Article Category: Research

Timing may be key to effective cancer treatments

When doctors biopsy and treat cancer may be just as important as how they treat it. New research from Erik Herzog, PhD, the Viktor Hamburger Distinguished Professor in biology at Washington University in St. Louis and a research member at Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine, revealed that when a treatment is given may play a key role in how well brain cancer patients respond to their chemotherapy.

Recently published in the Journal of Neuro-Oncology, the study centers around glioblastoma, an aggressive and treatment-resistant brain cancer that affects more than 300,000 people worldwide every year. The standard treatment plan for this cancer is the common chemotherapy drug temozolomide (TMZ), but its effectiveness is limited. Many tumors fight back with a DNA repair enzyme called MGMT that helps the cancer cells survive TMZ’s attacks.

However, the study finds that MGMT activity levels aren’t constant. Both MGMT methylation — which turns the gene off — and the amount of MGMT protein fluctuate throughout the day. This led the researchers to test if the timing of tumor biopsy would also influence diagnostic results. Colleagues at WashU Medicine — Joshua Rubin, MD, PhD, Will Leidig and Omar Butt, MD, PhD — provided five years of patient biopsy data, which Herzog and his team analyzed.

Rubin and Butt, both WashU Medicine neuro-oncologists, also are Siteman research members. Butt treats adults at The Brain Tumor Center at Siteman. Rubin treats pediatric patients at Siteman Kids at St. Louis Children’s Hospital.

“Presently, methylation is used for diagnostic purposes in cancer, particularly for identifying brain tumors with varying molecular subtypes that are correlated with differences in treatment response,” Rubin explained.

This new research focused on whether methylation levels are stable or if they might change with time of day.

“We found, repeatedly, an increased likelihood of morning biopsies being scored as methylated,” Herzog said. This means that taking a biopsy at different times of day could influence how doctors diagnose tumors. “We are hopeful that this chronodiagnostic approach will help identify better ways to treat this devastating disease.”

These circadian cycles in MGMT gene and protein expression also regulate tumor sensitivity to TMZ over the course of a day. “When we found that TMZ is more effective in the morning, we wondered if, perhaps, this coincides with when there is less MGMT around to repair TMZ-induced damage,” Herzog said.

To better understand how this timing works, Maria Gonzalez-Aponte, a graduate student in the Herzog lab, measured MGMT levels throughout the day in tumor cells and patient GBM samples. With Olivia Walch, a math biologist and co-author of the research, they created a mathematical model to predict when TMZ would be most effective relative to the daily rhythm in MGMT.

“I love when math pushes us past intuition and helps us see something new,” Walch said.

The model predicted that, because TMZ takes several hours to cause DNA damage and to activate cell death, dosing TMZ right after MGMT protein peaks gives the drug the best and longest window to act while the tumor’s repair mechanisms are slower.

“My main takeaway from the modeling part of this work is that, while chronomedicine sounds simple in theory, figuring out what that right time is can be tough,” Walch said.

Dosing time can depend on a multitude of factors, including dose and individual variations in circadian rhythms. “The good news is that math gives us a way to chop away at that complexity and get closer to answers that intuition alone can’t give us,” she added.

Herzog is optimistic that this research will also one day improve the effectiveness of other drugs with similar modes of action that have known circadian targets. Beyond testing chronotherapy with TMZ, the Herzog lab is looking forward to evaluating the importance of the time of day for other signals known to promote or suppress GMB growth. This includes substances like dexamethasone, a drug used to control brain swelling. “It may be important to avoid treatment at times of day when it also promotes tumor growth,” Herzog said.

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Gonzalez-Aponte MF, Huang Y, Leidig, WA et al. Circadian variation in MGMT promoter methylation and expression predicts sensitivity to temozolomide in glioblastoma. J Neurooncol 176, 36 (2026). DOI

This work was supported by National Institutes of Health (NIH) Grants NINDS R21NS120003 and NCI R01NS134885, and Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.

Connecting cancer patients to tobacco treatment is aim of $7.5 million, WashU-led trial

Cancer patients who quit smoking live significantly longer than those who don’t

The science is clear: Cancer patients who quit smoking fare much better than those who don’t. Quitters respond better to treatment and are less likely to see their disease come back or develop a new cancer, and they have a lower risk of other serious conditions such as heart disease. Quitting is hard, but people who participate in evidence-based tobacco-treatment programs are three times more likely to succeed in kicking the habit.

Still, despite the proven benefits of quitting, most cancer patients and survivors who smoke never receive treatment for their tobacco use.

A large-scale, multicenter trial led by researchers at Washington University in St. Louis aims to reduce the burden of cancer by getting more survivors the support they need to quit smoking. The trial — a four-year study to be conducted at 72 cancer centers across eight states, including Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine — will test different clinic-based approaches to connecting cancer survivors to tobacco treatment. The goal is to develop evidence-based recommendations on how to choose, implement and sustain an effective tobacco-treatment strategy at a cancer clinic.

“Even though smoking cessation is part of the standard of care, six out of seven patients with cancer who smoke are not getting any tobacco treatment, so they continue to smoke, and eventually they die early,” said Li-Shiun Chen, MD, MPH, ScD, a professor of psychiatry at WashU Medicine and one of three principal investigators on the trial. “That’s a big missed opportunity. We already know an important way to reduce cancer deaths, and we’re not implementing it.”

Chen and the two other principal investigators — Ross Brownson, PhD, and Alex Ramsey, PhD — are research members at Siteman.

A previous effort to integrate tobacco cessation into cancer care nationwide revealed sobering results. In 2017, the National Cancer Institute (NCI) launched the Cancer Center Cessation Initiative, an ambitious plan to roll out tobacco-treatment programs at the then-52 NCI-designated Comprehensive Cancer Centers nationwide. A five-year analysis revealed that the centers had succeeded in connecting only 15% of their cancer patients with such care, with huge variation in connection rates across centers.

