JACKSONVILLE, Fla. — Mayo Clinic researchers have developed an experimental drug with the help of artificial intelligence (AI) to target the "undruggable" PDZ-domain of GIPC1 protein that helps different types of cancer, including pancreatic cancer, to grow and resist treatment. In laboratory studies, the drug slowed tumor growth, improved survival and enhanced the effects of the chemotherapy drug gemcitabine.

The findings, published in Cell Reports, also demonstrate how AI could help develop a small molecule inhibitor of a target protein that can be less toxic and speed the discovery of new cancer treatments.

Pancreatic cancer is one of the most difficult cancers to treat because it is often diagnosed after it has spread and is resistant to many current therapies. While survival rates remain low, advances in research are creating new opportunities to develop more effective treatments. This study represents one of those promising advances, offering a potential new strategy for targeting pancreatic cancer.

Using AI, in collaboration with Sravathi AI Technology for IP Sharing, a company based in Bangalore, India, the research team screened nearly 40,000 potential compounds before identifying one that blocks GIPC1. The experimental drug also showed early signs of changing the environment around tumors in ways that could improve future combination therapies. Additional studies are needed before it can be tested in people.

"Pancreatic cancer has remained exceptionally difficult to treat because tumors rapidly adapt and become resistant to many available therapies," says Debabrata (Dev) Mukhopadhyay, Ph.D., senior author of the study and a cancer researcher at Mayo Clinic in Florida. "Our study demonstrates that AI can help us identify entirely new therapeutic opportunities against targets that have historically been considered undruggable. While these findings are preclinical, they provide a strong foundation for the next phase of research."

The therapy remains experimental, and additional studies are needed to evaluate its safety and determine whether it can advance to clinical trials.

This research was supported in part by the National Institutes of Health, the Florida State Fund for the Casey DeSantis Cancer Research Program and the U.S. Department of Defense. For a complete list of authors, disclosures and funding, review the study.

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About Mayo Clinic
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ROCHESTER, Minn. — Mayo Clinic researchers have identified a protein that cancer cells use to shut down the body's immune response, a discovery that could help scientists develop new treatments that make cancer immunotherapies more effective.

Published in the Journal of Clinical Investigation, the study identifies a previously unknown role for a protein called TRAILshort, which acts like an immune "off switch." The researchers found that TRAILshort prevents T cells — the immune system's primary cancer-fighting cells — from recognizing and destroying cancer and virus-infected cells. In preclinical models, blocking the protein restored T-cell activity and improved immune response. 

The researchers also found that TRAILshort reduces the effectiveness of chimeric antigen receptor-T cell therapy (CAR-T cell therapy), one of the most advanced forms of cancer immunotherapy. Their findings suggest that therapies designed to block TRAILshort could improve CAR-T treatment and potentially benefit other immune-based cancer therapies.

"What strikes me most is that TRAILshort appears in cancer, HIV, COVID-19, tuberculosis, lupus and Crohn's disease — almost every condition where the immune system is failing or misfiring. That tells us we may have identified a fundamental switch in human immunity, not just a curiosity in one disease," says Andrew Badley, M.D., senior author of the study. Dr. Badley is the HH Sheikh Khalifa Bin Zayed Al Nahyan Professor of Infectious Diseases and an immunologist at Mayo Clinic.

How cancer disrupts the immune response 

Mayo Clinic researchers first discovered TRAILshort while studying HIV nearly 15 years ago. In 2020, they found that cancer cells also produce the protein, but how it suppressed T-cell activity remained unknown. This new study reveals the mechanism for the first time.

Researchers found elevated levels of TRAILshort in melanoma, lung, breast, pancreatic and ovarian cancers, as well as Hodgkin lymphoma. Elevated levels also were found in infectious diseases, including COVID-19, tuberculosis and hepatitis C.

Using highly specific antibodies and engineered preclinical models, the team found that TRAILshort activates SHP-1, a protein that acts as a molecular brake, shutting down T cells before they can attack diseased cells.

"This is the first study to show that TRAILshort doesn't just block cell death — it also acts as a signaling molecule that directly suppresses T-cell activity," says Shahrzad Jalali, Ph.D., a research scientist at Mayo Clinic and lead author of the study. "That reveals an entirely new role for the protein in regulating the immune response."

