open to multiple viewpoints.
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Ronai discusses new AI-supported breast cancer findings on Arabic-language TV
This month, researchers in Sweden published a study in The Lancet Oncology that compared the efficacy of artificial intelligence-supported mammogram screening versus the standard double reading by radiologists.
The researchers found in their randomized trial that AI-supported mammography screenings are safe, almost halved radiologists’ workload, and detected cancers that reviewing doctors missed.
Not surprisingly, the findings garnered international news coverage. Breast cancer is a global health threat, with more than 2.3 million women worldwide diagnosed each year and nearly 700,000 deaths.
Ze’ev Ronai, PhD, director of the Cancer Center at Sanford Burnham Prebys, was among experts interviewed by global media to provide context to the Swedish findings. He was interviewed on Alhurra, a U.S. government-owned Arabic-language satellite TV news channel that broadcasts internationally outside of the U.S.
You can watch the interview here. It’s in Arabic, but essentially Ronai said:
“This randomized trial of over 80,000 women offers an important advance for early detection of breast cancer, based on AI support of radiologist workload. AI will assist but not replace the role of radiologists in these assessments, and thus, is expected to enable radiologists to attend to more difficult cases. Caution from detections of less harmful lesions (which was one of the outcomes in this study), requires more training and careful validation. Overall, this is an important and safe advance in our quest for early detection of cancer, in this case, breast cancer.”
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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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Top Sanford Burnham Prebys research stories of 2021
This year’s most popular research stories include scientific breakthroughs in COVID-19, cancer, schizophrenia and more.
As we bid farewell to 2021, let’s celebrate our most newsworthy research breakthroughs. Despite the continuing challenges brought on by COVID-19, Sanford Burnham Prebys achieved important milestones on the frontiers of biomedical science.
The following 10 research-related stories received top views on Newswise—the press release distribution service for journalists seeking health and science news.
COVID-19: Scientists identify human genes that fight infection A research team was able to pinpoint specific human genes that control viral infection. The information sheds new light on factors that lead to severe disease and guides therapeutic options.
Leprosy drug holds promise as at-home treatment for COVID-19 Scientists found that the leprosy drug clofazimine, which is FDA approved and on the World Health Organization’s List of Essential Medicines, exhibits potent antiviral activities against SARS-CoV-2, and could become an important weapon against future pandemics.
New drug combination shows promise as powerful treatment for AML Researchers identified two drugs that are potent against acute myeloid leukemia (AML) when combined, but only weakly effective when used alone. The study provides a scientific rationale for advancing clinical studies of the drug combination.
Biomarker could help diagnose schizophrenia at an early age A study described how elevated levels of a protein called CRMP2—found in the brain and blood—could become a format for a rapid, minimally invasive blood test to support the diagnosis of schizophrenia.
Scientists identify “immune cop” that detects SARS-CoV-2 Researchers discovered the sensor in human lungs that detects SARS-CoV-2 and signals that it’s time to mount an antiviral attack. The sensor activates interferon, the body’s own frontline defender against viral invasion.
Study finds promising therapeutic target for colitis Scientists identified an enzyme in the gut that triggers an inflammatory cascade leading to colitis. Therapeutically targeting the enzyme may be a viable approach to help the millions of people worldwide affected by the disorder.
Scientists shrink pancreatic tumors by starving their cellular “neighbors” For the first time, blocking “cell drinking,” or micropinocytosis in the thick tissue surrounding a pancreatic tumor, was shown to slow tumor growth—providing more evidence that micropinocytosis is an important therapeutic target.
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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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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.
The study’s DOI is 0.1021/acs.jmedchem.0c00873.
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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.”
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Prestigious Forbeck Scholar Award granted to Sanford Burnham Prebys cancer researcher
Breast cancer expert Brooke Emerling, PhD, an assistant professor at Sanford Burnham Prebys, has been named a Forbeck Scholar by the William Guy Forbeck Research Foundation.
This prestigious award recognizes early-career cancer researchers for their achievements, research and dedication to the field. As an award winner, Emerling receives rare access to several three-day “think tank” events featuring the world’s top cancer clinicians and scientists.
“My goal is to create therapies that help more breast cancer patients survive cancer,” says Emerling. “The opportunity to discuss my ideas and research with the absolute leaders in my field is incredible and only accelerates my work toward that end.”
Emerling is working to find treatments for triple-negative breast cancer, which is treatable only with standard surgery, chemotherapy and radiation. The lack of specific treatments means that it has a mortality rate three times higher than the other types of breast cancer. Emerling is working to find a personalized medicine that blocks several proteins she identified that allow the triple-negative breast cancer to grow, called PI5P4Ks.
The William Guy Forbeck Research Foundation was established in 1985 by George and Jennifer Forbeck in honor of their son, who succumbed to a rare childhood cancer at age 11. Today the foundation promotes advances in cancer research through collaboration. The foundation began the Forbeck Scholar award as a way to recognize early-career cancer researchers with great future promise. Past Forbeck Scholar award winners hail from Dana-Farber Cancer Institute, the Broad Institute, Cold Spring Harbor Laboratory and other top-tier institutes.