Article Category: Research

Finding Order in the Inner Chaos of our Cells

New technique wrangles evasive proteins to dissect the cause of diseases and design potential new therapeutics

The vast majority of proteins in our bodies contain regions that are in a constant state of wiggling, shape-shifting every few nanoseconds to completely change how they look. Information on how these shapeshifting proteins work is critical to understanding health and disease and to developing drugs for cancer, neurodegeneration and myriad other conditions. However, it has been challenging for scientists to pin down precisely how these regions function, and how they go awry in disease.

Now, researchers from Washington University School of Medicine in St. Louis and Syracuse University have built a tool that can design such “disordered” proteins and untangle their functionality. The innovation has the potential to accelerate the scientific exploration of a vast and underexplored area of biology.

The study is published in Nature July 29.

An important way scientists study proteins is to design synthetic equivalents of the molecules that they can then test in various ways. Until now, advances in such protein design have applied almost entirely to “folded” proteins — or their folded parts — that have a defined three-dimensional shape.

Yet 70% of human proteins also contain disordered regions that don’t have a stable 3D structure. These regions can play critical roles in a variety of different cellular processes and human diseases. Researchers’ ability to predict how they will behave, or to design synthetic versions to study their function, was limited.

“The way people would typically try to study and design stable, folded proteins doesn’t really work very well for disordered proteins,” said Alex Holehouse, PhD, an associate professor in the WashU Medicine Department of Biochemistry and Molecular Biophysics and a research member of Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine. He and his colleague Ryan Emenecker, PhD, a faculty instructor in the same department and lead developer and co-corresponding author on the study, have been working on an alternative way to tackle this challenge for almost five years.

“The ability to design disordered proteins at a large scale with our platform now allows us to learn how their component sequences affect the cell,” Emenecker said, “and it gives us a lens through which we can learn how naturally occurring changes in these proteins might drive diseases like cancer.”

The technique also has potential for driving medical advancements. For instance, Holehouse is seeking to optimize therapeutics that rely upon disordered proteins. Holehouse and Emenecker have received a grant through Siteman to improve CAR T-cells, an anti-cancer therapy in which immune cells are genetically modified to attack tumor cells.

A key protein on the surface of CAR T-cells contains a disordered region that guides the cell’s attack response. Until now, scientific efforts to improve its performance in destroying cancer cells have been conducted largely by trial and error.

“With our technique, we can design better versions of these disordered regions to do the signaling in different ways,” said Holehouse. “The hope is we won’t be limited by the types of constraints that are currently hurting the efficacy of CAR T-therapies. That’s a very concrete place where these tools can move medicine forward.”

A GOOSE chase for disordered proteins

Holehouse, Emenecker and their collaborators, including co-corresponding author Shahar Sukenik, PhD, a faculty member in the Department of Chemistry at Syracuse University, developed the protein-design system, called GOOSE (an acronym derived in an appropriately disordered way from Generate disOrdered prOtiens Specifying propErties).

Loaded with a large library of the sequences for protein building blocks that are associated with specific cell functions, GOOSE produces blueprints for custom-built disordered proteins that are then created in genetically engineered cells. Scientists can remove or add building blocks as desired and test what effect they have on the activities of a cell.

“This opens the possibility of being able to make new sensors that are sensitive to things outside what natural sequences would be attuned to, like toxins or cell damage.”

-Ryan Emenecker, PhD, WashU Medicine


Among various applications, one of GOOSE’s first tests was to generate synthetic proteins that could help cells respond to changes in external stressors — in this case, drought.

“We were able to very quickly design 2,300 different proteins that would respond to drought conditions in yeast,” said Emenecker. He said that many of these synthetic proteins proved GOOSE’s utility by working as intended, helping the cells’ recovery after drying out. Even more promising, many of them performed much better than the yeast’s natural proteins. This work directly contributes to Holehouse, Emenecker and Sukenik’s ongoing work as part of a larger National Science Foundation initiative to engineer more environmentally resilient crops.

“More broadly, this opens the possibility of being able to make new sensors that are sensitive to things outside what natural sequences would be attuned to, like toxins or cell damage,” Emenecker said. “It has the potential to be very valuable.”

Bergom Named ASTRO Fellow 

WashU Medicine radiation oncologist Carmen Bergom, MD, PhD, a renowned research member of Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine, has been named a fellow of the American Society for Radiation Oncology (ASTRO). 

The honor recognizes ASTRO members’ outstanding achievements and contributions to the organization, cancer research, education and patient care. Bergom and other newly named fellows will be recognized at ASTRO’s 68th Annual Meeting in Boston on Sept. 29. 

“The 2026 ASTRO Fellows reflect the depth and breadth of leadership in radiation medicine,” said ASTRO CEO Vivek S. Kavadi, MD, MBA, FASTRO. “Their careers demonstrate the many ways ASTRO members move our field forward through discovery, clinical excellence, education, mentorship and service. We are proud to recognize this distinguished class.” 

ASTRO is the world’s largest professional society dedicated to advancing radiation medicine, with 10,000 members, including physicians, nurses, physicists, radiation therapists and dosimetrists, who work to improve patient outcomes through clinical care, research, education and advocacy. 

Bergom, an associate professor of radiation oncology who joined the WashU Medicine faculty in 2020, treats breast cancer patients at Siteman Cancer Center. She also is an R01-funded investigator focused on increasing the therapeutic ration of radiation therapy by improving the effectiveness of radiation therapy and decreasing side effects. 

Bergom’s research specifically focuses on identifying the mechanisms of radiation-induced cardiac and lung dysfunction to better diagnosis, prevent and treat these toxicities. Her work is examining potential biomarkers and therapeutic targets that may enhance tumor responses to radiation therapy and minimize radiation-induced cardiac and lung dysfunction. 

Bergom’s leadership in the field extends beyond her research. She also serves as vice chair of the ASTRO Science Steering Committee and is a lead writer for the Pathology subgroup of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) CircuDis project, the reports of which are used by governments and agencies around the world to set radiation protection standards.  

In 2021, Bergom received the Michael Fry Research Award from the Radiation Research Society. The award recognizes one junior scientist each year who has made extraordinary contributions to the field of radiation research. 

Learn more about Bergom’s lab and research. 

Siteman Investment Program Awards $2.24 Million for Cancer Research

Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine is pleased to announce $2.24 million in new funding for 11 new projects, including three clinical trials. Through this research, investigators aim to improve the understanding of tumor formation and growth, develop safer, more effective therapies, and remove barriers to precision medicine. The funded projects focus on a variety of cancers, including breast, colorectal, leukemia, lung, lymphoma, and skin cancer.

Provided through the Siteman Investment Program (SIP), the funding supports innovative, high-impact cancer research across the continuum of discovery, diagnosis, treatment and prevention. This program is designed to advance promising ideas with strong potential for future external funding and meaningful clinical or community impact.