Why TRAILshort is a potential target for new therapies

The findings suggest several potential therapeutic applications.

Researchers found that TRAILshort significantly reduced CAR-T therapy's ability to control tumors in preclinical models. Blocking the protein restored immune activity, suggesting that targeting it could be a new strategy to improve CAR-T therapy and other immunotherapies. The researchers also believe that TRAILshort could serve as a biomarker to help identify tumors more likely to respond to targeted therapies.

"Discovering the role of TRAILshort and how it inhibits CAR-T cells opens the door for a new therapeutic strategy to improve their activity," says Saad Kenderian, M.B. Ch.B., an oncologist at Mayo Clinic Comprehensive Cancer Center and study co-author. "This is an important step as we work to make CAR-T therapy more effective for patients with cancer."

Beyond cancer, researchers say TRAILshort  may eventually provide a way to selectively reduce harmful immune activity in autoimmune diseases or transplantation without broadly suppressing the immune system.

"In cancer, there's too much TRAILshort, so our goal is to get rid of it with antibodies that remove it. In autoimmune disease, there's not enough TRAILshort, so our goal is to deliver more," Dr. Badley says.

Additional studies are needed to determine whether these approaches are safe and effective in patients.

"What excites us most is that this discovery gives us a new, actionable way to regulate the immune system," Dr. Badley says. "By targeting TRAILshort, we may be able to strengthen immune responses against cancer and chronic infections or, in other diseases, reduce harmful immune activity."

This research is part of a broader effort at Mayo Clinic known as the Precure Research initiative. It focuses on developing tools to help clinicians detect and address disease-related changes earlier, before symptoms appear or conditions become harder to treat. This discovery identifies the molecular mechanism behind T-cell failure across cancer and chronic infection, giving researchers a defined target and a road map for therapeutic development.

For a complete list of authors, disclosures and funding, review the study.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

About Mayo Clinic Comprehensive Cancer Center
Designated as a comprehensive cancer center by the National Cancer Institute, Mayo Clinic Comprehensive Cancer Center is defining the cancer center of the future, focused on delivering the world's most exceptional patient-centered cancer care for everyone. At Mayo Clinic Comprehensive Cancer Center, a culture of innovation and collaboration is driving research breakthroughs in cancer detection, prevention and treatment to change lives.

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• Julie Ferris-Tillman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu

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PHOENIX — An international phase 3 study performed at all three Mayo Clinic destination medical centers found that a new immunotherapy helped many patients with an aggressive form of bladder cancer keep their bladder instead of having it surgically removed. The treatment also kept many patients cancer-free for more than two years and caused mostly mild side effects. The findings were published in The Lancet Oncology.

Patients in the study had high-risk bladder cancer that had returned despite standard treatment with bacillus Calmette-Guérin (BCG). For these patients, surgery to remove the bladder is typically the recommended next step. The new immunotherapy treatment, called cretostimogene grenadenorepvec, produced a complete response, with no detectable signs of cancer in 75% of patients, with many of those responses lasting beyond two years.

"Until now, patients whose cancer returned after BCG therapy have had few effective options besides bladder removal," says Mark Tyson II, M.D., lead author of the study and a urologist at Mayo Clinic in Arizona. "This study shows we may be able to offer many of those patients another option without compromising cancer control."

Among patients whose cancer completely disappeared after treatment, about 60% remained cancer-free two years later. In one patient, the cancer has not returned for more than four years after completing treatment. Most treatment-related side effects were mild, temporary bladder symptoms, and researchers reported no severe treatment-related side effects.

"For patients, this isn't just about treating cancer — it's about preserving quality of life," says Dr. Tyson. "Avoiding bladder removal can have a profound impact on daily living. Seeing patients remain cancer-free for years while keeping their bladder is exactly the outcome we've been hoping to achieve."

The study included 115 patients treated at 41 medical centers across North America, Asia and Australia. Two years after starting treatment, an estimated 81% of patients had not needed surgery to remove their bladder. The researchers concluded that cretostimogene grenadenorepvec could become an important bladder-sparing treatment option for patients whose high-risk bladder cancer has returned after standard BCG therapy. They also noted that the treatment has not been directly compared with other bladder-sparing therapies in clinical trials.