“Scaling up is not a simple thing,” said Brownson, who is also the Steven H. and Susan U. Lipstein Professor at the WashU School of Public Health. “Many of these centers used similar strategies, but the results were varied. We need to understand why a strategy that was effective for one center didn’t work at another one, and what alternative strategy would be more effective.”

That need drove Chen, Brownson and Ramsey, who is also an associate professor of psychiatry at WashU Medicine, to propose the Implementation Science to Scale and Sustain Tobacco Treatment Leveraging a Point of Care Paradigm and Health Information Technology (IMPACT) trial. The three researchers co-lead the trial in collaboration with experts and colleagues at the University of Pennsylvania, Vanderbilt University Medical Center and the St. Louis VA Medical Center. The trial, which will be implemented at cancer clinics affiliated with the four hub sites, aims to determine how to match strategy to clinic, taking into consideration such factors as the size of a clinic, the barriers to receiving care faced by its patients, and the institutional support and resources available. The WashU team is implementing the trial at clinics affiliated with Siteman, where Chen serves as director of the Tobacco Treatment Program.

The trial is supported by a $6.9 million grant from the NCI, with an additional $600,000 provided by Siteman. It is one of four projects in the NCI’s Scaling-up and Maintaining Evidence-based Interventions to Maximize Impact on Cancer (SUMMIT) initiative, a major investment in improving cancer prevention and control by studying how to implement proven interventions in real-world settings.

As part of the trial, each clinic will be randomized to one of four strategies: usual care, referral to a specialist, point of care, or combined referral and point of care. The referral strategy is the most common way of getting patients into tobacco care: The oncologist asks about smoking during a regular visit and refers those who answer yes to a tobacco-treatment specialist. The patient then makes an appointment to meet the specialist at a separate visit. The strategy can work well when a cancer center is able to fund enough tobacco specialists, and patients have the time, resources and willingness to add more appointments to their calendars.

The point-of-care model was developed by Chen and colleagues at Siteman during a time when no tobacco-treatment specialists were on staff. In this model, all hands are on deck: Medical assistants, staff nurses, and nurse practitioners conduct the tobacco-use assessment, provide brief advice to quit smoking and queue cessation medication orders for the clinician to prescribe. They also refer patients to free phone, text or app-based cessation services such as Quitline, a phone-based service available nationwide at 1-800-QUIT-NOW; text messaging cessation services, reachable by texting QUITNOW to 333888; or an app supported by Smokefree.gov. In a recent study, Chen and colleagues showed that a point-of-care approach can be very effective at helping cancer patients quit smoking and improving outcomes.

The record of the Cancer Center Cessation Initiative suggests that many of the clinics may not initially succeed with the strategy they are assigned. Those that are unable to connect at least 15% of eligible patients to tobacco treatment after 18 months will be offered the options of continuing the current strategy, if more time is thought to be helpful; trying a different strategy; or modifying their strategy to include personalized tobacco-treatment plans based on each patient’s unique genetic, clinical and environmental factors.

In those clinics that do succeed, the focus will shift to sustainability. New clinical practices, even successful ones, are at risk of being abandoned when funding ends or priorities change. To minimize this risk, clinics will be provided either general sustainability support, or clinic-specific support based on data from the Clinical Sustainability Assessment Tool. The validated tool — developed at WashU Public Health’s Center for Public Health Systems Science — provides a systematic way to assess the factors that promote sustainability of clinical practices.

“Even when we know what treatments or prevention tools work, we don’t know enough about how we can implement them quickly, scale them up more widely or sustain them long enough,” Ramsey said. “The ultimate goal is to make sure that every single cancer patient who smokes is engaged with treatment, but the route to get there is going to be different for each clinic. We need to figure out which strategies will work best in which context, so we can use the evidence-based tools we already have to improve people’s health.”

Learn about smoking cessation tools available to our patients and community members.

WashU researchers at Siteman honored with NIH Director’s awards

Three investigators recognized by high-risk, high-reward research program

Three WashU researchers at Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine have received prestigious and highly competitive awards through the National Institutes of Health (NIH) Director’s High-Risk, High-Reward Research program. The awards support unconventional approaches to major challenges in biomedical and behavioral research.

Andrew L. Young, MD, PhD, and Janet Sorrells, PhD, each have received the NIH Director’s Early Independence Award, which supports the launch of research careers for exceptional junior scientists who recently received their doctoral degree or completed clinical training.

Michael P. Meers, PhD, has received the NIH Director’s New Innovator Award, which supports unusually innovative research from investigators who are within 10 years of their final degree or clinical residency and have not yet received a large independent NIH grant.

Understanding Aging’s Effect on Cancer Risk

Young, an assistant professor in the Division of Hematology at WashU Medicine, studies how genetic mutations in blood and bone marrow cells acquired with age contribute to cancer risk. Most previous work in this area has looked at mutations in individuals who have already developed cancer, to see which mutations might have been responsible. Young’s research will focus on studying such mutations in cancer-free adults at advanced ages to better understand who goes on to develop cancer and why.

Because most of these cancer-related mutations can exist in the body for long periods of time but never lead to cancer, studying such genetic changes in healthy adults could provide new clues to preventing cancer.

“We have a relatively good understanding of how germline genetic risk, such as inherited BCRA1 mutations, and environmental exposures such as smoking lead to disease,” said Young, who treats patients at Siteman Cancer Center. “But we know less about how the genomic changes associated with ‘normal’ aging drive the development of disease and could be used to predict or prevent those diseases. This support will allow us to conduct the foundational experiments necessary to understanding how aging affects our bodies at the genomic level and how those genomic changes influence human disease.”

