cancer Archives - Sanford Burnham Prebys

Tag: cancer

Institute News

Cell stress response bears good news and bad news for liver cancer

AuthorGreg Calhoun
Date

February 12, 2026

Human liver anatomy structure, 3d illustration. Image courtesy of Shutterstock
A new study shows that liver cell stress can lead to cancer, yet it also can make tumors less resistant to immunotherapy. The findings may lead to new treatments and help physicians determine which patients will benefit from existing immunotherapies. Image credit: crystal light/Sanford Burnham Prebys.

Cell stress response protein implicated in cancer progression, yet it also weakens resistance to immunotherapies

Metabolic disorders such as obesity and type 2 diabetes place extra stress on the liver. Liver cells try to protect themselves from the accompanying surge in dysfunctional proteins by activating factors that help restore an appropriate protein balance.

One of these factors is a protein called activating transcription factor 6 alpha (ATF6α) that was recently shown to drive the onset of liver cancer if left permanently active. In a Nature study published February 4, 2026, an international team of scientists demonstrated that activating ATF6α in mice caused liver disease that progressed to liver cancer.

In data from human liver cancer patients, ATF6α activation was linked with more aggressive tumors, a suppressed immune system surrounding tumors and reduced patient survival.

The researchers also uncovered ways that ATF6α might be used to advance the treatment of liver cancer. Liver cells with ATF6α switched off developed fewer tumors. While high ATF6α activity levels were associated with cancer progression, they also were found to make tumors more susceptible to certain immunotherapies.

These findings suggest the need for future clinical trials to test drugs that directly target ATF6α to treat the disease. Additionally, it might prove advantageous to screen liver cancer patients for ATF6α activity to find those most likely to benefit from existing immunotherapies.

Portrait of Randal J. Kaufman, PhD

Randal Kaufman, PhD, is a professor in the Center for Metabolic and Liver Diseases at Sanford Burnham Prebys and a co-corresponding author of the study. Image credit: Sanford Burnham Prebys.

To learn more, read the German Cancer Research Center press release.

Xin Li, PhD, a postdoctoral fellow at the German Cancer Research Center (DKFZ), shares first authorship of the study with co-corresponding author Cynthia Lebeaupin, PhD, principal scientist at Pfizer and former postdoctoral researcher at Sanford Burnham Prebys Medical Discovery Institute.

The other co-corresponding authors are Dirk Haller, PhD, Technische Universität München; Randal Kaufman, PhD, Sanford Burnham Prebys; and Mathias Heikenwälder, PhD, University of Tübingen and DKFZ.

Institute News

Sanford Burnham Prebys hosts inaugural event in the Women in Science Lecture Series

AuthorGreg Calhoun
Date

October 21, 2025

David Brenner, MD, meets with speaker Susan Tousi, MBA
Sanford Burnham Prebys president and CEO David Brenner, MD, meets with speaker Susan Tousi, MBA, CEO at DELFI Diagnostics, prior to the inaugural event in the Women in Science Lecture Series.

The series highlights the groundbreaking work and unique perspectives of women leaders in the biomedical sciences

Susan Tousi, MBA, CEO at DELFI Diagnostics, opened the event by discussing the lessons she learned throughout her career journey. At DELFI Diagnostics, she is leading a team focused on improving the detection of lung cancer. The company’s goal is to make lung cancer screening more accessible through a blood test that is analyzed by applying machine learning and next-generation sequencing.

Prior to this role, Tousi served as a senior vice president for more than 10 years at Illumina, Inc., including as chief commercial officer for three years. During her tenure, she contributed to making genomic sequencing more affordable as the cost of sequencing a single genome fell from more than $5000 in 2013 to $200 in 2023. Tousi also borrowed from her experience developing consumer printers for Eastman Kodak and Hewlett-Packard, emphasizing the importance of making Illumina’s sequencing machines easy to use for clients in research labs, hospitals and clinics.

“My time at Illumina was amazing,” said Tousi. “I had the absolute privilege of seeing our genomic capabilities installed in 155 countries around the world.”

Tousi concluded with her optimism about how technology is transforming healthcare.

“I think we are on the precipice of major shifts in technology with the advancement of AI and where we’ve come with genomics, multiomics and the access to large-scale molecular data,” said Tousi. “I think you know these new technologies like blood-based liquid biopsy testing are going to allow us to find disease earlier, to treat it more precisely and monitor its recurrence across many disease areas.