The study was funded by CG Oncology. For a complete list of authors, disclosures and funding, review the study. The therapy remains investigational.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

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ROCHESTER, Minn. — A major national cooperative group clinical trial led by Mayo Clinic researchers found that continuing maintenance therapy with lenalidomide beyond two years after initial treatment for standard-risk multiple myeloma did not improve overall survival compared with stopping treatment after two years. The findings, published in The New England Journal of Medicine, may help physicians and patients make more informed decisions about the duration of maintenance therapy.

"Longer treatment is often assumed to be better, but that's not always the case," says Shaji Kumar, M.D., a Mayo Clinic hematologist, the study's primary investigator. "As therapies become more effective, it's increasingly important to determine not only which treatments work, but also how long patients need them." The researchers say the findings may reduce treatment burden and lower the costs associated with years of ongoing therapy for many patients.

"Knowing that maintenance therapy can safely end after a defined period may help reduce the demands of long-term treatment for patients," says S. Vincent Rajkumar, M.D., a hematologist at Mayo Clinic and chair of the ECOG-ACRIN Cancer Research Group’s Myeloma Committee which spearheaded the trial. "These findings support informed, shared decision-making between physicians and patients."

New treatments for multiple myeloma over the past two decades have improved survival, and some patients now experience long-term disease control. The study applies specifically to patients with standard-risk multiple myeloma who did not receive an upfront stem cell transplant. Additional studies are underway to determine the optimal duration of maintenance therapy for patients with high-risk disease and to explore whether treatment duration can be tailored using measurable residual disease testing.

"This study reminds us that clinical trials shouldn't only focus on adding new therapies," Dr. Kumar says. "They should also help us understand when treatment can safely stop."

The trial was designed and conducted by the ECOG-ACRIN Cancer Research Group with support from the U.S. National Institutes of Health’s National Cancer Institute, through its National Clinical Trials Network. Amgen provided additional support.  

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

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• Julie Ferris-Tillman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu

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Mayo Clinic researchers are uncovering the earliest shifts in disease biology — long before symptoms appear — revealing how disease takes root and opening new possibilities to change its course. 

By the time a disease is diagnosed, it may have been developing silently for years. Along the way, the body leaves clues: proteins shift, metabolism changes, immune responses evolve, and environmental exposures leave measurable traces. Until recently, many of these early signals were impossible to detect.

Mayo Clinic researchers are now charting that hidden period between health and disease — a new frontier in medicine that could transform how conditions such as Alzheimer's disease, heart failure, pulmonary fibrosis, chronic liver disease and chronic kidney disease are identified and intercepted before symptoms emerge.

The new Mayo Clinic initiative, called Precure Research, brings together biospecimens, advanced biological data, environmental health research, longitudinal clinical data, wearable technologies and artificial intelligence (AI) to better understand how disease begins, predict risk earlier and create new opportunities for prevention.  

"Precure Research marks the beginning of the next era of scientific discovery and its translation into patient care."

Dr. Konstantinos Lazaridis

A glimpse of what's possible 

The initiative is already generating discoveries. Mayo Clinic scientists have identified inherited risks for cancer and cardiovascular disease in nearly 2,000 people — many of whom had no previous indication they were at risk. Other studies have shown that certain precancerous changes can be detected years before cancer develops. AI can help clinicians identify signs of pancreatic cancer years before diagnosis, while subtle biological changes linked to Alzheimer's disease begin decades before memory loss. Mayo Clinic researchers are using AI, genetics and wearable technologies to reveal inherited heart disease before heart failure.

"Precure Research marks the beginning of the next era of scientific discovery and its translation into patient care," says Konstantinos Lazaridis, M.D., the Carlson and Nelson Endowed Executive Director of Mayo Clinic's Center for Individualized Medicine and director of Precure Research. "We are building the analytical and clinical tools needed to investigate questions that medicine has long recognized but has not been able to fully answer in ways that directly benefit patients."

The invisible years before diagnosis 

The initiative combines data from genes, proteins, metabolites, clinical records, wearable devices and environmental exposures to create a comprehensive view of how health changes and disease develops over time.

Underlying Precure Research is a new Mayo Clinic research ecosystem designed to study health and disease at an unprecedented scale. The initiative aims to build Mayo Clinic's largest integrated collection of biospecimens and scientific and health data to accelerate disease prediction and prevention.