Boosting the Efficiency of Regenerating Tissue

Meers, an assistant professor in the Department of Genetics at WashU Medicine, is focused on developing new tools and techniques to help guide stem cells to becoming specific mature cell types. Such tools could nurture the nascent field of regenerative medicine, in which stem cells or even specialized cell types, such as skin cells, could be reprogrammed to form new tissues and organs that could replace those damaged by disease or injury.

Most existing processes for directing cells to take on particular functions or identities are inefficient in producing the targeted cell type, making them unsuitable to treating human disease. Meers and his team are developing a novel time-lapse profiling method to monitor changes in how a cell’s genes are regulated as it goes through the reprogramming process. A better understanding of these changes could lead to the development of more precise and efficient cell conversion methods that are more suitable for human therapeutics.

“Some of the most groundbreaking, paradigm-shifting science has historically come from the sorts of research that took risks, and we’re pleased to have the opportunity to pursue that sort of research with this NIH support,” Meers said. “This award is a green light to focus solely and without distraction on exactly what we think will make the greatest positive impact on scientific knowledge and human health.”

Revealing the Origins of Inflammatory Bowel Disease

Sorrells, an assistant professor in the Preston M. Green Department of Electrical & Systems Engineering at the McKelvey School of Engineering, is focused on developing a new imaging tool to study inflammatory bowel disease (IBD), a chronic gastrointestinal disorder that increases the risk of colorectal cancer. Significant gaps exist in the knowledge of how host cells and intestinal microbes interact in real time within the intestinal microenvironment.

Sorrells is developing an integrated optical imaging platform that can observe the intestinal microenvironment in mice with unprecedented spatial and temporal resolution. Most laboratory methods rely on bulk analysis of extracted tissue, which eliminates spatial context, or use imaging techniques that cannot achieve both the resolution and the speed needed to capture microbial behavior and host metabolism in vivo.

“We lose the ability to look at complicated dynamics that happen on the seconds scale within biological systems, and we also lose the ability to get higher throughput of larger areas,” she said. “One of the goals of this grant is to develop a new method for label-free super-resolution, with nonlinear optical microscopy.”

Sorrells’ approach ensures that the measurements reflect native physiology rather than an experimental artifact.

“The application is to look at a living gut microbiome,” she said. “Seeing how both bacteria and host cells are interacting over time and looking at how that changes spatially will help us better understand the many factors at play in the gut microbiome. Looking at live bacteria-host interactions will allow us to understand healthy and diseased states.”

The new imaging tool also could be used to study other complex tissue microenvironments, including those relevant to cancer, infection and autoimmune disorders.

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This work is supported by NIH grant numbers DP2 GM164659-01 (Meers), DP5 OD038607-01 (Sorrells) and DP5 OD039424-01 (Young). This work is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Breast cancer startup founded by WashU Medicine researchers acquired by Lunit

Prognosia’s AI-based imaging tech could improve prevention, early detection of breast cancer

An innovative biotech startup founded by researchers at Washington University School of Medicine in St. Louis has been acquired by Lunit, a leading company in developing AI-based technologies for cancer prevention and early detection. The WashU startup, Prognosia, was created to develop software that harnesses AI to analyze mammograms and more accurately predict a woman’s five-year risk of developing breast cancer.

The startup’s first software package, Prognosia Breast, received Breakthrough Device Designation from the Food and Drug Administration (FDA) earlier this year, putting it on a fast track to full market approval. Lunit’s acquisition of Prognosia can help accelerate the final steps of the process to bring the technology into the clinic.

Prognosia was co-founded by Graham A. Colditz, MD, DrPH, the Niess-Gain Professor of Surgery at WashU Medicine and associate director of prevention and control at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine; and Shu (Joy) Jiang, PhD, an associate professor of surgery in the Division of Public Health Sciences in the Department of Surgery at WashU Medicine and a research member at Siteman.

“We are excited to work with Lunit to bring this technology to the clinic,” Jiang said. “Lunit already has the infrastructure in place to streamline production and clinical implementation of our software that would be extraordinarily difficult for a new startup to build from scratch. Integrating our software into their existing systems could help this new technology get into the hands of physicians and patients very quickly.”

The system produces a five-year breast cancer risk score that makes it possible to compare a woman’s personalized risk to an average risk based on national breast cancer incidence rates. This provides a meaningful estimate that is aligned with the U.S. national risk reduction guidelines, so that clinicians will know what options to discuss if a patient’s breast cancer risk is elevated.

“Improved risk prediction can help early detection, which has the potential to increase the likelihood of successful treatment that is less disruptive to people’s lives,” said Colditz, an internationally renowned cancer prevention researcher who has led the field for decades. “We recognized that there is a tremendous wealth of information about breast cancer development already stored and continuing to be newly collected in the form of regular mammograms. Until recently, there was no way to use this information to inform risk prediction or to develop new and better prevention strategies.”

Improving Accuracy

Past research led by Colditz and Jiang has shown their system is more than twice as accurate as the standard method of identifying individuals at high risk of developing breast cancer over the next five years. The standard method is based on questionnaires that include factors such as age, race and family history of breast cancer. Research also has shown that the technology maintains its high performance across multiple demographic groups, including among people of diverse races, ages and differing breast densities.

These results led to the technology’s recent FDA Breakthrough Device designation, which provides an accelerated review process for full market approval with the goal of giving patients and clinicians access to promising new medical devices sooner. The designation recognizes that the software already has undergone rigorous testing and has shown excellent promise in its potential to improve clinical care.

The developers said the technology could be easily integrated into existing clinical workflows and is compatible with both types of mammogram imaging available: the four 2D views of the breast produced by full-field digital mammography and the synthetic 3D view of the breast produced by digital breast tomosynthesis.

A Roadmap for Growth

Colditz and Jiang worked with WashU’s Office of Technology Management (OTM) to found their AI-based biotech startup.