“This can be the dawn of a new beginning in science and the advancement of healthy lives.”

Susan Tousi and Brooke Emerling

From left: Brooke Emerling, PhD, and Susan Tousi, MBA
Image credit: Sanford Burnham Prebys

Kevin Tharp, PhD, assistant professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, then moderated a fireside chat and audience question-and-answer session with Tousi and Brooke Emerling, PhD, director and associate professor in the Cancer Metabolism and Microenvironment Program. Topics included: different gender-based expectations in scientific fields; the importance of mentorship and paying it forward; dealing with the emotional toll of studying diseases more prevalent in women; and programs providing opportunities for future leaders in science and medicine.

The Women in Science Lecture Series features quarterly events and is part of broader efforts at Sanford Burnham Prebys to foster an environment that nurtures the success of individuals from all backgrounds. The series is hosted by the Office of Workforce Engagement & Belonging and highlights the groundbreaking work and unique perspectives of women leaders in the biomedical sciences, while fostering mentorship and collaboration across the Torrey Pines Mesa.

Women in Science lectures are free and open to the public. Registration is open for the next event in the series on February 11, 2026.

Institute News

Sanford Burnham Prebys expert surveys science on how to treat the most common brain cancer

AuthorGreg Calhoun
Date

October 6, 2025

Glioblastoma brain cancer cells under microscope. Image credit: Anna Durinikova/Shutterstock
Glioblastoma brain cancer cells under a microscope. Image credit: Anna Durinikova/Shutterstock.

New editorial recommends a multimodal perspective examining glioblastoma from tumor biology through to surgery

Glioblastoma is one of the most aggressive and treatment-resistant forms of brain cancer. It also is the most common form of cancer that originates in the brain, making research into new and better therapies even more imperative.

Physician–scientist Theophilos Tzaridis, MD, a postdoctoral fellow at Sanford Burnham Prebys Medical Discovery Institute in the lab of Peter Adams, PhD, recently surveyed promising glioblastoma studies after being invited to serve as a guest editor for a special issue of Frontiers in Oncology and Frontiers in Neurology.

More exact and safe surgeries

Tzaridis highlighted two studies focused on improving surgery for glioblastoma, as it continues to be the primary treatment for the disease. The recent publications discussed how to enhance the use of MRI to map out tumors and surrounding tissue, as well as other innovative mapping and monitoring techniques. These approaches would enable neurosurgeons to create better and safer plans for reducing risk of recurrence and avoiding side effects before starting surgery.

Targeted treatments and immunotherapies

Scientists have sought to add treatment options for glioblastoma beyond surgery, radiation therapy and chemotherapy. Some other cancers can be treated with targeted therapies that exploit a unique characteristic of certain tumors, but this approach has yet to yield long-term successes for glioblastoma patients. Tzaridis brought forward a case report of a patient whose tumors were nearly completely cleared by a targeted therapy after chemotherapy was unsuccessful. He suggests that future studies are warranted to identify patient subpopulations that can benefit from these treatments.

Theophilos Tzaridis, MD. Image credit: Sanford Burnham Prebys.

Theophilos Tzaridis, MD, a postdoctoral fellow at Sanford Burnham Prebys Medical Discovery Institute. Image credit: Sanford Burnham Prebys.

Immunotherapies that supercharge the immune system to better detect and eliminate cancer have transformed the treatment of many blood cancers and solid tumors. It has not, however, yet born fruit as an effective treatment for glioblastoma. Tzaridis spotlights a study discussing the potential use of chimeric antigen receptor (CAR) natural killer (NK) cells in glioblastoma rather than the more common CAR T-cell therapies.

The blood brain barrier and brain cancer biology

In addition to demonstrating how research is contributing to improving existing treatments and finding new potential therapies, Tzaridis emphasized the importance of continued studies of brain cancer cell biology and the obstacle to treatment posed by the blood brain barrier. He highlighted two studies focused on overcoming the blood brain barrier along with another two studies regarding cellular models and the use of extracellular vesicles to package and deliver treatments.

“With a multimodal perspective from addressing challenges in neurosurgery to improving our understanding of tumor biology and achieving therapeutic delivery into the brain, we have the best chance of improving survival of patients with this devastating disease,” said Tzaridis.