Biological samples become data, and data becomes insight into the mechanisms of disease. Those insights drive the discovery of new biomarkers and therapies while informing smarter clinical trials.

AI helps researchers power that transformation, analyzing billions of data points simultaneously to reveal patterns that would otherwise remain invisible.

"Genomics showed us the blueprint, the underlying architecture of human biology," Dr. Lazaridis says. "Now we're watching that structure in motion — shifting, adapting, unfolding over time, shaped by the world around us and inside us, ultimately influencing the unique lives we each live." 

A lifetime of exposures

Disease is shaped by more than genetics alone. Across a lifetime, environmental and lifestyle exposures leave biological changes that accumulate over time. Scientists call this the exposome: the sum of those exposures and their effects on human biology.

These influences range from air, water and diet to pollutants, heavy metals, pesticides, physical activity, sleep, stress, noise and light.

"The air we breathe, the food we eat and the places we live leave a biological imprint," Dr. Lazaridis says. "Understanding those accumulated influences is essential to understanding why disease develops in one person and not another."

Researchers can now measure many of these exposures directly in blood and other biospecimens. Early efforts focus on heavy metals, pesticides and microplastics, linking those findings with geographic data to better understand how the places people live may influence their long-term health.

The exposome also captures protective influences, including nutrients and bioactive compounds that may support resilience and regulate inflammation, aging and metabolism.

A new vision for medicine 

The initial focus of Precure Research includes diseases of the brain, heart, kidneys, liver, and lungs, and their intersection with biological pathways such as inflammation, oxidative stress, aging and metabolic dysfunction.

Its long-term aim is to extend healthspan — the number of years people live in good health, free from chronic disease and disability — by addressing the drivers of chronic disease.

Precure Research is part of Mayo Clinic's Bold. Forward. strategy to Cure, Connect and Transform healthcare — helping define a future where disease is identified earlier, understood more completely and intercepted before it takes hold.

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ROCHESTER, Minn. — Researchers at Mayo Clinic have uncovered a previously hidden step in how the immune system prepares to fight cancer, a discovery that could help scientists develop more effective and longer-lasting cancer immunotherapies.

Published in Nature Communications, the study found that some cancer-fighting immune cells begin preparing for their role much earlier than previously believed — while they are still maturing in the thymus, an organ behind the breastbone that plays a central role in training T cells, particularly early in life.

The findings challenge the long-standing view that CD8-positive T cells — a type of immune cells that finds and destroys cancer cells — can leave the thymus in an inactive state and acquire their cancer-fighting abilities only after encountering threats elsewhere in the body. Instead, the research suggests that the thymus may help prepare these immune cells for rapid responses before they enter circulation.

CD8-positive T cells are among the immune system's primary cancer-fighting cells. The researchers found that PD-1 — a protein that is the target of several widely used cancer immunotherapy drugs — acts as a brake during their development, helping prevent these cells from becoming exhausted too quickly.

"Cancer immunotherapy has transformed treatment for many patients, but those responses don't always last," says Zhiming Mao, Ph.D., a recent graduate of Mayo Clinic Graduate School of Biomedical Sciences and first author on the paper. "We've discovered that the immune system may begin preparing for its fight against cancer much earlier than we realized. That insight could help us design therapies that are both more powerful and more durable."

PD-1 is already the target of several immune checkpoint inhibitor therapies used to treat a wide range of cancers, making the discovery particularly relevant to ongoing efforts to improve those treatments.

The findings may provide insight into why some immune responses against cancer are powerful but short-lived. Researchers say future therapies may need to strike a balance between boosting the immune system's attack on tumors and preserving the long-term function of cancer-fighting cells.

In preclinical models, removing PD-1 helped these immune cells control certain tumors more effectively. But the stronger response came at a cost: the cells became exhausted sooner, limiting their long-term cancer-fighting ability.

"Understanding how these immune cells are programmed at the earliest stages of development gives us a new way to think about improving cancer treatment," says Haidong Dong, M.D., Ph.D., an Iris and Winston Clement Professor of Research at Mayo Clinic and senior author of the study.

The findings come as researchers seek ways to make cancer immunotherapies more effective and longer lasting. While these treatments have transformed care for many patients, they do not work for everyone and can lose effectiveness over time.

The findings were based primarily on laboratory and preclinical model studies, and additional research will be needed to determine how they apply to patients.