These SIP Research Development Awards are supported by a variety of sources including: The Cancer Frontier Fund at The Foundation for Barnes-Jewish Hospital, which includes gifts from Pedal the Cause, the Foundation’s annual Illumination Gala and donations throughout the year; the Cancer Center Support Grant (CCSG) from the National Cancer Institute; the Alvin J. Siteman Cancer Research Fund; Swim Across America – St. Louis; and various philanthropic gifts via Siteman Cancer Center.

Please see below for more details on each funded project.

New Clinical Trial Category

Project Title: Phase II Trial Evaluating Trastuzumab Deruxtecan and Lovastatin in HER2-low and Ultralow Advanced or Metastatic Breast Cancer

Patricia Ribeiro Pereira 150x150
Patricia Ribeiro Pereira, PhD
Headshot of Andrew Davis, MD
Andrew Davis, MD

Principal Investigator: Andrew Davis, MD
Co-PI: Patricia Ribeiro Pereira, PhD

Goal: To evaluate a new drug combination that could help improve outcomes without added toxicity in up to 75% of patients with metastatic breast cancer who are HER2-low or ultralow

Project Summary: Trastuzumab deruxtecan (T-DXd) is approved for patients with metastatic breast cancer whose tumors express various levels of the HER2 protein. However, how well T-DXd works and how long patients stay on this therapy is related to the level of HER2 protein. T-DXd is a treatment that uses an antibody to deliver chemotherapy directly to breast cancer cells in a targeted way. It has improved outcomes for many patients whose tumors have lower levels of the HER2 protein (HER2-low or ultralow). However, these patients do not benefit from T-DXd as much as patients with metastatic breast cancer whose tumors have higher HER2 levels. Based on studies in laboratory models that closely resemble human tumors, we have identified a new way to increase how much T-DXd accumulates in tumors and works in tumors with low HER2 levels using lovastatin, an inexpensive drug that is commonly prescribed to lower cholesterol. These studies suggest that the combination of T-DXd and lovastatin could be more effective than T-DXd alone and safe, as the lovastatin would only need to be given twice every three weeks.

Project Title: Cancer Immunotherapeutic (PCI) Strategy in Triple Negative Breast Cancer Patients

Headshot of Katherine Clifton, MD
Katherine Clifton, MD
Headshot of William Gillanders, MD
William Gillanders, MD

Principal Investigator: William Gillanders, MD
Co-PI: Katherine Clifton, MD

Goal: This is a phase 1 clinical trial to evaluate the safety, feasibility and effectiveness of a personalized cancer vaccine in combination with CD8-selective IL-2 in patients with newly diagnosed triple-negative breast cancer (TNBC) in the window before surgery.

Project Summary: TNBC is an aggressive subtype of breast cancer, accounting for about 15% of all breast cancers. TNBC is more likely to spread, has fewer treatment options and poor clinical outcomes. TNBC disproportionately impacts Black women. The researchers have completed two phase 1 clinical trials of DNA personalized cancer vaccines (PCV) in patients with TNBC (NCT02348320, NCT03199040). In NCT02348320, they demonstrated that DNA PCV can induce neoantigen-specific T cell responses and that patients treated with DNA PCV have improved progression-free survival when compared to institutional historical controls. In NCT03199040, the researchers combined DNA PCV +/- anti-PD-L1 and confirmed these findings, although the addition of anti-PD-L1 did not significantly improve correlative or clinical outcomes.

The focus of this application is a phase 1 clinical trial of a synthetic long peptide (SLP) PCV alone or in combination with CD8-selective IL-2 in patients with newly diagnosed TNBC in the window prior to surgery following neoadjuvant chemoimmunotherapy. Newly diagnosed TNBC patients being treated with chemoimmunotherapy before surgery are eligible to enroll. Patients undergoing standard-of-care neoadjuvant chemoimmunotherapy will be randomized into two treatment arms: SLP PCV alone (Arm 1) or SLP PCV + CD8-selective IL-2 (Arm 2). The primary objective is to evaluate the safety and feasibility of SLP PCV +/- CD8-selective IL-2. The secondary objective is to assess the neoantigen-specific T cell response. The researchers plan to recruit and treat patients at Siteman Cancer Center and satellite locations. To rigorously define the response to SLP PCV +/- CD8-selective IL-2, the researchers will perform state-of-the-art correlative studies focused on neoantigen-specific CD8 T cells in the peripheral blood (Aim 1), neoantigen-specific type 1 regulatory T cells (Tr1) in the peripheral blood (Aim 2), and neoantigen-specific CD8 and Tr1 cells in the tumor microenvironment (Aim 3). The hypothesis is that CD8-selective IL-2 will enhance neoantigen-specific CD8 T cell responses and abrogate neoantigen-specific Tr1 responses. The proposed correlative studies form the basis of an R01 application and will accelerate the clinical development of PCI for the treatment of TNBC.

Project Title: A Pilot Study of Golidocitinib, a JAK1 inhibitor, in Patients with Mycosis Fungoides/Sezary Syndrome and T-Cell Large Granular Lymphocytic Leukemia

Headshot of Neha Mehta-Shah, MD, MSCI
Neha Mehta-Shah, MD, MSCI

Principal Investigator: Neha Mehta-Shah, MD, MSCI

Goal: To examine the safety, toxicity and efficacy of golidocitinib in advanced-stage cutaneous T-cell lymphomas and T-cell large granular lymphocytic leukemia (T-LGLL). The researchers will also collect blood and skin samples to help understand the mechanisms of response and resistance to golidocitinib and provide insight into the biology of these diseases using DNA, RNA analysis, measurement of how much the drug inhibits this pathway, and assessment of how gene expression is regulated by golidocitinib.

Project Summary: Cutaneous T-cell lymphomas (CTCL) and T-LGLL are a rare subset of T-cell non-Hodgkin lymphomas for which patients are treated to improve disease burden and improve quality and duration of life. Currently available therapies only work in 5% to 40% of patients, and each therapy has a limited duration of effectiveness and significant cumulative toxicity. Given the relatively meager response rates to currently available therapy, limited duration of response and their toxicity profile, there is a need to develop better-tolerated therapies for these rare diseases.


Golidocitinib is an oral, selective JAK1 inhibitor which is approved in China for the treatment of peripheral T-cell lymphomas. In international studies, it works to reduce the cancer in over half of patients and works for years with limited side effects. Through work done at Siteman Cancer Center and at other centers, the researchers have found that both CTCL and TLGLL cells have activation of the JAK-STAT pathway. Other less selective JAK inhibitors are effective in the treatment of these diseases. Given the known biology of these diseases, which is hinged on this pathway, the researchers are studying the use of golidocitinib in these rare T-cell lymphomas.

Pre-R01 Category

Project Title: Epigenetic Evolution of Cutaneous Squamous Cell Carcinoma

Headshot of David Chen, MD, PhD
David Chen, MD, PhD

Principal Investigator: David Chen, MD, PhD

Goal: Cutaneous squamous cell carcinoma is a skin cancer with an estimated incidence of greater than 1 million cases per year and is a major driver of cancer-related death, disfigurement and healthcare costs. This study aims to develop a better understanding of the early initiating events in skin cancer development, which may potentially lead to novel therapeutic and preventive strategies for squamous skin cancer.