Institute News

Xueqin Sun awarded $600,000 V Foundation grant to study one of the most common and deadly brain cancers

AuthorGreg Calhoun
Date

September 29, 2025

Xueqin (Sherine) Sun, PhD. Photo credit Sanford Burnham Prebys
Xueqin (Sherine) Sun, PhD. Image credit: Sanford Burnham Prebys

The new award will fund research regarding a hidden weakness in glioblastoma tumors that could lead to a new treatment

Xueqin (Sherine) Sun, PhD, was awarded a three-year, $600,000 V Foundation for Cancer Research grant to study glioblastoma, one of the most common and deadly brain cancers.

Sun will use the award to follow up on her lab’s research regarding a hidden weakness in glioblastoma tumors that could lead to a new treatment. Her team will focus on tumor protein 53, or p53, which normally prevents tumors by detecting DNA damage so it can be repaired, or the cell can self-destruct.

“Think of p53 as the body’s security guard that protects against cancer,” said Sun. In glioblastoma tumors, however, p53 often is unable to do its job.

In nearly three out of every four glioblastoma tumors, another protein called bromodomain-containing protein 8 (BRD8) locks up p53, preventing a key piece of the body’s natural defense mechanisms from fighting back against the growing threat.

“We discovered a way to break apart BRD8, which could free up p53 and let it fight the cancer again,” said Sun.  

The Sun lab will test this approach using lab-grown glioblastoma cells and mini-brain tumor models created from patient samples.

“Our goal is to advance this approach that may lead to new therapeutic strategies for patients facing this devastating disease,” said Sun.

The V Foundation for Cancer Research was founded in 1993 by ESPN and the late Jim Valvano, North Carolina State University basketball coach, ESPN commentator and member of the Naismith Memorial Basketball Hall of Fame. The V Foundation has funded nearly $400 million in cancer research grants in North America.

Institute News

From lab insight to patient impact: Physician–scientist Theophilos Tzaridis on advancing treatments for pediatric brain tumors

AuthorCommunications
Date

September 18, 2025

Theophilos Tzaridis, MD. Photo credit Sanford Burnham Prebys

Recipient of the Fishman Awards: Cynthia Schwartz Shenkman Research Excellence Fishman Award Theo Tzaridis discusses his work on pediatric brain tumors, why rigorous preclinical science matters, and how donor support accelerates discoveries.

Established in 2024, the Cynthia Schwartz Shenkman Research Excellence Fishman Award is unique in nature because it recognizes a Sanford Burnham Prebys postdoc for their outstanding biomedical research contributions and demonstrated track record of research excellence.

What’s your current role and focus at Sanford Burnham Prebys?
I’m a physician–scientist studying pediatric brain tumors. I focus on diffuse midline glioma (DMG). I joined Rob Wechsler-Reya’s group at the institute and benefited from him as an amazing mentor and his expertise in mouse modeling of brain tumors tremendously. After Rob moved institutions, I joined Peter Adams’s lab. Peter’s aging and cancer perspective gives my immunotherapy work a fresh lens and he is a truly spectacular mentor. We’ve built a DMG “niche” in the lab and I’ve deepened my in vivo skills, which are essential for translating ideas toward the clinic.

What drew you into oncology and neurology?
Even in high school I was fascinated by how a cell can go “crazy”, grow uncontrollably and form a tumor. Medicine let me pair that curiosity with real patient impact. My MD thesis work in Heidelberg, Germany, suggested an old chemotherapy could reactivate a tumor suppressor which paved the way for a clinical trial. During my neurology residency in Bonn, Germany, I helped plan, analyze, and published results from  a clinical trial that became the first positive glioblastoma study in 14 years. Those experiences were very rewarding and cemented my focus on translational research.

You mentioned that your approach to immunotherapy starts with “back to basics.” What does that mean?
Many brain tumor trials borrowed targets from other cancers without confirming those targets exist in the brain tumor microenvironment. We went back to basics, systematically profiled immune checkpoint molecules present in DMG and found CD155 (also called the poliovirus receptor) consistently expressed across models and patient samples. That points to smarter targeting rather than one-size-fits-all strategies.

How has the Institute’s environment shaped your work?
The culture at Sanford Burnham Prebys is genuinely team oriented. Core facilities (flow cytometry, mouse) are exceptional partners in experimental design. We also engage in a cross-institution “Brain Tumor Club” on the Mesa and contribute data to a molecular tumor board that informs real treatment decisions. In one case, marker data I generated supported a physician’s plan to pursue a personalized immune therapy known as CAR T-cells for a child which was an incredibly meaningful moment.