For a complete list of authors, disclosures and funding, review the publication.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Julie Ferris-Tillman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu

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Study uncovers structure of protein that helps cells communicate, a potential drug target

ROCHESTER, Minn. — After nearly four decades of research, Mayo Clinic scientists have revealed the molecular structures of protein kinase C beta (PKCβ), a key protein linked to cancer and neurological diseases. The findings, published in Nature Communications, provide the first detailed view of how the protein works and how the breast cancer drug endoxifen can target this protein.

PKCs are a family of proteins that help cells communicate. They act as molecular switches that regulate cell growth, survival and behavior. Because they play a role in many diseases like Alzheimer's and cancers like breast, lymphoma and colorectal, scientists have long viewed them as promising drug targets. However, without understanding their structure, designing effective therapies has been difficult.

"For decades, scientists have been trying to understand how these proteins function," says study co-author Matthew Goetz, M.D., a medical oncologist at Mayo Clinic Comprehensive Cancer Center. "These findings create new opportunities to develop more precise therapies for cancer and other diseases."

Solving a 4-decade-long mystery

Since PKC was first discovered in the 1980s, scientists have been unable to determine the structure of full-length human PKC enzymes, limiting efforts to understand how they function and how they might be targeted therapeutically.

Led by senior author Matthew Schellenberg, Ph.D., Mayo Clinic researchers overcame this mystery by producing human PKC enzymes that more closely resemble their natural state than proteins generated using traditional insect cell approaches. Their method revealed the structures of human PKCβ1 and PKCβ2.

"By producing the protein in human cells, we were able to obtain high-quality material that enabled us to finally see how this enzyme is organized and regulated," says Dr. Schellenberg, a molecular biologist at Mayo Clinic. "Now, we can begin investigating how changes in these proteins contribute to disease and how new therapies might selectively influence their activity."

How a breast cancer drug inhibits PKCβ

It has been known for decades that PKCβ becomes activated when it interacts with lipid membranes inside cells, but it was not known how this could happen. Structural studies revealed that when membrane lipids bind to PKC, they act like a molecular lever, shifting the enzyme from a closed, inactive state to an open, membrane-bound active state. These membranes trigger changes in the protein, exposing its active site and switching it on.

The researchers then combined structural biology, biochemistry and cellular studies to understand how endoxifen affects PKCβ. They found that endoxifen inhibits PKCβ through an allosteric mechanism, meaning it changes the protein's behavior without directly competing for its active site. The drug appears to stabilize PKCβ at cellular membranes, triggering changes that ultimately lead to its degradation.

"This mechanism is fundamentally different from previous PKC inhibitors that have been tested over the years," Dr. Goetz says. "That distinction may help explain why endoxifen shows biological effects that earlier compounds did not."

Implications for precision medicine

The findings establish a framework for understanding how different PKC family members function in health and disease. Some PKC isoforms may promote tumor growth while others may suppress it. The PKC family includes 10 related proteins, each with distinct roles. Determining when each protein should be activated or inhibited has remained a major unanswered question.

"This study gives us the tools to ask those questions in a much more sophisticated way," Dr. Schellenberg explains. "We can now investigate how different PKC proteins contribute to cancer and design drugs that target the right protein in the right context."

Mayo Clinic researchers are currently studying endoxifen in premenopausal women with estrogen receptor-positive breast cancer and investigating whether its effects on PKCβ contribute to its anticancer activity. The team is planning future work to expand beyond PKCβ to all 10 members of the PKC family, seeking to understand how each enzyme functions and responds to therapeutic compounds in its own unique way.

"We've opened a new door," says Dr. Goetz. "For the first time, we can see how these proteins are organized, how they function and how they may be targeted with greater precision. That understanding could help guide the next generation of therapies."

For a complete list of authors, disclosures and funding, review the study.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

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ROCHESTER, Minn. — One of the most detailed maps to date of meningioma — the most common brain tumor in adults — reveals how the tumor's surrounding environment helps drive disease behavior and patient outcomes, according to new research from Mayo Clinic.

The study, published in Nature Genetics and conducted in collaboration with scientists at Princess Margaret Cancer Centre in Toronto, combines several advanced laboratory techniques to examine tumors at an unprecedented level of detail, offering clues to why some meningiomas grow slowly while others recur or become more aggressive. The findings could lead to more precise ways to predict risk and guide treatment decisions.