“Prognosia is a superb example of harnessing all the resources available to WashU faculty to accelerate the launch of a company,” said Nichole R. Mercier, PhD, assistant vice chancellor and managing director of OTM. “Dr. Colditz and Dr. Jiang were proactive in adapting and learning through the resources and guidance of WashU’s OTM and the entrepreneurship ecosystem of St. Louis. Through Lunit’s acquisition of Prognosia, we’re excited to see this powerful startup venture become even better positioned to make transformative improvements in breast cancer risk estimation, prevention and early detection.”

Colditz and Jiang said Prognosia would not have been possible without OTM’s GAP funding program, which allowed them to do the work required for the FDA’s Breakthrough Device designation, as well as support from BioGenerator Ventures, which provided both financial support and expertise in business strategy from Entrepreneur-in-Residence David Smoller, PhD.

“With the guidance of OTM and David Smoller, we broadened our perspective beyond the technical aspects of the software to focus on the needs of the health-care providers who will use it to care for patients,” Colditz said. “That shift in mindset has been crucial to developing a technology that’s truly useful in the clinical setting.”

Colditz and Jiang will hold advisory roles at Lunit during the pre-market review process that precedes full FDA approval of the technology and for ongoing development projects. The regulatory plan includes an initial submission for the static model of risk prediction based on mammograms taken at a single timepoint, with a roadmap to expand functionality of the software by analyzing mammograms from the same person taken at multiple timepoints to improve the accuracy of the prediction.

New center to develop AI-based imaging tools to improve diagnosis, care

WashU Medicine Mallinckrodt Institute of Radiology leads effort on image-based precision medicine

Mallinckrodt Institute of Radiology (MIR) at Washington University School of Medicine in St. Louis is establishing a new center dedicated to developing AI-based imaging tools to improve the diagnosis and precision treatment of cancers, cardiovascular disease, neurological diseases and numerous other conditions. The new Center for Computational and AI-enabled Imaging Sciences brings together collaborators from across WashU Medicine — including Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine — and others from WashU’s McKelvey School of Engineering.

AI already has shown promise for its ability to analyze vast collections of medical images to generate clinically relevant insights, identifying patterns and anomalies that physicians might otherwise not detect on their own.

“Mallinckrodt Institute of Radiology has long been a national leader in developing innovative imaging technologies, from the invention of positron emission tomography to today’s AI applications in diagnostics and image analysis, and this new center represents an ambitious expansion of our capability,” said Pamela K. Woodard, MD, the Elizabeth E. Mallinckrodt Professor and head of MIR at WashU Medicine. “Integrating AI into imaging will enhance how we diagnose disease, predict its progression and tailor treatments to the unique needs of each patient.”

The new center will help advance AI-driven imaging technologies, such as two recently developed at WashU Medicine — in collaboration with MIR — that are being commercialized. One tool can analyze mammograms to predict an individual patient’s risk of breast cancer over the next five years. Another rapidly maps the brain to help neurosurgeons plan delicate surgeries and avoid sensitive areas that control speech, movement and cognitive function. The center will be a hub for expertise in image analysis that uses sophisticated computing tools to find patterns in datasets of millions of medical images and de-identified patient records, providing insight on both the progression and the potential treatment of disease. The center will also support training on these tools for clinicians and researchers.

The new center will join a growing WashU ecosystem of collaborative AI initiatives that are helping to shape the future of medicine. These include the Center for Health AI (CHAI), which was established as part of the joint agreement to build deeper collaboration between BJC Health System and WashU Medicine and is focused on making health care more personalized and effective for patients and more efficient for providers; and the AI for Health Institute at WashU McKelvey Engineering, which is working on other AI-powered medical innovations.

The Center for Computational and AI-enabled Imaging Sciences will primarily focus on developing AI-based medical imaging applications that integrate information from different imaging types — ranging from digital microscope images of cells to MRI scans to X-rays — to identify clinically informative connections between them. This may include identifying previously unknown early indicators of disease onset that could allow for more effective clinical interventions.

The center will bring together AI imaging experts and researchers from across the Medical Campus, including Siteman Cancer Center, and from the school’s Departments of Medicine, of Neurology, of Psychiatry and of Radiation Oncology.

A Clear Image of the Future of Medicine

The new center will house information from the imaging databases of all the participating departments, collectively representing a range of imaging modalities across many different types of disease. The AI-powered tools developed from those large datasets will enable increasingly precise diagnosis for individual patients, Woodard said.

AI algorithms applied to medical imaging have already been used to detect and classify new subtypes of some disorders in ways that can guide clinical treatment decisions. The breadth of information that will be available at the new center will accelerate this work in a broader range of conditions.

The new center will be led by Mark Anastasio, PhD, a leading expert in computational imaging science and AI for imaging applications. He joins WashU as the Mallinckrodt Endowed Professor of Imaging Sciences for MIR, where he will also be the Vice Chair for Imaging Sciences and AI Research. He will also be Professor of Electrical & Systems Engineering in McKelvey Engineering. Anastasio comes to WashU from the University of Illinois Urbana-Champaign, where he has served as head of the Department of Bioengineering for the past six years.

“Institutions with leading academic medical centers that unite medical data, clinical expertise and advanced AI research will lead the next revolution in healthcare,” said Anastasio. “WashU is exactly such an institution and an ideal home for this center that will enable us to build a community to drive innovation that advances patient care in ways few other institutions can achieve.”

As part of that community building, Anastasio will join the leadership team of the Oncologic Imaging Program at Siteman Cancer Center. He will also be the associate Chief Research Information Officer for Biomedical Imaging at the Institute for Informatics, Data Science & Biostatistics (I2DB), where he will work with institute director Philip R.O. Payne, PhD, the Janet and Bernard Becker Professor of Medicine. Payne is also the chief health AI officer for CHAI and the Vice Chancellor for Biomedical Informatics and Data Science at WashU Medicine.