Any notable collaborations beyond campus?
Yes. Our in vivo expertise enabled joint studies with Emory University, including work on small molecules for pediatric brain tumors. We have also collaborated with Columbia University and the Dana Farber Institute. These multi-site projects help validate findings independently which is critical in pediatrics where patient numbers are limited.

How did the Fishman Awards affect your trajectory?
The Fishman Career Development Award I received in 2023, and the Cynthia Schwartz Shenkman Research Excellence Fishman Award I recently received provided fuel at key moments. The Fishman Career Development Award sent me to the American Association for Cancer Research (AACR) conference in 2024, where I met a company carrying the only clinical-grade antibody to my target; after an MTA, we’re now testing it here. I also attended the La Jolla Immunology Conference and received a best oral presentation award which is validation that stretching into complex immunology is worth it. Importantly, the Fishman Award application process itself which includes writing, presenting, getting feedback, built resilience and sharpened my vision.

Where do you want to take this next?
I aim to lead an independent lab tightly linked to a clinical trials unit. Success requires basic scientists and clinicians at the same table from day one, plus rigorous preclinical “homework” to identify the subgroups most likely to benefit before launching trials. It’s harder, but in the long run it saves precious time and resources and gives patients better odds.

What is life like outside the lab?
I’m a dad of two, so there is hardly time for anything, but we try to do hikes and some beach time. San Diego’s landscapes are a gift. Before kids I did theater; these days, I read when I can, and we take short family adventures (Anza-Borrego is a favorite).

Is there anything you’d like supporters to know?
Your support is more than funding, it’s belief. At a time when the value of science may be questioned, you’re helping researchers communicate clearly, collaborate widely, and move ideas toward children who can’t wait. The Fishman Awards exemplify that: they strengthen science and the storytelling that brings people along. Thank you.

Institute News

PERCEPTION proves a predictable NCI milestone

AuthorScott LaFee
Date

May 9, 2025

false-colored scanning electron micrograph of a breast tumor spheroid
A false-colored scanning electron micrograph of a breast tumor spheroid (cluster of cells). The spheroid has been treated with the anti-cancer drug doxorubicin, which is causing some cells to die (yellow). Healthy cells are colored pink and violet. Image courtesy of Khuloud T. Al-Jamal, David McCarthy and Izzat Suffian, Wellcome Collection.

PERCEPTION is the acronym for PERsonalized Single-Cell Expression-Based Planning for Treatments In Oncology, an artificial intelligence-based tool that, in findings first reported last year, was able to predict tumor response to targeted therapy using single-cell datasets.

The work, published in Nature Cancer, is the result of first study author Sanju Sinha, PhD, assistant professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, with senior authors Eytan Ruppin, MD, PhD, and Alejandro Schaffer, PhD, at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues.

Recently, the NCI’s Center for Cancer Research highlighted PERCEPTION in its 2024-2025 annual Milestones report.

The researchers said PERCEPTION not only helped predict which anti-cancer drugs are most effective for individual patients, but also tracked the evolution of drug resistance over the course of the disease and treatment — something never before achieved.

“A tumor is a complex and evolving beast. Using single-cell resolution can allow us to tackle both of these challenges, Sinha said when their findings were published. “PERCEPTION allows for the use of rich information within single-cell omics to understand the clonal architecture of the tumor and monitor the emergence of resistance.” (In biology, omics refers to the sum of constituents within a cell.)

“The ability to monitor the emergence of resistance is the most exciting part for me. It has the potential to allow us to adapt to the evolution of cancer cells and even modify our treatment strategy.”

PERCEPTION was previously named among the National Institutes of Health director’s highlights for 2024.

Institute News

Kelly Kersten awarded Melanoma Research Alliance grant to support research on melanoma immunotherapy

AuthorGreg Calhoun
Date

May 2, 2025

Kelly Kersten
Kelly Kersten, PhD, is an assistant professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. Credit: Sanford Burnham Prebys

The newly created Paul Walks – MRA Young Investigator Award in Memory of Chad Johnson is part of the alliance’s $9.3 million commitment to melanoma research funding in 2025.