Project Summary: Squamous cell skin cancer is the second most common cancer in people, yet it remains relatively understudied because it can often be cured with surgery. However, given its prevalence — over 1 million estimated cases annually in the United States — squamous skin cancer is still a major cause of cancer-related mortality, disfigurement, and healthcare costs. Despite ongoing public health efforts promoting ultraviolet (UV) light avoidance, the incidence of cutaneous squamous cell carcinoma (cSCC) continues to rise, particularly among older age populations. The limited availability of robust cSCC animal models and human translational studies has impeded researchers’ ability to gain a detailed understanding of the molecular causes of cSCC. These resources are critically needed to identify new targets for therapy. In this proposal, the researchers will address these gaps by leveraging two critical resources they have established: a novel mouse model of spontaneous squamous cell carcinoma and a human skin cancer tumor bank. They will investigate how defects in the tumor suppressor gene KDM6A contribute to early stages of squamous skin cancer development. By validating their findings using both their mouse model and patient-derived samples, the researchers will ensure that the findings of this study are relevant to human disease. Ultimately, the insights gained from this study have the potential to inform new preventive and therapeutic approaches for squamous skin cancer.

Project Title: Stress-Activated Enteric Glia Reprogram Premalignant Epithelium to Promote Colorectal Cancer Onset

Headshot of Xue-Yan He, PhD
Xue-Yan He, PhD

Principal Investigator: Xue-Yan He, PhD

Goal: To understand how chronic psychological stress changes enteric glial cells, which are the supporting cells of the gut’s nervous system, in a way that helps start colorectal cancer (CRC). The investigators hope this work will show how stress, acting through these glial cells, creates a tumor-permissive environment in the gut and could point to new ways to prevent stress-related colorectal cancer in high-risk individuals.

Project Summary: CRC is a leading cause of cancer-related mortality worldwide. While genetic mutations such as loss of the APC gene are known to initiate tumor formation, the factors that determine whether mutant intestinal stem cells progress toward malignancy remain poorly understood. Chronic psychological stress has long been suspected of influencing cancer development, yet the biological mechanisms linking stress to CRC initiation are largely unknown. Epidemiological studies using large population datasets, including the UK Biobank, have shown that individuals with psychiatric disorders such as depression, anxiety or stress-related conditions have a significantly increased risk of developing CRC. These findings raise an important question: Can chronic stress actively promote the early onset of CRC? Based on these findings, the researchers hypothesize that chronic stress promotes CRC initiation by activating enteric glial cells (EGCs) to create a protumorigenic niche that drives the malignant transformation of mutant intestinal stem cells. To test this hypothesis, the researchers will: 1) Determine how stress-activated EGCs promote the malignant transformation of mutant intestinal stem cells, and 2) Define the epithelial mechanisms that enable stress-induced malignant conversion. These studies will establish a new conceptual framework linking chronic stress to colorectal cancer onset and may identify novel opportunities for CRC prevention and early intervention.

Project Title: Rational Design of Enhanced CAR Signaling Domains Through Deep Learning

Headshot of Nathan Singh, MD
Nathan Singh, MD
Headshot of Alex Holehouse, PhD
Alex Holehouse, PhD

Principal Investigator: Alex Holehouse, PhD
Co-PI: Nathan Singh, MD, MS

Goal: To re-envision the design of cell-based immunotherapies by leveraging an emerging field that combines advanced protein engineering with machine learning. This approach has the potential to empower a new era of highly effective immunotherapies and lay the groundwork for future personalized medicine-based approaches against leukemia.

Project Summary: Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary treatment that re-engineers a patient’s own immune system to identify and destroy cancer cells. While this approach has achieved remarkable success in treating blood cancers, many patients still experience relapses because the engineered cells often fail to persist long enough in the body to fully eradicate the disease. This failure is largely due to current CAR designs relying on “copied and pasted” parts from natural receptors that evolved to fight temporary infections rather than to provide the sustained, synthetic immunity required to cure cancer. This project aims to overcome these limitations by redesigning the “engine” of the CAR T cell from the ground up. To do this, the researchers are taking two complementary strategies. First, they are taking existing machinery that underlies CAR T function and re-engineering it to work more efficiently. Second, they are using advanced computational modeling and artificial intelligence to “evolve” entirely new, synthetic signaling components that outperform anything found in nature. By discovering these new design principles, the researchers will deliver a more durable and potent generation of cell therapies specifically optimized to survive in the patient’s body until the cancer is permanently eliminated. Ultimately, this work shifts the field from simple trial-and-error engineering toward a predictable, chemistry-based framework that will provide more reliable and lasting cures for patients facing aggressive leukemias.

Project Title: Developing 5-year Risk Thresholds for the Initiation, Frequency, and Discontinuation of Supplemental Breast Cancer Screening MRIs

Headshot of Ashley Housten, OTD, MSCI, OTR/L
Ashley Housten, OTD, MSCI, OTR/L

Principal Investigator: Ashley Housten, OTD, MSCI, OTR/L

Goal: To design and pilot a doctor- and patient-facing decision support tool about supplemental breast MRI screening for those with dense breasts. The central research question is to investigate if a decision support tool guided by expert consensus and designed with user-centered methods will be feasible,acceptable and improve well-informed decision-making for doctors and patients.

Project Summary: Almost half of all women in the U.S. have dense breast tissue, which is a breast cancer risk factor and makes it harder to spot tumors on mammograms. While federal law requires patients to be notified about their breast density, this often leaves both women and their doctors in a difficult situation, as there is no clear agreement on how often someone should get a supplemental MRI or when the benefits of extra testing outweigh the physical, psychological and financial costs. This research project aims to bridge that gap by creating a decision support tool designed for use during doctor visits to help doctors and patients make well-informed decisions together. To achieve this, the research team will first gather a panel of experts in oncology and radiology to establish clear, consensus-based guidelines on who should get an MRI and how frequently, based on specific risk levels. Next, the researchers will work directly with patients and doctors to design a tool that translates complex medical information into plain language, ensuring it effectively communicates the tradeoffs of extra screening. Finally, the research team will pilot this tool in real-world clinics to see if it is easy to use and if it helps women feel more confident and informed about their decisions. Ultimately, this study will provide the foundation for a larger trial, transforming an unclear notification process into a clear, evidence-informed approach.

Project Title: Modulating Host Myeloid Cells to Enhance CAR T Cell Activity

Headshot of Miriam Kim, MD
Miriam Kim, MD

Principal Investigator: Miriam Kim, MD

Goal: To improve long-term survival for patients with cancer by using myeloid cells to help chimeric antigen receptor (CAR) T cells fight cancer more effectively

Project Summary: The researchers aim to mobilize the immune system to fight cancer and improve survival for patients. CAR T cells are immune cells that have been genetically engineered to attack cancer cells and have been very effective in treating certain types of cancers. In this project, the team will investigate how myeloid cells can aid CAR T cells in their fight against cancer. Myeloid cells are the most common type of white blood cell in our bodies and are the first line of defense against injury or infection. In addition to responding directly to threats, they play a key role in supporting the rest of the immune system to restore the body to health. The researchers’ preliminary work shows that CAR T cells perform much better when they receive support from myeloid cells. The team will study how different types of myeloid cells influence CAR T-cell behavior using both mouse models and samples from human patients treated with CAR T cells. The researchers will also test drugs that are known to activate myeloid cells and enhance their ability to stimulate CAR T cells.