“AI-enabled imaging has the potential to be as transformative for medicine as earlier waves of innovation — from the adoption of electronic health records to the rise of precision medicine and the advent of real-world evidence generation,” said Payne. “That transformation is being realized here at WashU Medicine because of the dynamic and collaborative environment that exists at our institution, exemplified by leading-edge, transdisciplinary initiatives like this one.”

Aaron Bobick, PhD, dean of WashU McKelvey Engineering and the James M. McKelvey Professor, said dedicated centers such as this will be crucial to maximizing the medical and engineering expertise needed to build out the potential for AI in medical applications.

“Medical imaging offers some of the most exciting challenges in imaging science and artificial intelligence, both of which are core domains for McKelvey Engineering,” said Bobick. “I am certain that the innovations that this center will facilitate by combining the skills of WashU Engineering faculty with the broad range of medical expertise at WashU Medicine will lead to advances that both drive the science forward and benefit patients.”

Working together, cells extend their senses

New research from Amit Pathak’s lab has implications for tracking cancer

The story of the princess and the pea evokes an image of a highly sensitive royal young woman so refined, she can sense a pea under a stack of mattresses. When it comes to human biology, it also takes an abnormal individual to sense far beyond its surroundings, in this case, a cancer cell. Now, researchers also know that normal cells can pull a similar trick by working together.

Research published in the journal PNAS from engineers at Washington University in St. Louis offers a clearer picture of how cells can sense beyond their direct environment. The research can help further the understanding of how cancer moves and points to potential targets to stop that migration.

Amit Pathak, PhD, a professor of mechanical engineering and materials science at the McKelvey School of Engineering and a research member of Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine, explained that “depth mechano-sensing” is how cells sense beyond what they are attached to. In previous research, he and colleagues discovered that abnormal cells with a “high front-rear polarity” (indicative of migrating cells) can sense the farthest depth, up to 10 microns beyond their adhered environment.

Part of that sensory ability has to do with how the cell deforms the surrounding fibrous collagen to reach out into extracellular matrix (ECM) and “feel” the next layer, whether that’s a hard tumor, soft tissue or bone just around the bend. The single abnormal cell can “feel” the stiffness of the ECM and set its course based on that input.

The new research shows that a collective of epithelial cells, found on the surface of tissue, can do the same and then some, working together to muster enough force to “feel” through the fibrous collagen the layer as far as 100 microns away.

“Because it’s a collective of cells, they are generating higher forces,” said Pathak, who authored the research along with PhD student Hongsheng Yu.

According to their models, this occurs in two distinct phases of cell clustering and migration. What those clustering cells “feel” will impact migration and dispersal.

The extra sensing power of cancer cells means that they can get out of the tumor environment and evade detection, migrating freely thanks to their enhanced sense of what’s ahead, even in a soft environment. Researchers’ next step will be understanding how that works, and if certain regulators allow for the range. Those regulators could be potential targets for cancer therapy. If a cancer cell can’t “feel” its way forward, its toxic spread may be put in check.

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Hongsheng Y, Pathak A. Emergent depth-mechanosensing of epithelial collectives regulates cell clustering and dispersal on layered matrices. PNAS, Sept. 11, 2025. DOI: https://doi.org/10.1073/pnas.2423875122

Funding for this research was provided by the National Institutes of Health (NIH) (R35GM128764) and National Science Foundation, Civil, Mechanical and Manufacturing Innovation (2209684).

Study sheds light on how pediatric brain tumors grow

Blocking a chemical messenger in the brain that helps tumor cells multiply could offer new route to treatment

The most common type of brain tumor in children, pilocytic astrocytoma (PA), accounts for about 15% of all pediatric brain tumors. Although this type of tumor is usually not life-threatening, the unchecked growth of tumor cells can disrupt normal brain development and function. Current treatments focus mainly on removing the tumor cells, but recent studies have shown that non-cancerous cells, such as nerve cells, also play a role in brain tumor formation and growth, suggesting novel approaches to treating these cancers.

Scientists have long known that a nerve cell signaling chemical called glutamate can increase growth of cancers throughout the body, but despite years of investigation, they haven’t figured out exactly how this happens, or how to stop it. Now, an interdisciplinary team of researchers at Washington University School of Medicine in St. Louis has uncovered how glutamate regulates pediatric brain tumor growth. Using tumor cells isolated from patient PA samples, they found that PA cells hijack the function of proteins on cells’ surface that normally respond to glutamate, called glutamate receptors. Instead of transmitting glutamate’s typical electrical signal, these receptors are reprogrammed to send signals to increase cell growth.

They also observed that drugs that block these glutamate receptors — including memantine, which is approved to treat dementia and Alzheimer’s disease — reduced human pediatric brain tumor growth in mice, a finding that points to a potential new treatment opportunity.

The results appear Sept. 1 in Neuron.

“With these kinds of pediatric brain tumors, we just don’t have that many tools in our toolbox for treating patients,” said senior author David Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology at WashU Medicine. Gutmann treats patients at Siteman Kids at St. Louis Children’s Hospital.

“The potential to repurpose drugs that are already in use for other neurological disorders means we may have another trick up our sleeves for treating patients.”

The research team, which included first author Corina Anastasaki, PhD, a research assistant professor of neurology at WashU Medicine, also showed for the first time that glutamate receptors abnormally couple with growth receptors in PAs to fuel the tumors. The findings offer a roadmap for future studies to explore if the same process is happening in different types of cancers.