Kelly Kersten, PhD, an assistant professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, was awarded a new type of grant from the Melanoma Research Alliance (MRA). The funding will support Kersten’s research on reactivating “exhausted” immune cells within melanoma tumors to restore their cancer-fighting ability and improve the effectiveness of melanoma immunotherapy.

“Inside tumors, immune cells often lose their strength to attack cancer,” said Kersten. “Our work is focused on understanding and reversing this exhaustion to make therapies more effective for more people.”

The MRA is the world’s leading nonprofit funder of melanoma research. The organization created the Paul Walks – MRA Young Investigator Award in Memory of Chad Johnson to provide support for the next generation of scientists driving innovation against melanoma.

“Our Young Investigator Awards fuel the creativity and drive of early-career scientists whose work can redefine the future of melanoma research.” said Joan Levy, PhD, MRA Chief Science Officer.

The new grant pays tribute to Chad Johnson, a beloved friend and surfer who died from his melanoma diagnosis at age 55. Funding for the award was made possible through “Paul Walks,” a community fundraiser organized by Chad’s lifelong friend, Paul Giobbi.

The Paul Walks – MRA Young Investigator Award in Memory of Chad Johnson is part of MRA’s $9.3 million commitment to fund melanoma research in 2025, supporting more than 30 researchers across the U.S., Europe and Australia. Melanoma remains the deadliest form of skin cancer, with more than 100,000 people expected to be diagnosed this year and one death every hour in the U.S. alone.

Institute News

Curebound awards two grants to Sanford Burnham Prebys scientists

AuthorGreg Calhoun
Date

February 12, 2025

split photo of Brooke Emerling and Michael Jackson
Brooke Emerling, PhD, is director of the Cancer Metabolism and Microenvironment Program. Michael Jackson, PhD, is senior vice president for Drug Discovery and Development in the Conrad Prebys Center for Chemical Genomics.

The San Diego-based philanthropic organization has awarded $43 million in cancer research to date

Curebound recently announced the awarding of 17 grants in December 2024 for a total of $8.25 million in funding to advance cancer research in 2024.

Two new grants will support cancer research conducted by scientists at Sanford Burnham Prebys. Since 2014, 32 Curebound grants have supported projects that included scientists at the institute.

A workaround for a tricky target

The TP53 gene contains the blueprint for constructing a protein called tumor protein p53. This protein is considered a tumor suppressor because it helps cells grow in a controlled manner.

When cell growth goes awry, however, the TP53 gene is a common culprit as the most frequently mutated gene in cancers. While this ubiquity has placed a bullseye on the mutated tumor protein p53 for aspiring drug developers, it has proven tricky to target directly.

Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program, and her collaborators have shown that the growth of cancer cells with a mutated TP53 gene is dependent on lipid enzymes called phosphatidylinositol-5-phosphate 4-kinases (PI5P4K). Emerling and her collaborators have identified compounds that break down these enzymes.

The researchers have demonstrated the ability of these compounds to target and eliminate cancer cells with a mutated TP53 gene without harming normal cells. Curebound will support the team’s ongoing efforts to work around the difficult-to-target tumor protein p53 by instead targeting PI5P4K.

Next, the group plans to optimize the compounds that break down PI5P4K to develop cancer drugs that are strong candidates for future clinical trials.

Curebound collaborators: Patrick Kearney, PhD, director of Medicinal Chemistry in the Conrad Prebys Center for Chemical Genomics, and Eric Wang, PhD, assistant professor in the Cancer Molecular Therapeutics Program.

Boosting the immune system against lung cancer

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.

Immunotherapies that boost the anti-cancer capabilities of T cells have revolutionized the way we treat cancer, especially in blood cancers such as leukemia, lymphoma and myeloma. More recently, immunotherapies are rapidly advancing to become mainstream treatments for solid cancers as well.

Currently, however, less than a third of patients with lung cancer benefit from immunotherapies. Pandurangan Vijayanand, MD, PhD, the William K. Bowes Distinguished Professor at the La Jolla Institute for Immunology, discovered that certain T cells called cytotoxic T lymphocytes have molecular features associated with a robust immune response against lung cancer tumors. His work has identified new targets for lung cancer immunotherapy.

Curebound will support Vijayanand’s collaboration with Michael Jackson, PhD, senior vice president for Drug Discovery and Development in the Conrad Prebys Center for Chemical Genomics, to use this research to identify agents to boost tumor immune responses.