Project Title: The Role of YTHDF1 and Acid Signaling in Colon Cancer

Christopher Maher 150x150
Christopher Maher, PhD

Principal Investigator: Christopher Maher, PhD

Goal: To understand how a modification to RNA affects both cancer cells and immune cells. In this case, cancer cells make the area around them more acidic, which weakens the immune system response to treatment and enables cancer cells to spread to other parts of the body. By studying this process in colorectal cancer, the researchers hope to better understand how colorectal cancer spreads and to find new ways to treat it.

Project Summary: Despite advances in the understanding of how a colon tumor progresses, the mechanisms by which the tumor spreads throughout the body remain poorly characterized. To address this knowledge gap, the research team studies how the primary tumor spreads and interacts with neighboring cells to reduce response rates and promote further tumor growth. This proposal focuses on a novel regulatory mechanism of a “vicious cycle” whereby tumor cells secrete acid to prevent nearby cells from mounting an immune response, further enabling tumor cells to metastasize and remain resistant to existing therapies. The long-term impact of this research is to significantly advance the understanding of colon cancer metastasis and reveal therapeutic vulnerabilities in these aggressive, treatment-resistant tumors to improve the dismal response rates to existing treatments.

Project Title: Evaluation of CD19 CAR-Modified Immune Cells as Novel Chronic GVHD Therapy

Headshot of Melissa Mavers, MD, PhD
Melissa Mavers, MD, PhD

Principal Investigator: Melissa Mavers, MD, PhD

Goal: To test a method of engineering immune cells to target harmful B cells — a new treatment approach — with the goal of improving chronic graft-versus-host disease (GVHD) outcomes and making hematopoietic cell transplantation (HCT) safer for patients

Project Summary: Many patients with blood cancers must undergo a treatment called HCT, sometimes known as bone marrow transplantation. However, a serious complication called GVHD can occur. Chronic GVHD can significantly impact patients’ quality of life and even be deadly. Immune cells called B cells play an important harmful role in chronic GVHD, and mice without B cells do not develop this disease. Prior treatments targeting B cells did not work in most patients, likely because they were unable to fully eliminate B cells or stop their function. Other current treatments for chronic GVHD cause broad immune suppression (increasing the risk of infections) and other significant side effects, and do not work in many patients. Therefore, new treatments are needed. One promising approach involves engineering certain immune cells to target and kill B cells. This approach has been used previously in B cell cancers and can very effectively kill cancerous and healthy B cells. Therefore, in this project, the researchers will test whether targeting B cells more effectively with this new approach will lead to better treatment of chronic GVHD in a mouse model. They will engineer two different types of killer immune cells to target and kill B cells and monitor for survival and signs of disease in tissues. This project is very important to providing early data that will allow the team to get additional grant funding to study this novel treatment further. Ultimately, they aim to improve the management and outcomes of chronic GVHD, making HCT a safer and more effective treatment for blood cancers.

Project Title: Adenovirus-Targeted Expression of an Immune Checkpoint Stimulator in Pulmonary Endothelial Cells for Lung Cancer Immunotherapy

Headshot of Zhi Hong Lu, PhD
Zhi Hong Lu, PhD
Headshot of Haval Shirwan, PhD
Haval Shirwan, PhD

Principal Investigator: Haval Shirwan, PhD (University of Missouri-Columbia)
Co-PI: Zhi Hong Lu, PhD

Collaboration with University of Missouri-Columbia

Goal: To develop an effective immunotherapeutic approach to treating lung cancer. Pulmonary endothelial cells play a critical role in cancer development and the modulation of the immune system, often promoting cancer progression. The proposed immunotherapeutic approach directly targets both pulmonary endothelial cells and the immune system to generate a response that effectively destroys cancer cells.

Project Summary: This project aims to use a harmless virus to deliver a gene into cells in the lungs. That gene would make the lung cells produce a special immune-boosting molecule. The hypothesis is that these lung cells would begin producing large quantities of this molecule right where the lung tumor is growing. This should help the immune system attack the cancer more strongly, while causing fewer side effects throughout the rest of the body. Researchers will test this idea in mice with a type of lung cancer similar to human non-small cell lung cancer, which is often hard to treat.

New approach to designing drugs supercharges cancer medication

Shape-shifting drug hits tumors in multiple ways, improves outcomes in mice

Modern anticancer medications that combine tumor-fighting drugs with proteins that specifically target cancer cells are a relatively new class of drug, often given to patients for whom standard chemotherapy has not worked. The drugs are precise, but can attack only one kind of target in the cancer cell at a time. This limits their effectiveness against tumors containing multiple types of targets, which becomes more likely as a cancer progresses or as tumors become resistant to conventional therapies.

Researchers at Washington University School of Medicine in St. Louis have shown in mice that it is possible to increase the potential effectiveness of these drugs, which are known as antibody-drug conjugates. By modifying such drugs already approved by the U.S Food and Drug Administration so that they self-assemble in the body and attack more than one cancer target, the researchers dramatically improved the effectiveness of these medications.

The study was published July 15 in Nature.



“We’ve shown that when two cancer-targeting antibodies bind together inside the body, they accumulate at the tumor more effectively and improve treatment response,” said Patrícia M. Ribeiro Pereira, PhD, an assistant professor of radiology at WashU Medicine Mallinckrodt Institute of Radiology and a research member of Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.

“There is a lot of excitement here because we have shown that it isn’t necessary to create a whole new drug platform for each therapeutic target,” added Ribeiro Pereira. “We can repurpose antibodies that already exist to improve treatments.”

Two drugs in one

In recent years, antibody-drug conjugates have been transforming cancer care, with 15 such drugs approved since 2011 for leukemia and lung, cervical and breast cancer, among others.

The medications combine three components, each with a specialized role. One is the cytotoxic drug that kills a cancer cell when directed to the correct cell. Another is the antibody protein that binds to receptors unique to cancer cells, so that the drug acts specifically within tumors and does not attack healthy tissue. The third is a linking molecule that connects the other two components.

Because each drug can be attached to only one antibody partner, these conjugates are highly specific and attack only cells containing the appropriate receptors. This makes them very effective in relatively homogeneous tumors, but their long-term effectiveness against more complex tumors with a diversity of cell types is limited.

Ribeiro Pereira and her team developed an approach to overcome these limitations using what’s known as click chemistry, a technique that enables adaptable connector molecules to click into a variety of other compounds to form interchangeable molecular structures in a modular way. They created a self-assembling drug apparatus that could tack on a second antibody if needed, thereby doubling the receptor types it could bind to in a tumor.

Both antibodies used in this study are FDA-approved for cancer therapies and target receptors that control tumor growth. One antibody binds to the EGFR receptor; the second, to the HER2 receptor. Another form of the treatment allows two different types of HER2 antibody to bind to different parts of the same receptor, which helps them work together more effectively.