New uses for familiar tools

Glutamate is what is known as a neurotransmitter, a molecule that nerve cells, including neurons in the brain, use to communicate with each other. On their path to understand how glutamate helps brain tumors grow, Gutmann, who is also the director of the Neurofibromatosis Center at WashU Medicine, and Anastasaki worked closely with collaborators across WashU Medicine — including in neurosurgery, pediatrics, genetics, neuropathology, biostatistics and more — to acquire and analyze samples of PAs that had been surgically removed. They found that these PA cells had unusually high levels of glutamate receptors.

By testing how glutamate affected these tumors, the researchers discovered that glutamate increased PA cell numbers by kicking off a chain reaction inside the tumor cells that urged cells to divide. These findings suggest that tumor cells exploit normal brain-cell interactions to spur their own growth.

“This novel mechanism for tumor growth combines two normal but unconnected brain processes — growth and electrical signaling — in an aberrant way,” Anastasaki said. “Now that we’ve figured out how these cells work and grow, the sky’s the limit for looking at other neurotransmitters and the different avenues of communication between neurons and cancer cells. Understanding that will tell us why tumors grow and behave the way they do. That may lead to us treating them very differently.”

Such new treatments might come from familiar sources. The researchers showed that inhibiting glutamate receptors of tumor cells in mice with PAs — either with medications or by genetically altering the cells — reduced tumor growth. This points to a potential opportunity to repurpose glutamate receptor-targeting drugs such as memantine for the treatment of PAs.

The next steps are to determine whether such medications are safe to use in children with brain tumors and in what amounts they would be effective, Gutmann noted, which will require clinical trials.

“This study provides compelling preclinical data to look at medications that are otherwise safe and approved to treat other neurological conditions,” Gutmann said. “That would enable new therapeutic approaches and could help minimize the damage to a child’s developing brain by reducing engagement between brain cells and tumor cells.”

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Anastasaki C, Mu R, Kernan CM, Li X, Barakat R, Koleske JP, Gao Y, Cobb OM, Lu X, Eberhart CG, Phillips JJ, Strahle JM, Dahiya S, Mennerick SJ, Rodriguez FJ, Gutmann D. Aberrant coupling of glutamate and tyrosine kinase receptors enables neuronal control of brain tumor growth. Neuron. September 1, 2025.

This work was partially funded by grants from the National Institute of Neurological Disorders and Stroke (R35NS07211-01), National Cancer Institute (1-R50-CA233164-01), National Institutes of Health (P50MH122379 and R01MH123748), Taylor Family Institute for Innovative Psychiatric Research, and the Pediatric Brain Tumor Foundation. Corrine Gardner and the Pediatric Neurosurgery Tissue Bank coordinated the acquisition of fresh operative specimens. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

1,000th patient treated at Siteman with AI-enabled radiation therapy system

Combining artificial intelligence (AI) with advanced imaging, the technology supports more precise, personalized daily treatments by WashU Medicine physicians

Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine has treated its 1,000th patient using state-of-the art radiation therapy technology that allows physicians to update a patient’s treatment plan on each day of treatment.

Called adaptive technology, the system incorporates slight changes in tumor shape, size and location, as well as the movement of surrounding healthy organs and tissue, to adjust a patient’s daily radiation therapy treatment plan for the best possible outcome.

The system is used to treat a range of tumors, including head and neck, central nervous system, thoracic, abdominal and pelvic cancers.

“We are pleased to offer this advanced technology to our patients — from the first person we treated with this system in 2020, to the 1,000th person in August 2025,” said WashU Medicine radiation oncologist Hyun Kim, MD, associate professor of radiation oncology and chief of Adaptive Radiation Therapy at WashU Medicine and Siteman.

“The milestone of 1,000 patients treated on this platform is literally the result of thousands of hours dedicated by our faculty and staff to personalize treatment every day for every patient,” he said.

Also known as online adaptive radiation therapy, it requires a team of expert physicians, physicists and radiation therapists to develop and review a treatment plan after the patient’s arrival — all within minutes after the patient is positioned to receive treatment.

In addition to the AI component and machine learning, the platform is equipped with cone-beam computed tomography (CT). Cone-beam CT quickly provides high-quality images and leads to better visualization of the tumors and surrounding healthy organs and tissue, allowing the physician to develop even more accurate, personalized treatment plans than with some older radiotherapy platforms.

In clinical trials incorporating the new technology, patients experienced decreased times to treatment and, in some cases, improved cancer control with less damage to surrounding healthy organs and tissue.

For some gynecologic cancers, treatment can involve imaging the ovaries of pre-menopausal patients. As a result, some patients have experienced premature ovarian failure and early menopause when treated with older radiotherapy technologies. WashU Medicine physician-scientists are conducting an ongoing clinical trial using the new technology with the hope that they can spare these organs.

Known as Ethos, the platform is manufactured by Varian Medical Systems, which also makes the cone-beam CT imaging component, called HyperSight.

AI-Based Breast Cancer Risk Technology Receives FDA Breakthrough Device Designation

Software developed at WashU Medicine on accelerated path to approval

A new technology that harnesses AI to analyze mammograms and improve the accuracy of predicting a woman’s personalized five-year risk of developing breast cancer has received Breakthrough Device designation from the Food and Drug Administration (FDA). Developed by researchers at Washington University School of Medicine in St. Louis, the software has been licensed to Prognosia Inc., a WashU startup company.

The system analyzes mammograms to produce a risk score estimating the likelihood that a woman will develop breast cancer over the next five years. The technology is compatible with both types of mammogram imaging available: the four 2D views of the breast produced by full-field digital mammography and the synthetic 3D view of the breast produced by digital breast tomosynthesis.

Importantly, the system produces an absolute five-year risk that makes it possible to compare a woman’s risk to an average risk based on national breast cancer incidence rates. This provides a meaningful estimate that is aligned with the U.S. national risk reduction guidelines, so that clinicians will know what steps to take next if a woman’s risk is elevated.