The research team’s work has the potential to identify a new class of immunotherapy drugs for patients with lung cancer.

Curebound collaborator: Changlu Liu, PhD, director of Receptor Pharmacology in the Conrad Prebys Center for Chemical Genomics.

Pandurangan Vijayanand

Pandurangan Vijayanand, MD, PhD, is the William K. Bowes Distinguished Professor at the La Jolla Institute for Immunology.

Institute News

A monster, MASH

AuthorGreg Calhoun
Date

January 28, 2025

3D illustration of liver cancer
3D illustration of liver cancer.

Scientists show how the advanced form of fatty liver disease has monstrous effects on liver cancer risk

Liver cancer has proven to be a tough beast to tame. Experts expected rates of the cancer to decrease following the development of the hepatitis B vaccine in the 1980s, which reduced one of the major risk factors for the disease.

Research in Taiwan showed that its universal infant hepatitis B vaccination program led to young adults experiencing a 35.9% reduction in cases of hepatocellular carcinoma (HCC), the most common liver cancer.

Despite innovation leading to the world’s first cancer-preventing vaccine, incidence of HCC has been on the rise due to a spike in fatty liver disease over recent decades. Lifestyle factors such as high-calorie diets, excessive alcohol consumption and minimal exercise — along with genetic predispositions — can lead to problematic changes in the liver, heart and kidneys.

Specifically in the liver, growing deposits of fat in the tissue can lead over time to an advanced form of fatty liver disease marked by chronic inflammation and the accumulation of thickened scar tissue, a condition known as metabolic-associated steatohepatitis (MASH). MASH significantly increases a patient’s risk of developing HCC.

Debanjan Dhar, PhD, headshot outside

Debanjan Dhar, PhD, is an associate professor in the Cancer Genome and Epigenetics Program.

In a paper published January 1, 2025, in Nature, scientists at Sanford Burnham Prebys, the University of California San Diego, Curtin University, the University of Pennsylvania and The Liver Cancer Collaborative, demonstrated that MASH damages the DNA of liver cells. The study also linked these changes to the development of liver cancer.

Peter Adams profile photo in lab

Peter Adams, PhD, is the director of the Cancer Genome and Epigenetics Program.

“DNA damage from MASH causes liver cells to stop dividing and enter a zombie-like state called senescence,” said Debanjan Dhar, PhD, associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and coauthor on the study. “This study’s results demonstrate that some of these cells later exit senescence and are likely to become cancerous due to their accumulation of damage and mutations.”

“In the future, we can apply what we’ve learned to study potential opportunities to prevent or repair DNA damage from MASH to reduce patients’ risk of developing liver cancer,” said Peter Adams, PhD, director of the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and coauthor on the study.

Michael Karin, PhD, Distinguished Professor in the Department of Pharmacology at the University of California San Diego School of Medicine, is the senior and corresponding author on the study.   

Li Gu, PhD, a former postdoctoral fellow in the Karin lab, shares first authorship of the study with visiting scientist Yahui Zhu. 

Additional authors include:

  • Marcos Teneche and Souradipta Ganguly from Sanford Burnham Prebys
  • Shuvro Nandi, Maiya Lee, Kosuke Watari, Breanna Bareng, Masafumi Ohira, Yuxiao Liu, Sadatsugu Sakane, Mojgan Hosseini, Tatiana Kisseleva, Ludmil Alexandrov, Consuelo Sauceda and David Gonzalez from the University of California San Diego
  • Rodrigo Carlessi and Janina Tirnitz-Parker from Curtin Universit
  • The Liver Cancer Collaborative
  • M. Celeste Simon from the University of Pennsylvania
Institute News

Bile may be key to immunotherapy effectiveness in liver cancer

AuthorGreg Calhoun
Date

January 17, 2025

A 3D illustration of hepatocellular carcinoma
A 3D illustration of hepatocellular carcinoma, the most common liver cancer.

Understanding the crucial ingredient in bile may unlock the potential of treatments that help patients’ immune systems eliminate cancer

Hepatocellular carcinoma (HCC) is the most common liver cancer and a growing threat to public health across the globe due to the rising rate of fatty liver disease.

Liver cancer is difficult to treat as it often causes few if any symptoms early on, so it tends to be diagnosed at later, more aggressive stages. While immunotherapies that supercharge patients’ immune systems have proven effective in some cancers, this approach has had limited success in patients suffering from HCC or other forms of the disease.