Growing evidence suggests that traditional grading systems for meningioma do not fully capture the behavior of these complex tumors, prompting the development of molecular classification tools that more accurately predict which tumors are more likely to recur after surgery. These new findings build on recent developments by investigating the signal from individual cells rather than whole tumors, demonstrating that the tumor microenvironment — the mix of immune and support cells surrounding the tumor — plays a critical role in shaping outcomes.

"We're seeing that it's not just the tumor cells themselves but the ecosystem around them that influences how these tumors grow and respond to treatment," says Gelareh Zadeh, M.D., Ph.D., a Mayo Clinic neurosurgeon and senior author of the study.

Understanding tumor behavior

An estimated 30,000 to 40,000 people in the U.S. are diagnosed with meningioma each year. While many tumors are benign, others can recur or become life-threatening, and predicting that risk has remained a major challenge.

In this study, researchers analyzed hundreds of tumor samples using techniques that allow them to study individual cells rather than averaging signals across the entire tumor. Using single-cell sequencing and spatial transcriptomics, the team mapped more than 500,000 individual cells and millions of data points across tumors. This created a high-resolution "atlas" of the genetic footprint of individual cells and how they differ between aggressive and benign tumors, how they change and evolve over space, and how they interact with other cells in their environment.

"Instead of looking at the tumor as a whole, we can now break it down into its individual components and understand what is driving its behavior," says Dr. Zadeh.

The researchers identified multiple distinct states of immune cells, particularly myeloid cells, that behave differently depending on the tumor. Some of these cell states were linked to more aggressive disease, while others were associated with better outcomes.

Implications for patient care

The findings build on earlier work from Mayo Clinic researchers outlining a new era of personalized care for meningioma, where molecular and cellular insights guide clinical decision-making. This latest study adds a critical layer by showing how the tumor microenvironment contributes to that personalization.

Researchers found that certain immune cell programs were strongly linked to how quickly tumors returned after treatment. In some cases, these signals were able to add value to tumor grade and even modern molecular classification systems in their ability to predict patient outcomes, suggesting they could help refine decisions about surgery, radiation or closer follow-up in the future.

The study also showed that these biological signatures may be detectable through noninvasive approaches, such as blood-based biomarkers, raising the possibility of monitoring patients over time without repeated surgery.

"This moves us closer to a future where we can better stratify patients — identifying who needs more aggressive therapy and who may avoid overtreatment," says Dr. Zadeh.

Beyond improving prognostic tools, the research highlights potential therapeutic targets. By identifying how immune cells and tumor cells communicate, the study points to pathways that could be disrupted to slow tumor growth or enhance treatment response.

Next steps include validating the findings in larger, multicenter cohorts and translating these biological insights into clinical tools and prospective trials.

For a complete list of authors, disclosures and funding, review the study. 

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news. 

Media contact:

• Tia Ford, Mayo Clinic Communications, newsbureau@mayo.edu

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ROCHESTER, Minn. — Mayo Clinic researchers and collaborators have shown that an artificial intelligence (AI) tool can analyze routine pathology slides to help clinicians classify meningiomas, the most common primary brain tumor in adults, and better understand a patient’s risk of tumor recurrence.

The study, published in The Lancet Digital Health, demonstrates that deep learning models can support the extraction of molecular and prognostic information from standard hematoxylin and eosin, or H&E, slides — the same type of tissue images already used in routine clinical care. These insights are typically obtained through DNA methylation profiling, an advanced genetic test which provides valuable diagnostic and prognostic information but can be costly, time-consuming and is unavailable in many hospitals.

"This is one of the many studies where we can harness the strength of digital pathology by capturing the last two decades of genomic and molecular knowledge into AI algorithms," says Gelareh Zadeh, M.D., Ph.D., chair of the Department of Neurologic Surgery at Mayo Clinic in Rochester and the David C. and Flora C. Pratt Distinguished Chief Medical Officer for Mayo Clinic Platform.

Making advanced tumor insights more accessible

Meningiomas can vary widely in behavior. Some grow slowly and may never return after treatment, while others are more aggressive and more likely to recur. Understanding that risk is critical for patients and care teams deciding whether additional treatment, such as radiation therapy, may be needed after surgery.

