Improving Human Health Archives - Sanford Burnham Prebys
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The Cancer Letter covers collaboration between Sanford Burnham Prebys and the National Cancer Institute to precisely prescribe cancer drugs

AuthorGreg Calhoun
Date

May 14, 2024

The May 10 issue of The Cancer Letter details a recent publication explaining the investigation of a new AI tool that may be able to match cancer drugs more precisely to patients.

The Cancer Letter—a news organization and weekly publication based in Washington, D.C., that focuses on cancer research and clinical care—included an article in its May 10 issue about a partnership between scientists at Sanford Burnham Prebys and the National Cancer Institute (NCI).

Authored by Sanju Sinha, PhD, assistant professor in the Cancer Molecular Therapeutics Program at Sanford Burnham Prebys, and the NCI’s Eytan Ruppin, MD, PhD, the “Trials & Tribulations” feature describes a first-of-its-kind computational tool to systematically predict patient response to cancer drugs at single-cell resolution. The study regarding this new tool was published on April 18, 2024, in the journal  Nature Cancer.

The Cancer Letter was founded in 1973 and focuses its coverage on the development of cancer therapies, drug regulation, legislation, cancer research funding, health care finance and public health.

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How cancer research silos perpetuate inequity in cancer outcomes: An interview with Svasti Haricharan

AuthorMiles Martin
Date

April 18, 2023

The National Institutes of Health recognizes National Minority Health Month each April. This is a time to raise awareness about the importance of reducing the health disparities faced by racial and ethnic minorities.

For our part, we spoke to Assistant Professor Svasti Haricharan, PhD, about her recently published review in Clinical Cancer Research. The paper describes some of the shortfalls of the current research focusing on cancer disparities. It also reveals what needs to happen to solve this problem. 

This paper describes “research silos” in cancer disparities, but what does this term mean?
The cancer research community has made a lot of progress recognizing that cancer research has a data diversity problem. We know that we need more researchers working on cancer disparities—for example, finding explanations as to why some racial and ethnic minorities have worse cancer survival rates than others. We also know that we need to generate more inclusive data in cancer research generally, which means building databases that include data from people of different backgrounds.

However, what we’re talking about in this new paper is a bit more subtle than that. It has more to do with which disparities researchers are studying and how they’re studying them. Cancer-disparities researchers tend to fall into two different categories with two very different approaches. One group focuses more on the societal problems driving disparities, and the other group is looking closely at the biology. But these two paths aren’t intersecting, which is preventing us from truly addressing racial disparities in cancer.

Can you tell us more about those two groups and how this division affects cancer research?
The first group includes researchers who study cancer disparities in the way most people understand them. They focus on social determinants of health, such as socioeconomic status and systemic bias in the healthcare system. The second group looks at the biology directly, focusing on how genetics impacts the molecular biology of cancer. These are both important research areas, and we’ve made a lot of progress independently with each of them.

The problem is that focusing on one or the other ignores something critical that has gained attention in recent years: lifestyle factors have a direct impact on the molecular biology of cancer. Our lived experiences leave a unique footprint in our cells on top of what’s already there because of what we inherited at birth. By keeping these two types of cancer research trapped in silos, we’re missing synergistic leaps that could truly transform our understanding of cancer outcome inequity. Breaking down these silos is the only way to keep moving this type of research forward.

How can we break down these silos? 
Looking at it broadly, funding bodies need to invest more in research that develops datasets using biological samples from underrepresented groups. This will help us learn more about how societal factors can have a different impact on the biology of cancer—depending on the person with the disease. Here in the lab, we need to create experimental systems that better represent the biology of people from racial and ethnic minorities. This could also help us solve an even bigger problem.

Therapeutic strategies for cancer that we find in the lab don’t often make it to the clinic. Improving the diversity of our cancer data will improve this success-to-failure ratio. It will help us identify treatments that work better in some people than in others and choose the best treatments for each patient. In other words, it will help us work toward truly individualized medicine. Ultimately, we can only develop good precision medicine for cancer when we start looking at all patient demographics more equitably.