In mice modeling pancreatic, gastric or breast cancer tumors containing cells that expressed EGFR receptors and other cells that expressed HER2 receptors, Ribeiro Pereira’s team first administered an antibody targeting either EGFR or an antibody that binds to a particular portion of the HER2 receptor. The antibodies had all been engineered with one-half of a specialized “click” molecule.

About a day later, the team administered a second type of the HER2 antibody, that binds to a different portion of that receptor, with a drug conjugate and that also carried the complementary click partner. Once in the body, the two antibodies then selectively snapped together. Depending on the approach, the HER2 receptor could be attacked twice as effectively, or both HER2 and EGRF could be targeted at the same time. Both approaches gave the tumor a one-two punch of antibody-drug conjugate — and it made the treatment far more effective than the FDA-approved versions.

Radioactive tags developed by Ribeiro Pereira’s colleagues at WashU Medicine enabled the team to visualize how much drug bound to tumor cells. Ribeiro Pereira and her team found that tumor cells took up much higher amounts of the modified antibody-drug conjugates than is typical for the antibody-drug conjugates that they were derived from, possibly because the click chemistry promotes clustering of antibodies on the cancer cell surface, which enhances internalization by the cell.

Tumors treated with the new form of the drugs resulted in significantly improved survival: as much as 90% of the animals survived 120 days after treatment in the pancreatic model, where animals treated with standard antibody-drug conjugates survived less than 80 days on average. The team also was able to optimize the technique to reduce off-target accumulation of the drug in the liver.

While this study tested the drug in pancreatic, gastric and breast cancer models, Ribeiro Pereira said the modified antibody-drug conjugates have the potential to treat many different tumor types and possibly many other diseases, including some that are currently very difficult to treat with conventional medicine. The linking molecules used in this study only take one to three days to manufacture and allow for greater flexibility when creating precision medicines for individual patients because of the versatile click chemistry approach.

“We’re trying to optimize this tool to help antibodies reach tumors that are normally very difficult to treat, such as brain tumors,” Ribeiro Pereira said. “It’s exciting, because the drug development process doesn’t need to start from the beginning — we can use drugs that are already FDA-approved, which could help bring improved treatments to the clinic more quickly. At the same time, the approach is flexible enough to be adapted to new cancer targets as we learn more about what drives treatment resistance.”

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Simó C, Vanover AC, Albanus RD, Panikar SS, Shmuel S, Benton A, Giraldo-Guzman J, Luna JM, Xu Y, Berry N-K, Keltee N, Liu J, Dehdashti F, Pereira PMR. Modular in vivo antibody-ADC click to reverse drug resistance in tumors. Nature. July 15. DOI: 10.1038/s41586-026-10789-w



Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health (R37CA276498 and R21CA291680), internal funds provided by the Mallinckrodt Institute of Radiology, and the American Cancer Society (IRG-21–133–64–03) and the Breast Cancer Alliance. Further support came from the Alvin J. Siteman Cancer Center through The Foundation for Barnes-Jewish Hospital and the National Cancer Institute (P30 CA091842). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Other support came from the W. M. Keck Foundation and the American Cancer Society Award (PF-25-1515996-01-PFCDET), National Institutes of Health (K99AG086583), a Gates Sr. Alzheimer’s Disease Research Fellowship from the Alzheimer’s Disease Data Initiative, the National Cancer Institute of the National Institute of Health under Award Number K22CA282357. The Preclinical Imaging Facility was supported by NIH/NCI Siteman Cancer Center (SCC) Support Grant P30CA091842, NIH instrumentation grants S10OD018515 and S10OD030403, and internal funds provided by the Mallinckrodt Institute of Radiology. TEM and confocal experiments were supported by the Washington University School of Medicine, The Children’s Discovery Institute of Washington University, and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4642). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.



About WashU Medicine



WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 3,100 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 78% since 2016. Together with institutional investment, WashU Medicine commits over $1.6 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently among the top five in the country, with more than 2,550 faculty physicians practicing at 200 locations. WashU Medicine physicians exclusively staff Barnes-Jewish and St. Louis Children’s hospitals — the academic hospitals of BJC HealthCare — and Siteman Cancer Center, a partnership between BJC HealthCare and WashU Medicine and the only National Cancer Institute-designated comprehensive cancer center in Missouri and southern Illinois. WashU Medicine physicians also treat patients at BJC’s community hospitals in our region. With a storied history in MD/PhD training, WashU Medicine recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

The Future of Brain Tumor Care is Being Built Now — at Siteman Cancer Center

WashU Medicine experts at Siteman’s Brain Tumor Center are accelerating the science that will create a new standard and new survivorship for brain tumor care

For years, progress against glioblastoma has been measured in small steps with only slight improvements in survival. Now, at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, bold research and remarkable advances against this deadliest form of brain cancer are driving real progress and offering new hope for patients and families.

“We’re at a turning point — a real transition point. We’re potentially on the cusp of breakthroughs over the next five years that we haven’t seen in decades,” said Gregory J. Zipfel, MD, the Ralph G. Dacey Distinguished Professor of Neurological Surgery and chair of the Taylor Family Department of Neurosurgery at WashU Medicine and a founding member of The Brain Tumor Center at Siteman Cancer Center. “But those breakthroughs aren’t going to come from a single discovery — they’re going to come from combining approaches that we are actively investigating and using here.”

Access to clinical trials and second opinion consults are available at The Brain Tumor Center by calling our Siteman care coordinators — oncology-trained nurses who help with scheduling and navigation — at 800-600-3606 or by requesting an appointment here.

Make a referral here.



The Brain Tumor Center at Siteman Cancer Center is recognized internationally for fostering what Zipfel calls “convergence science,” where teams approach understanding and treating brain cancers from all angles — and explore how combination approaches might further advance patient outcomes. That approach is working. In just five years, their work here has moved the needle on effective strategies to treat brain cancers, and they are now poised for major advancements in the treatment of glioblastoma, a particularly aggressive, fast-growing cancer.

WashU Medicine physicians and scientists at Siteman Cancer Center are transforming brain tumor care through the relentless and imaginative pursuit of innovative science and research. Advances in research and clinical trials include developing groundbreaking artificial intelligence (AI) brain-mapping software, initiating groundbreaking radiation and immunotherapy clinical trials, and advancing the use of laser interstitial thermal therapy (LITT) to treat recurrent glioblastoma.

In 2021, Zipfel helped establish The Brain Tumor Center at Siteman Cancer Center, bringing together a team of influential neuro-oncologists, neurosurgeons, radiation oncologists and others focused on providing care attuned to the needs of each patient and aimed at improving lasting outcomes. Working together, the center’s translational researchers, who oversee clinical trials, and basic scientists are focused on creating even better treatment paradigms moving forward.

The Brain Tumor Center at Siteman is led by neurosurgeon Albert H. Kim, MD, PhD, the August A. Busch Jr. Professor of Neurological Surgery and senior vice chair of the Department of Neurosurgery at WashU Medicine. Associate directors are neuro-oncologist Milan G. Chheda, MD, associate professor of medicine and director of neuro-oncology, and radiation oncologist Jiayi Huang, MD, professor of radiation oncology and chief of the CNS/Gamma Knife Service, both also of WashU Medicine.