The FDA Breakthrough Device designation provides an expedited review process for full market approval in an effort to give patients and clinicians accelerated access to new medical devices. Products that receive the designation have already undergone rigorous testing and shown excellent promise in their potential to improve treatment or the diagnosis of debilitating or life-threatening conditions.

The software package, called Prognosia Breast, was developed by Graham A. Colditz, MD, DrPH, the Niess-Gain Professor of Surgery at WashU Medicine and associate director of prevention and control at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine; and Shu (Joy) Jiang, PhD, an associate professor of surgery in the Division of Public Health Sciences in the Department of Surgery at WashU Medicine. Colditz and Jiang co-founded Prognosia in 2024 in collaboration with WashU’s Office of Technology Management (OTM) and BioGenerator Ventures, the latter of which provided both financial support and business strategy expertise from Entrepreneur-in-Residence David Smoller, PhD.

The software is a pre-trained machine learning system that analyzes mammogram images and provides an estimate of how likely a patient is to develop breast cancer over the next five years, based solely on images and a woman’s age. According to the developers, Prognosia Breast estimates a person’s five-year risk of developing breast cancer 2.2 times more accurately than the standard method, which is based on questionnaires that consider factors such as age, race and family history. The system was trained on past mammograms from tens of thousands of individuals who underwent breast cancer screening through Siteman Cancer Center. Some of them went on to develop cancer, teaching the system what to look for in the earliest stages of tumor development. Such early signs of disease can’t be perceived even by a well-trained human eye.

“We’re excited about the potential of this technology to improve risk prediction and prevention of breast cancer broadly, no matter where a woman is getting screened,” Colditz said. “The long-term goal is to make this technology available to any woman having a screening mammogram anywhere in the world. No matter the type of imaging they receive, our data show the software’s potential to identify women at increased risk of developing breast cancer over the next five years, providing them with opportunities to take targeted steps to reduce that risk.”

The new device could have a large impact on risk prediction because the infrastructure is already in place to begin immediately using the software anywhere mammography is provided. Furthermore, many women already receive regular mammograms. According to 2023 survey data from the Centers for Disease Control and Prevention, more than 75% of women ages 50 to 74 reported having received a mammogram in the past two years.

Even with widespread screening, about 34% of breast cancer patients in the U.S. are diagnosed at later stages of the disease. According to the investigators, being able to assess risk up to five years in advance of the onset of cancer is likely to improve early detection, reducing the number of late-stage cancers diagnosed. Early detection has been shown to make treatment more effective and reduce deaths from breast cancer.

“Receiving a Breakthrough Device designation is a powerful validation of the extraordinary dedication and vision of this research team to improve breast cancer diagnosis and care,” said Doug E. Frantz, PhD, vice chancellor for innovation and commercialization at WashU. “It takes years of concerted effort to produce software that could quickly be integrated into the workflow of any mammography center, significantly enhancing the clinical value of routine mammograms no matter where they are provided. This is a prime example of the vital role of entrepreneurship and commercialization at WashU in transforming cutting-edge research into real-world technologies that improve patient care.”

The device produces a five-year risk score that is intended to complement, not replace, the analysis provided by radiologists, who will continue to review the mammograms following standard protocols. According to the American Society of Clinical Oncology and the U.S. Preventive Services Task Force, a five-year risk score of 3% or higher is considered elevated. According to guidelines from these organizations, women with elevated scores should be referred to specialists who can further advise them on their options for additional screening and prevention strategies.

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About one in eight women in the U.S. will be diagnosed with breast cancer in their lifetime. Those found to be at elevated risk of this cancer have the option to receive more frequent screening — which may include other types of imaging, such as MRI — and in some cases may choose to take a type of chemotherapy called tamoxifen or endocrine therapy as preventive treatments. With such options available, identifying women at high risk is important so they have access to specialists who can help guide them in making these important choices.

The developers are planning a clinical trial at Siteman Cancer Center that will apply the risk score from Prognosia Breast in combination with the standard mammography screening protocols. Standard screening protocols include the review of mammograms and measures of breast density already provided to all patients. Individuals found to be at elevated risk will be referred to Siteman’s breast health specialists, who focus on helping individuals navigate the options they have for managing high breast cancer risk.

“Despite the sophistication of today’s breast imaging and its broad use for identifying existing tumors, today’s risk prediction for breast cancer is still questionnaire-based and not very good at estimating future risk,” Jiang said. “Our work has focused on filling that need for better methods. Moving to image-based risk prediction — which our studies have shown is much more accurate — has the potential to be revolutionary for patient care.”

The current FDA designation applies to the software’s analysis of mammogram images taken at a single time point. In the future, the researchers plan to update Prognosia Breast to analyze several years of mammograms from the same individual, which may further improve the accuracy of the prediction.

Genetic study suggests ways to catch blood cancer earlier

New understanding of how mutations interact could pave way for early detection, prevention strategies

As we age, our cells replicate, and the DNA in these cells can acquire mistakes — or mutations — every time the sequence is copied. Most newly acquired mutations are harmless, but some can tip the balance toward cancer development later in life.

Now, a new study led by researchers at Washington University School of Medicine in St. Louis shows that such newly acquired mutations interact with our inherited mutations — those passed down by our parents — in important ways that influence a person’s lifetime cancer risk. Understanding such interactions could guide development of new methods for early detection and prevention of cancer.

The research, published in Nature Genetics, focused specifically on the risk of blood cancers such as acute myeloid leukemia (AML), although interactions between inherited and acquired mutations likely have roles in other types of cancer.

Inherited mutations are carried in the egg and sperm and are therefore present in every cell starting at birth, whereas acquired mutations accumulate gradually with age in different cells. Led by Kelly Bolton, MD, PhD, an assistant professor of medicine in the Division of Oncology at WashU Medicine and the study’s senior author, the research team set out to understand how interactions between these two types of mutations influence a person’s risk of developing blood cancer.