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Padres Pedal the Cause 2023: Team Sanford Burnham Prebys raises $50,000 for cancer research

AuthorMiles Martin
Date

March 20, 2023

Team Sanford Burnham Prebys hit the pavement this weekend for Padres Pedal the Cause, an annual fundraising event that invites participants to cycle, spin, run or walk to support local cancer research. The funds raised through each year’s race go to seed grants that fund collaborative cancer research projects in San Diego. 

“Padres Pedal the Cause is a chance for the cancer community to come together and remember why collaboration is so important in cancer research,” says bike rider Ze’ev Ronai, PhD, director of the Institute’s NCI-designated Cancer Center. “Virtually all of us know somebody who has been impacted by cancer, including me. This is my fifth Padres Pedal the Cause, and every year I’m so proud to be part of our Institute’s team and help contribute to cancer research outside the lab.”

This year’s team was formidable: 56 employees and friends of the Institute signed up to either ride, run, or walk in the event. Team members came from all areas of the Institute, including faculty, staff scientists, administrative staff, postdocs, and even current and former members of the Institute’s Board of Trustees, such as Bill Gerhart and Steve Williams. Other notable names on this year’s team included longtime participants such as Professor Nicholas Cosford, PhD and James Short, associate director of Digital Communications and Design. 

“I’ve been with Padres Pedal the Cause since the very beginning, and it’s one of the highlights of my year,” says Short, who has helped lead the Institute’s team for the last 10 years.

The team also included some new members this year, such as Assistant Professor Lukas Chavez, PhD, and Director of Experimental Pharmacology Raghu Ramachandra, PhD, who both joined the Institute late last year. 

While Institute employees were well represented on this year’s team, there were also current some of the team’s top fundraisers had a different reason to join team 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. 

“I pedal for my husband, Ray, who is in remission from leukemia because of science and research, the very focus of the grants that are given from the fundraising that comes out of this event,” she writes in her website bio.

It’s not too late to support Team Sanford Burnham Prebys
To date, team Sanford Burnham Prebys has raised more than $300,000 through Padres Pedal the Cause since its inception in 2013. And while this year’s ride is over, there is always time to support local cancer research. The fundraising deadline for this year’s Padre’s Pedal the Cause is April 18, and 100% of every dollar raised goes toward lifesaving cancer research. Help team Sanford Burnham Prebys create a world without cancer.

 

Support Team Sanford Burnham Prebys

 

 

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Sanford Burnham Prebys researchers awarded Curebound grants

AuthorMiles Martin
Date

March 20, 2023

Each year, Sanford Burnham Prebys joins Padres Pedal the Cause, an annual fundraising event that raises money for Curebound which awards collaborative cancer grants in the San Diego area.

These grants include Discovery Grants, which provide seed funds for high-risk/high-reward research in the earliest phases, and Targeted Grants, which are larger awards ($500K) that help translate promising discoveries into treatments for the clinic.

In the 2022-2023 Curebound Research portfolio, five researchers from Sanford Burnham Prebys were awarded grants: Associate Professor Anindya Bagchi, PhD, Professor Linda Bradley, PhD, Assistant Professor Lukas Chavez, PhD, Professor Nicholas Cosford, PhD, and Professor Michael Jackson, PhD

2022 Discovery Grant: Treating incurable pediatric brain tumors 
Bagchi and Chavez will collaborate to advance a new therapeutic approach for medulloblastoma, the most common childhood brain tumor. They will be focusing on a gene called MYC, found only in the deadliest forms of medulloblastoma. This form of brain cancer is currently untreatable, but Bagchi and Chavez recently discovered a molecule that can help control the activity of the MYC gene and potentially inhibit the growth of medulloblastoma tumors. The researcher holds promise to reveal a new treatment approach for this incurable cancer. 

The grant is titled “Decoding the Role of the Long Non-Coding RNA PVT1 in Medulloblastoma.”