Other leaders of The Brain Tumor Center are:

  • Research Director Alexander H. Stegh, PhD, who also is a professor of neurosurgery and vice-chair of neurosurgery research at WashU Medicine
  • Caroline H. Ko, PhD, the center’s associate director of research strategy and clinical translation and an associate research professor of neurosurgery at WashU Medicine

Advancing Glioblastoma Treatment Through Translational Science

Even with surgery, chemotherapy and radiation, glioblastoma remains very difficult to treat. Average survival is 15-18 months after diagnosis. Because standard therapies are not curative, the tumor almost always returns.

“The problem isn’t always the main tumor,” Chheda explained. “It’s the microscopic cells that have already spread. Those are what cause recurrence.”

While the primary tumor may be visible and treatable, those microscopic cells often evade therapy. Many are resistant to chemotherapy and radiation. At the same time, the brain itself presents unique barriers. As with the normal brain, brain tumors remain shielded by the blood-brain barrier, a protective network of blood vessels and tissue that prevents entry of many drugs.

“The therapies we currently have are not always reaching the right place, and even when they do, they may not target the right cells,” Chheda said.

Overcoming the challenges of glioblastoma treatment requires more than a single breakthrough. At Siteman, physician-scientists are developing complementary strategies that target the disease from multiple directions — advancing discoveries that are already reshaping how brain tumors are studied and treated here and around the world.

Leaders in Laser Interstitial Thermal Therapy (LITT)

Eric C. Leuthardt, MD, MBA, the Shi H. Huang Professor of Neurological Surgery and vice chair of innovation in the Department of Neurosurgery at WashU Medicine, is a global leader in the research and use of laser interstitial thermal therapy (LITT) to treat glioblastomas and deep-seated brain tumors.

He was one of the first in the country to use LITT for brain cancers when it was cleared by the federal Food and Drug Administration (FDA) in 2010. He has since refined the therapy for minimally invasive tumor ablation and helped to define the national patient criteria for its use.

Leuthardt, Kim and Zipfel are now advancing the use of MRI-guided LITT. A pioneering discovery found that LITT temporarily disrupts the blood-brain barrier, creating a window of opportunity of up to six weeks during which anti-tumor drugs can be used after tumor ablation. They also are investigating how adding checkpoint inhibitors, a type of immunotherapy, into the mix can also improve outcomes.

Research has found that LITT improves the length of survival by up to 40% for certain patients with recurrent glioblastoma. A highly specialized laser ablation surgical suite is now in regular use at Barnes-Jewish Hospital, and the team has performed several hundred LITT procedures, making it one of the busiest centers in the world.

Chheda is rethinking how brain tumors form. Because glioblastoma predominantly occurs in older adults, he is investigating how the aging process itself contributes to brain tumor development.

“You could argue that with time, cells pick up mutations and eventually something goes wrong,” Chheda said. “But it’s also true that the brain itself changes as it ages.”

Instead of viewing glioblastoma as a disease caused by rogue cancer cells, it may also be influenced by changes in the surrounding tissue, called the tumor microenvironment. To Chheda, aging is not just a risk factor. It may also actively influence how tumors emerge, evolve and resist treatment.

“This is a relatively new and exciting area of research, and not many groups are focused on it yet,” he said. “We are exploring how aging alters the brain at a molecular level. By doing so, we may uncover new strategies that can prevent tumor formation, or at the very least, make other treatments more effective.”

Planning Underway for First-in-Human Clinical Trials Using Zika Virus

Ongoing in Chheda’s lab are groundbreaking studies with a modified version of the Zika virus that is engineered to kill glioblastoma. He and colleague Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and professor of molecular microbiology and of pathology and immunology at WashU Medicine, have confirmed that combining the modified Zika virus with standard immunotherapy drugs increased survival rates in mice, from 30% to nearly 90%. The researchers now have created a strain of Zika that is safe for use in humans.

“In mouse models, combining this approach of using Zika-based oncolytic viruses with immunotherapy makes previously ineffective treatments work,” Chheda said. Phase I first-in-human clinical trials are expected to begin before the end of 2026.

Sonobiopsy: Rapidly Advancing New Technology Discovered at Siteman

As multiple researchers explored ways to open the blood-brain barrier to allow for targeted therapies, a team led by Leuthardt and WashU bioengineer Hong Chen, PhD, a professor of biomedical engineering and of neurosurgery and a Siteman research member, invented an ultrasound technology that temporarily opens that barrier. Now called sonobiopsy, the technique uses focused ultrasound and microbubbles to open the blood-brain barrier, which then allows for a non-invasive “liquid biopsy” of the brain tumor, as well as opening the door to add anti-tumor drugs. A first-in-human clinical trial began in 2023 in select patients with high-grade gliomas, including glioblastoma, which originate in the brain or spinal cord.

“What’s remarkable about this is the speed of translation,” Kim said. “It moved from concept to human trials in about three to five years, much faster than normal, which is about a decade. It’s exciting and probably is one of the most significant technological advances coming out of The Brain Tumor Center at Siteman.”

The Most Advanced Radiation Research is Focused on Protecting the Brain

Radiation oncology research is focused on a fundamental challenge: delivering more effective treatment while preserving the healthy brain. Through investigator-initiated and national multicenter clinical trials, WashU Medicine radiation oncologist Jiayi Huang, MD, and colleagues are evaluating innovative approaches designed to improve tumor control, reduce injury to normal tissue and help patients maintain cognitive function throughout treatment. Huang leads pioneering radiation oncology clinical trials that are showing promise in treating glioblastoma.

He is the principal investigator of a multicenter, randomized Phase III clinical trial comparing temporally modulated pulsed radiation therapy (TMPRT) to standard radiotherapy in patients with a type of recurrent glioma, including glioblastomas. TMPRT divides radiation into small pulses with short breaks in between rather than giving radiation to the patient all at once. Early studies found that TMPRT improved survival and preserved cognitive function and memory. The current large-scale study is funded by the National Cancer Institute and conducted through NRG Oncology, one of five national research groups in the NCI’s National Clinical Trials Network. The goal is to enroll almost 400 patients in the Phase III trial over the next four years.

“We think it will control the tumor spread better,” Huang said, “and also cause less injury to normal tissue and less cognitive deficit in patients.”

He is also testing the combination of radiation with an oral agent to enhance immune responses in patients with glioblastoma. Based on his own early-phase investigator-initiated trial, it is hoped that immune-modulating radiation will improve survival. Already, the therapy is moving toward testing in newly diagnosed brain cancer patients later this year.

In a collaboration between neurosurgeons and radiation oncologists, Huang points to the excitement surrounding an industry-led clinical trial that uses radiation seeds implanted into a foam tile that is then placed directly into the brain during surgery to remove a tumor. Called GammaTile, it functions much like the more well-known radiation seeds for prostate cancer.