In particular, they focused on a blood condition called clonal hematopoiesis that is known to increase a person’s risk of developing blood cancer. Clonal hematopoiesis is caused by a mutation in blood stem cells — cells that give rise to all the different cell types in the blood — that gives those cells a slight survival advantage over the normal stem cells. Such stem cell clones multiply more and are at risk of transforming to blood cancer.

“Most people with clonal hematopoiesis never develop blood cancer,” said Bolton, who treats patients at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine. “To a certain extent, it’s a normal aging process. However, we think that many if not all individuals who develop blood cancer pass through a phase of clonal hematopoiesis at some point. We are still in the early stages of trying to figure out which individuals with clonal hematopoiesis will go on to develop blood cancer and which will not.”

Studying genomic data of more than 730,000 people, including from blood samples, the researchers found that clonal hematopoiesis was more common among those with inherited mutations in certain genes already known to increase the risk of cancer. They also found that such inherited mutations had an impact on patterns of newly acquired mutations that cause clonal hematopoiesis. If stem cell clones go on to acquire just a handful more harmful mutations, the clonal hematopoiesis can transform into a blood cancer, such as AML, in which the cells stop doing their jobs and multiply until they crowd out healthy cells.

With the goal of finding ways to detect and eliminate pre-cancerous cells in people at high risk of blood cancer, Bolton and her colleagues found that among individuals with clonal hematopoiesis, those who had inherited mutations that predispose to clonal hematopoiesis had a higher risk of developing blood cancer than those without inherited mutations.

“Our study is a first look at the inherited genetic background that is providing the soil, so to speak, and we’re seeing what undesirable seeds that are acquired later in life are more or less likely to grow from that soil,” Bolton said. “The goal is to stamp out the weeds early, before they can take root and become full-blown cancer.”

Though clonal hematopoiesis is part of normal aging, certain factors such as smoking or prior exposure to radiation or chemotherapy can speed up the process and increase the risk of it transforming into cancer. Still, some people progress to cancer without major environmental risk factors, and the new study suggests that the interaction of their inherited genome with newly acquired mutations plays an important role in this cancer progression.

The study’s first author Jie Liu, a graduate student in Bolton’s lab, noted: “It’s exciting to see how combining large-scale genomic data can reveal how inherited and acquired mutations work together to influence cancer risk. These insights move us closer to identifying high-risk individuals before cancer develops. Our work shows that it’s not just the mutations you’re born with or those you acquire later in life, it’s the interaction between them, and we can now measure that.”

Earlier intervention

Bolton said being able to detect and measure both inherited cancer risk and clonal hematopoiesis would likely be a powerful way to identify individuals who would benefit most from early prevention strategies, such as targeted therapies for the most damaging mutations. At present, clonal hematopoiesis is difficult to identify without specialized blood tests that are not given as part of routine care. Even though such individuals already have clones taking up a greater proportion of their blood stem cells, they can still show normal blood cell counts as part of blood tests typically given at an annual well visit, for example.

In theory, if scientists know what gene mutations to look for, they could develop new blood tests to identify such individuals before any evidence of a problem could be detected with routine blood screening tests. The new study singles out many genes of interest that could be key in the future development of such a blood test.

“Because leukemia is so hard to treat, we hope to find ways to intervene early — when it’s still pre-cancerous — so we can stop clonal hematopoiesis from transforming into leukemia,” Bolton said. “We would want to start with preventive clinical trials for people who have certain inherited mutations and who already have evidence of clonal hematopoiesis, such as one or two clones expanding in their blood.”

Researchers at Siteman are now conducting clinical trials investigating whether specific drugs called IDH1 and IDH2 inhibitors can stop the expansion of certain types of blood stem cell clones before they become cancer. For now, such trials only include people who could be identified as having clonal hematopoiesis because they already had progressed to having abnormal blood cell counts, placing them on the cusp of full-blown leukemia.

“We are hopeful about the prospects of these preventive treatments, but we would like to have tools to identify these individuals even earlier, before their blood cell counts become abnormal,” Bolton said. “There are a lot of targeted therapies that are being developed right now and new approaches researchers are looking at for this purpose.”

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Liu J, Tran D, Xue L, Wiley BJ, Vlasschaert C, Watson CJ, MacGregor HAJ, Zong X, Chan ICC, Das I, Uddin MM, Niroula A, Griffin G, Ebert BL, Mack T, Pershad Y, Sharber B, Berger M, Sehir A, Ptashkin R, Levine RL, Papaemmanuil E, Joseph V, Gao T, Kemel Y, Mandelker D, Stopsack KH, Pharoah PDP, Mukherjee S, Ding L, Cao Y, Walter MJ, Blundell JR, Chatterjee N, Offit K, Godley LA, Link DC, Stadler ZK, Bick AG, Natarajan P, Bolton KL. Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy. Nature Genetics. July 15, 2025. DOI: 10.1038/s41588-025-02250-x.

This work was supported by the National Institutes of Health (NIH), grant numbers R01HL148050, R01HL168894, DP5 OD029586, R01AG088657 and R01AG083736; the MDS Foundation; the Children’s Discovery Institute; a Prostate Cancer Foundation Challenge Award; the Edward P. Evans Foundation; the SciLifeLab & Wallenberg Data Driven Life Science Program, grant number KAW 2020.0239; the Swedish Cancer Foundation, grant numbers 22.0577JIA and 22.2362Pj; the Swedish Research Council, grant number 2023-03131; a Burroughs Wellcome Fund Career Award for Medical Scientists; a Pew Charitable Trusts and Alexander and Margaret Steward Trush Pew-Stewart Scholar for Cancer Research Award; and a Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience Research. The study was conducted using the U.K. Biobank Resource and data provided by patients and collected by the National Health Service. It was also conducted using data from the All of Us Research Program of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.