2023 Targeted Grant: Discovering a new immunotherapy drug for melanoma
Bradley will be working with Soo Jin Park, MD, from UC San Diego Health to advance a new immunotherapy approach for malignant melanoma. Despite recent advances, this type of skin cancer still causes thousands of deaths in the U.S. each year. The goal of their project is to develop a new drug for melanoma that can reactivate the tumor-killing properties of the patient’s own immune system. This therapeutic approach has the potential to destroy tumors that are resistant to existing therapies, which could help save lives.

The grant is titled, “Advancing Immune Checkpoint Inhibition of PSGL-1 for Treatment of Malignant Melanoma.
 

2022 Discovery Grant: Developing drugs for bone-metastatic prostate cancer
Cosford will work with Christina Jamieson, PhD, from the University of California, San Diego, to advance a new treatment approach for prostate cancer that has spread to the bones. Bone is the most common place for prostate cancer to metastasize, and this form of cancer is currently incurable. The researchers will look for drugs that can kill tumor cells by inhibiting autophagy, a process that promotes tumor progression. The results of the study could identify a new drug ready for clinical trials.

The grant is titled “Pre-Clinical Development of New Autophagy Targeting Drugs for Bone Metastatic Prostate Cancer.”

2022 Discovery Grant: Repurposing drugs for deadly childhood brain cancer
Jackson and Chavez will collaborate to identify new treatment options for ependymoma, an aggressive pediatric brain tumor and leading cause of death among childhood cancer patients. The researchers will screen patient tumor cells against drugs already approved by the FDA for other conditions, looking for drugs that could be repurposed to fight these tumors. Because FDA-approved drugs are known to be safe for humans, this may prove to be the quickest way to help patients currently living with this cancer. 

The grant is titled “High Throughput-Screen for Inhibitors of Pediatric Ependymoma.”

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Is cloud computing a game changer in cancer research? Three big questions for Lukas Chavez

AuthorMiles Martin
Date

February 22, 2023

As an assistant professor at Sanford Burnham Prebys and director of the Neuro-Oncology Molecular Tumor Board at Rady Children’s Hospital, Lukas Chavez, PhD, leverages modern technology for precision diagnostics and for uncovering new treatment options for the most aggressive childhood brain cancers.

We spoke to Chavez about his work and asked him how modern technology—particularly cloud computing—is shifting the approach to cancer research.

How are you using new technologies to advance your research?

New technologies are helping us generate a huge amount of data as well as many new types of data. All this new information at our disposal has created a pressing need for tools to make sense of it and maximize their benefits. That’s where computational biology and bioinformatics come into play. The childhood brain cancers I work on are very rare, which has historically made it difficult to study large numbers of cases and identify patterns.

Now, data for thousands of cases can be stored in the cloud. By creating data analysis tools, we can reveal insights that we would never have seen otherwise. For example, we’ve developed tools that can use patient data in the cloud to categorize brain cancers into subtypes we’ve never identified before, and we’re learning that there are many more types of brain tumors than we’ve previously understood. We’re basically transforming the classic histo-pathological approach that people have studied for decades by looking at tumor tissues under the microscope and turning that into data science.

How is cloud computing improving cancer research in general?

Assembling big datasets delays everything, so I believe the main idea of cloud computing is really to store data in the cloud, then bring the computational tools to the data, not the other way around.

My team did one study where we assembled publicly available data, and basically downloaded everything locally. The data assembly process alone took at least two to three years because of all the data access agreements and legal offices that were involved.

And that is the burden that cloud computing infrastructures remove. All of this personalized cancer data can be centrally stored in the cloud, which makes it available to more researchers while keeping it secure to protect patient privacy. Researchers can get access without downloading the data, so they are not responsible for data protection anymore. It’s both faster and more secure to just bring your tools to the data.

Are there any risks we need to be aware of?

Like any new technology, we need to be clear about how we use it. The technology is another tool in the toolbox of patient care. It will never entirely replace physicians and researchers, but it can complement and assist them.

Also, because we use costly and sophisticated tools that are being built and trained on very specific patient groups, we need to be careful that these tools are not only helping wealthier segments of society. Ideally, these tools will be expanded worldwide to help everybody affected by cancer.