“The seed itself is not new, and it can move if you insert it into the brain separately,” Huang explained. “Using the seed-implanted foam keeps the seeds in one location to better direct the radiation.”

First Vaccine and Other Innovative Therapies for Glioblastoma

Another major effort involves the development of personalized vaccines tailored to each patient’s brain tumor. A key discovery was that different regions of a tumor can have different mutations. As a result, current clinical trials now sample multiple tumor regions and target shared mutations, improving the effectiveness of treatment options.

Exciting and promising news came just this spring, after an early-stage clinical trial co-led by WashU Medicine researchers at Siteman Cancer Center found that a personalized vaccine to treat glioblastoma is safe and resulted in robust and broad immune responses. The responses appear to increase recurrence-free survival in a subset of patients after surgery.

“We are extremely encouraged by these results,” said lead author Tanner M. Johanns, MD, PhD, assistant professor of medicine at WashU Medicine and a Siteman research member. “This kind of vaccine is a first for glioblastoma, and it is exciting to think how we can leverage this individualized therapeutic DNA cancer vaccine platform to make a positive impact on the lives of patients who are fighting this disease.”

While directly delivering medicines to the brain remains extremely challenging, Stegh and his team have developed a novel drug delivery method that can cross the blood-brain barrier and activate the immune system to attack glioblastoma.

Their technology uses precisely engineered structures assembled from nano-size materials to deliver potent tumor-fighting medicine to the brain through nasal drops. This method is less invasive than similar treatments in development and was shown to be effective in mice. The researchers are now working toward a first-in-human clinical trial.

“This redefines how cancer immunotherapy can be achieved in otherwise difficult-to-access tumors,” Stegh said.

Global Leaders in Advancing Pediatric Brain Tumor Care

In addition to researching effective treatments for adults with brain cancers, The Brain Tumor Center at Siteman has been at the forefront of advancing targeted therapies for children diagnosed with certain types of brain tumors.

WashU Medicine’s Eric M. Thompson, MD, chief of pediatric neurosurgery at Siteman Kids at St. Louis Children’s Hospital, is exploring the effectiveness of a new targeted therapy called moxetumomab pasudotox for children whose brain tumors have not responded well to standard treatment options.

Mohamed Abdelbaki, MD, director of the pediatric brain tumor program at WashU Medicine and Siteman Kids, is investigating another experimental therapy, ONC-212. The tailored therapy attacks cancer cells at the molecular level.

The pediatric brain tumor program at Siteman Kids at St. Louis Children’s Hospital is recognized globally. Abdelbaki founded and leads an international pediatric brain tumor board that comprises experts from around the world who meet regularly to review difficult brain cancer cases. The tumor board has rapidly become the leading consortium of experts committed to collaborative, multidisciplinary discussions that inform recommendations for pediatric brain cancer treatment.

“These studies ensure that innovation in brain tumor care and research reaches patients at every stage of life,” Zipfel said.

One of the Nation’s Most Advanced Brain Tumor Centers

The Brain Tumor Center at Siteman Cancer Center brings together one of the nation’s most comprehensive programs in brain tumor research and care, integrating neurosurgery, neuro-oncology, radiation oncology, advanced imaging, artificial intelligence and translational science to accelerate discovery and improve patient outcomes. That collaborative model is driving innovations ranging from FDA-approved, real-time brain-mapping technology used during surgery to machine learning tools that help predict tumor growth, guide surgical planning and personalize care after treatment.

“Our environment is built for discovery,” said Jiayi Huang, MD. “The Brain Tumor Center and the WashU Jeffrey T. Fort Neuroscience Research Building bring together neurosurgeons, radiation oncologists, physician-scientists and basic researchers in ways that accelerate new ideas into new treatments. That level of collaboration is what distinguishes Siteman and WashU Medicine.”

Albert H. Kim, MD, PhD, director of The Brain Tumor Center, says the program’s scale strengthens both patient care and scientific discovery. Each year, the multidisciplinary team performs more than 700 brain tumor surgeries and cares for approximately 2,000 new patients while training the next generation of surgical and medical neuro-oncology specialists.

“Our goal is not simply to advance today’s standard of care,” Kim said. “It’s to define what the next standard should be.”

WashU Medicine science writer Mark Reynolds contributed to this report.

Cynthia Ma Receives Susan G. Komen Leadership Grant

Cynthia X. Ma, MD, PhD, a renowned WashU Medicine physician-scientist at Siteman Cancer Center, has received a Leadership Grant from Susan G. Komen to advance breast cancer research focused on endocrine resistance, a major challenge in treatment for hormone receptor-positive breast cancer.

A medical oncologist, Ma treats patients with this and other types of breast cancer at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.

She will use the grant to study tumor samples collected from postmenopausal women with ER-positive, HER2-negative breast cancer who participated in a major phase III study called the ALTERNATIVE trial, which Ma leads. The tumor samples were collected at diagnosis and then again during surgery after the patients received endocrine therapy, also called hormone therapy. By comparing these samples, her team will investigate the genetic features present before treatment and the changes that occur during therapy that may cause tumors to become resistant. The goal is to better understand why some tumors stop responding to therapy and to identify patients who are at risk of treatment resistance. Ultimately, this knowledge could help guide more personalized treatments that improve patient outcomes and save lives.

Susan G. Komen announced the award July 23, part of $15.4 million total in research grants awarded to 35 leading U.S. researchers, including long-term, well-established researchers such as Ma who have made a profound impact in the field, as well as early-career investigators.

“The researchers receiving grants from Susan G. Komen are making lasting contributions to our understanding of breast cancer and bringing the innovation and technology that’s needed to this disease so that all patients can receive the best care possible and enjoy a high quality of life after a breast cancer diagnosis,” said Ann H. Partridge, MD, MPH, chief scientific adviser for Komen.

Faster Aging in Younger Generations Linked To Rise in Early-Onset Cancer

Immune system aging linked to earlier lung cancer; fat tissue aging linked to earlier colorectal cancer

Cancer is often considered a disease of aging. Older adults are at higher risk because they have had more time to accumulate cellular damage that can trigger tumor formation. But as cancer rates in younger adults rise, with each successive generation facing higher risks than the one before it, researchers are asking whether cellular damage is accumulating faster in recent generations, accelerating their body’s biological aging.

A new study led by researchers at Washington University School of Medicine in St. Louis provides evidence that younger generations are indeed aging faster biologically than their older counterparts. The causes remain under investigation around the world, including global efforts led by research members of Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, and Cancer Grand Challenges, a global initiative co-founded by the National Cancer Institute and Cancer Research U.K.; but importantly, the new research links this accelerated aging to an increased risk of early-onset cancers in younger generations. In general, early-onset cancers are those diagnosed at age 55 or younger.

The larger the gap between biological age — that is, how old our bodies appear to be — and chronological age — which is how many years we have actually lived — the higher the cancer risk, according to the researchers. They found that people in more recent birth cohorts had larger age gaps than those in older birth cohorts, which may help explain the rise in early-onset cancer in recent generations.