Molecular testing can help identify which tumors are more likely to recur and which may respond differently to treatment. But these tests require specialized technology and expertise, limiting access for many patients.

Using tissue samples, pathology images and clinical data from 672 patients, researchers developed and tested AI models designed to help identify patterns linked to a tumor's biology. Drawing on multiple de-identified datasets, including data resources from Mayo Clinic Platform, the models supported classification of meningioma subtypes and recurrence risk prediction using standard pathology slides that are already part of routine patient care.

The findings suggest that, with further validation, AI-based tools could one day help clinicians obtain more detailed tumor information to inform patient care, without requiring every patient to undergo advanced genetic testing.

Helping guide treatment decisions

For patients with meningiomas, recurrence risk can influence follow-up care, imaging frequency and whether radiation therapy should be considered. The study found that AI-based predictions remained useful even after accounting for traditional clinical factors such as tumor grade, the extent to which surgery was able to remove the tumor and patient age.

Researchers also found that the AI models could identify patterns of tumor heterogeneity — differences within the same tumor — that may help explain why some tumors behave more aggressively or respond differently to treatment.

The researchers note that additional prospective studies are needed before the AI models can be used routinely in clinical care. Still, they say the findings lay the groundwork for more accessible, personalized care for patients with meningiomas — and potentially for similar AI approaches in other cancers.

As with any clinical decision-support tool, the researchers emphasize that these models would require rigorous evaluation, validation and ongoing physician oversight before being considered for routine care. "The aim is to make these algorithms readily and simply accessible for use globally, improving patient care across many healthcare settings," says Dr. Zadeh.

For a complete list of authors, disclosures and funding, review the publication.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

About Mayo Clinic Platform
Founded on Mayo Clinic's dedication to patient-centered care, Mayo Clinic Platform enables new knowledge, new solutions, and new technologies through collaborations with health technology innovators to create a healthier world. To learn more, visit Mayo Clinic Platform at www.mayoclinicplatform.org.

Media contact:

• Tia Ford, Mayo Clinic Communications, newsbureau@mayo.edu

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PHOENIX — An experimental drug combination may help overcome treatment resistance in advanced kidney cancer, according to early results from a first-in-human clinical trial led by Mayo Clinic researchers.

The study evaluated the investigational drug darlifarnib in combination with the targeted therapy cabozantinib, a standard treatment for clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer. Among patients whose disease had progressed despite prior treatment, 44% responded to the combination therapy, while disease control was achieved in 94% of participants.

"These early findings are encouraging, as more effective treatments are urgently needed for patients with advanced disease," says Yousef Zakharia, M.D., principal investigator of the study and a medical oncologist at Mayo Clinic in Arizona. He presented the findings at the 2026 International Kidney Cancer Symposium: Europe in Paris.

ccRCC accounts for most kidney cancer cases in adults, and many patients eventually experience disease progression despite treatment.

In the phase 1a/b study, researchers evaluated 18 patients who had previously received cabozantinib. About half had undergone at least three prior therapies.

"For many patients, the benefit of cabozantinib can be temporary. Tumors may develop resistance and activate alternative pathways that allow the cancer to continue growing," Dr. Zakharia says.

Researchers investigated whether adding darlifarnib, a next-generation targeted therapy designed to inhibit cancer growth signaling pathways, could help overcome treatment resistance.

The combination produced tumor shrinkage in 7 of 16 evaluable patients, corresponding to an overall response rate of 44%. Disease control, defined as either tumor stability or shrinkage, was achieved in 15 of 16 patients (94%).

"These findings require validation in a larger clinical trial to confirm the efficacy observed thus far; however, the early signal is intriguing," says Dr. Zakharia. "This study represents an important step forward and provides insight into how treatment resistance might be overcome."

The multicenter, international trial will further evaluate the benefit of the combination in a larger group.

For a complete list of trial and funding information, review the study.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

About Mayo Clinic Comprehensive Cancer Center
Designated as a comprehensive cancer center by the National Cancer Institute, Mayo Clinic Comprehensive Cancer Center is defining the cancer center of the future, focused on delivering the world's most exceptional patient-centered cancer care for everyone. At Mayo Clinic Comprehensive Cancer Center, a culture of innovation and collaboration is driving research breakthroughs in cancer detection, prevention and treatment to change lives.

Media contact:

• Julie Ferris-Tilman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu

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