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Facing cancer disparities head-on: An interview with Svasti Haricharan

AuthorMiles Martin
Date

May 25, 2022

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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Scientists design potential drug for triple-negative breast cancer

AuthorMonica May
Date

February 16, 2021

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

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.

Research funding 

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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Meet immunologist Jennifer Hope

AuthorMonica May
Date

February 12, 2021

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.

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Mining “junk DNA” reveals a new way to kill cancer cells

AuthorMonica May
Date

February 11, 2021

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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Scientists “turn back time” on cancer using new stem cell reprogramming technique

AuthorMonica May
Date

August 21, 2020

Discovery opens new research avenues that may help catch cancer early and identify potential preventive treatments

Scientists at Sanford Burnham Prebys Medical Discovery Institute have reprogrammed cancer cells back into their pre-cancer identity—opening new doors for studying how cancer develops and how it might be prevented. The research, published in Stem Cell Reports, may lead to tests that identify cancer early on, when it can be more easily treated, and uncover preventive treatments that stop cancer before it starts.

“We believe we have been able to contribute to one of the major goals of modern cancer research: creating next-generation models for studying how cancer develops from its earliest state,” says Evan Snyder, MD PhD, professor and director of the Center for Stem Cells & Regenerative Medicine at Sanford Burnham Prebys and senior author of the study. “We essentially took an adult cancer that has accumulated many mutations and pushed it back to the earliest stages of development, allowing us to emulate a tumor’s premalignant state. Then we watched cancer emerge from normal cells before our eyes.”

Turning back the clock on cancer 

In the study, the scientists set out to transform cells from anaplastic thyroid tumors—an aggressive, fast-growing cancer that is nearly always diagnosed at late stages—into induced pluripotent stem cells (iPSCs). These cells model the embryonic cells that are present at the earliest stages of human development and can become any cell in the body. While iPSCs are used today to create unlimited supplies of cells for research and therapeutic purposes—usually to correct abnormalities—the scientists recognized that tumor-derived iPSCs could be used to study the development of cancer.

However, this feat turned out to be easier said than done. The standard reprogramming method didn’t work, requiring the researchers to hunt for a different method that would induce the cancer cells to reset. Inhibiting a protein called RAS was the key ingredient that coaxed these thyroid cancer cells to become normal iPSC cells.

“We have named the pathway that is critical for making a cancer cell act as if it were a normal cell its ‘reprogram enablement factor,’” explains Snyder. “That factor will likely be different for every cancer and, in fact, may help in defining that cancer type.

“For this cancer type, which we examined in our study as a proof-of-concept, the reprogram enablement factor turned out to be blunting an overactive RAS pathway,” Snyder continues. “Our results suggest that losing control of RAS was the ‘big bang’ for this cancer—the very first event that leads to out-of-control cell growth and development of a tumor.”

The scientists next plan to reprogram additional cancers—including brain and lung cancer—into iPSCs to determine their “reprogram enablement factors.” If successful, they will next map the molecular changes that occur immediately before and after the tumors develop, which could reveal early signals of cancer and new preventive or early treatment measures.

“Unlike other cells, cancer cells are notoriously resistant to reprogramming,” says Snyder. “Our study is the first to successfully reprogram cancer cells into completely normal iPSCs, which opens new doors for cancer research.”

A team effort

The first author of the study is Yanjun Kong of Sanford Burnham Prebys and Shanghai Jiao Tong University. Yang Liu of Sanford Burnham Prebys is a co-corresponding author. Additional study authors include Ryan C. Gimple of UC San Diego; Rachael N. McVicar, Andrew P. Hodges and Jun Yin of Sanford Burnham Prebys; and Weiwei Zhan of Shanghai Jiao Tong University.

This study was funded by the Stem Cell Research Center & Core Facility at Sanford Burnham Prebys and by the China Scholarship Council (201606230202). The study’s DOI is 10.1016/j.stemcr.2020.07.016.