Scientists are investigating the unique qualities of different tissues that may explain why the effectiveness of immunotherapy varies depending on the location of a tumor. The liver is known to have a flexible immune system capable of defending itself when necessary while not overreacting to a constant flood of foreign materials from digesting food, including metabolic byproducts from bacteria residing in the gut microbiome.

Transplant surgeons see the unique properties of the liver’s immune system firsthand when transplanted livers are typically integrated by recipients with only a low dose of immunosuppressive drugs. This ability to maintain immune tolerance, however, may reduce the ability of the liver’s immune system to find and destroy cancer cells, even when that capability is enhanced by immunotherapy.

In a paper published January 9, 2025, in Science, scientists at Sanford Burnham Prebys, the Salk Institute, the University of California San Diego, Columbia University Irving Medical Center, Memorial Sloan Kettering Cancer Center and the Geisel School of Medicine at Dartmouth, found that a critical ingredient in bile hinders the liver’s immune response against cancer.

Bile is a fluid made by the liver that assists in breaking down fats during digestion. This function is made possible by steroidal acids known as bile acids. The scientists found an increased amount of bile acids in tumor samples from patients with HCC. The team also found that genes involved in creating bile acids were being transcribed to make proteins and enzymes at an abnormally high rate in human samples and in mice genetically modified to develop liver cancer.

The authors went on to remove genes related to bile acid construction to demonstrate that mice without these blueprints developed fewer, smaller tumors. In addition, the liver’s T cells — the primary anti-tumor immune cells — were able to dig deeper into tumors and persist for longer without the immunosuppressive effects of certain bile acids.

“These findings underscore a new appreciation for the influence of bile acids on the liver’s immune system,” said Debanjan Dhar, PhD, associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and coauthor on the study. More research is needed to test the potential use of drugs to directly inhibit certain bile acids or bile acid receptors as a therapeutic strategy to reduce liver cancer growth.

Debanjan Dhar, PhD, headshot outside

Debanjan Dhar, PhD, is an associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys.

Peter Adams profile photo in lab

Peter Adams, PhD, is the director of the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys.

It may also be possible to achieve this effect through dietary changes that alter the microbiome and result in modified bile acid production. Based on their findings, the research team suggests that this could be done by using ursodeoxycholic acid, a bile acid that currently is used to treat an autoimmune condition called primary biliary cholangitis. The acid is found at high levels in bear bile, which has served for thousands of years as a treatment in traditional Chinese medicine.

“Given the safety profile of ursodeoxycholic acid and the limited effectiveness of immunotherapy on liver cancer, this study shows significant potential for testing this bile acid as a combination treatment for patients with HCC,” said Peter Adams, PhD, director of the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and coauthor on the study.

Susan Kaech, PhD, NOMIS Chair, professor and director of the NOMIS Center for Immunobiology and Microbial Pathogenesis at the Salk Institute is the senior and corresponding author on the study.   

Siva Karthik Varanasi, PhD, assistant professor at the UMass Chan Medical School and a former postdoctoral fellow in the Kaech lab at the Salk Institute, is first author on the manuscript. 

Additional authors include:

  • Souradipta Ganguly, Marcos G. Teneche and Aaron Havas, from Sanford Burnham Prebys
  • Dan Chen, Melissa A. Johnson, Kathryn Lande, Michael A. LaPorta, Filipe Araujo Hoffmann, Thomas H. Mann, Eduardo Casillas, Kailash C. Mangalhara, Varsha Mathew, Ming Sun, Yagmur Farsakoglu, Timothy Chen, Bianca Parisi, Shaunak Deota, H. Kay Chung, Satchidananda Panda, April E. Williams and Gerald S. Shadel, from the Salk Institute
  • Yingluo Liu, Cayla M. Miller, Jin Lee and Gen-Sheng Feng, from the University of California San Diego
  • Isaac J. Jensen and Donna L. Farber, from Columbia University Irving Medical Center
  • Andrea Schietinger from Memorial Sloan Kettering Cancer Center
  • Mark S. Sundrud from the Geisel School of Medicine at Dartmouth

Wolfram Goessling, MD, PhD, the Robert H. Ebert Associate Professor of Medicine and associate professor of Health Sciences and Technology at Harvard Medical School, authored a Perspective article on the new study in Science called, “Ena-bile-ing liver cancer growth.”