Their study also identified links between faster aging in particular organ systems and increased risks for certain cancers. For instance, an immune system that appears older than its actual age was associated with early-onset lung cancer. Similarly, fat tissue that appears older than its chronological age was associated with early-onset colorectal cancer.

The study, published June 22 in the journal Nature Medicine, suggests that measures of accelerated aging could help identify individuals at higher risk of early-onset cancer and guide new strategies for cancer prevention and early detection.

“Our goal is to determine whether blood carries a biological imprint of a person’s past exposures, providing a window into how environmental and lifestyle factors have changed across generations,” said Yin Cao, ScD, MPH, a molecular epidemiologist and an associate professor of surgery and of medicine at WashU Medicine and a research member at Siteman. “We also tested whether blood samples collected years before diagnosis contain early biological signals that could help identify younger people at higher risk of developing cancer at younger ages. On a practical level, this approach complements our efforts to elucidate the underlying causes of rising cancer rates in younger adults.”

“Our ultimate goal is to decode how modern environments become biologically embedded to drive cancer risk, transforming prevention from broad recommendations to personalized interventions,” Cao added. “Blood-based biomarkers offer a unique opportunity to capture how a lifetime of exposures becomes biologically embedded in the body. By integrating multi-omics data, we can now detect both systemic and organ-specific signals of dysregulation, providing a much more comprehensive picture of cancer risk through these signals. This brings us closer to identifying risk earlier and developing prevention strategies that are tailored to an individual’s biology.”

Biological aging

Cao’s team has been at the forefront of identifying individual factors that influence cancer risk across the life course, such as obesity, metabolic dysregulation, alcohol consumption, sedentary behavior, poor diet quality and cesarean delivery. Although these discoveries have revealed important clues to the origins of cancer at younger ages, the contribution of any single factor is modest.

With that in mind, Cao and her colleagues have sought ways to capture the influence of multiple risk factors operating together to spur cancer development. With support from Cancer Grand Challenges, Cao, as co-lead of Team PROSPECT, has been able to go after this problem.

For the current study, Cao’s team analyzed data from more than 154,000 young adults in the UK Biobank, a large biomedical dataset containing biological, health and lifestyle data, and from more than 10,000 individuals in the U.S. participating in the National Institutes of Health’s (NIH) All of Us Research Program, an effort to build a comprehensive health dataset on more than 1 million people living in the U.S.

To estimate the level of biological aging — or age gap — the researchers, including first author Ruiyi Tian, a doctoral student in the Cao lab, examined aging at two levels: across the body as a whole, known as systemic aging, and within individual organs, known as organ-specific aging. For systemic aging, the researchers used established measures, including clinical biomarker-based measures such as PhenoAge and the Klemera-Doubal Method, as well as a metabolomic age score.

PhenoAge, for example, measures nine blood biochemistry markers such as albumin, made by the liver, and creatinine, a waste product removed by the kidneys. For organ-specific aging, the researchers used blood proteomic data, which measure levels of multiple proteins linked to specific organ systems, to estimate biological aging in individual organs.

The researchers calculated the average age gap for each birth cohort and used standard deviation to describe how much each group differed from the study average. Standard deviation is a measure of how spread out data points are around the average. The researchers found that individuals in the UK born between 1965 and 1974 had systemic aging that was 23% of one standard deviation higher compared with those born between 1950 and 1954, after accounting for chronological age. In other words, people in the younger birth cohort showed a modest shift toward older biological profiles than people in the older birth cohort when at the same chronological age. The researchers observed a similar pattern in the U.S cohort. Participants born between 1990 and 1999 had systemic aging that was 92% of one standard deviation higher compared with those born between 1965 and 1969.

This increased systemic aging in the younger group was associated with an 8% increased risk of early-onset solid cancers, especially lung, gastrointestinal and uterine cancers. When participants were divided into three groups based on their level of systemic aging, those with the most advanced systemic aging had 15% increased risk of early-onset solid cancer compared with those with the least advanced systemic aging. According to the analysis, the increased risk persisted even after controlling for inherited genetic risks of cancer and genetic susceptibility to accelerated aging. By zooming into organ-specific aging, the researchers found that advanced immune system aging was associated with increased risk of early-onset lung cancer, and advanced adipose (fat) tissue aging was associated with increased risk of early-onset colorectal cancer.

“If we can identify younger people with the highest cancer risk when they are still healthy, we can focus on prevention and early-detection strategies for the individuals who will benefit most from early interventions,” Cao said.

This research is part of Team PROSPECT, a Cancer Grand Challenges team co-led by Cao. Cancer Grand Challenges is a global research funding initiative co-founded by Cancer Research UK and the National Cancer Institute (NCI) that brings together world-leading researchers to take on cancer’s toughest challenges.

“Right now, we don’t have a definitive answer to what’s driving the rise of early-onset cancers around the world, but studies like this are helping us piece together the bigger picture, showing that cancer may be influenced not just by changes inside individual cells, but by wider changes happening across the body as a whole,” said David Scott, PhD, director of Cancer Grand Challenges.  “Research on this scale is possible through Cancer Grand Challenges, which brings together scientists from different fields around the world to tackle these complex questions together.”

Cao and her colleagues are leading efforts to transform the understanding of why cancers are increasingly striking younger generations. Their next frontier is to decipher how environmental, lifestyle and societal changes leave lasting biological imprints, including accelerated aging and other markers of heightened susceptibility. By illuminating the pathways through which risk accumulates across the life course, they seek to uncover the origins of early-onset cancers and redefine opportunities for prevention. In parallel, their work will enable more precise approaches to identify those at greatest risk and intervene earlier, shifting the paradigm from reacting to disease to preventing it before it begins.

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Tian R, Zong Y, Ren D, Tica S, Hong D, Odulyale O, Buenrostro J, Govindan R, Cao Y. Biological aging and generational shifts in early-onset cancer risk. Nature Medicine. June 22, 2026. DOI: 10.1038/s41591-026-04448-w.

This work was part of the PROSPECT team supported by the Cancer Grand Challenges initiative funded by Cancer Research UK, grant numbers CGCATF-2023/100043 and CGCATF-2023/100037; the National Cancer Institute of the NIH, grant numbers OT2CA297577 and OT2CA297576; the French National Cancer Institute; and the Bowelbabe Fund for Cancer Research UK. The project was also supported by grants from NIH/National Cancer Institute, grant number R37CA246175; the NIH/National Institute of Diabetes and Digestive and Kidney Diseases, grant number P30DK052574; the Alvin J. Siteman Cancer Center through the Foundation for Barnes-Jewish Hospital. Further support was provided by a pre-doctoral fellowship in the Cancer Biology pathway supported by NIH Molecular Oncology Training Grant T32CA113275 to Washington University School of Medicine in St. Louis; the Pediatric Gastroenterology Research Training Program grant T32DK077653 to Washington University School of Medicine in St. Louis; the Washington University School of Medicine in St. Louis Institute of Clinical and Translational Sciences, grant number UL1TR002345; and the Foundation for Barnes-Jewish Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Quick Optical Biopsy Could Be Early Detection Method for Endometrial Cancer

WashU researchers at Siteman Cancer Center combine optical coherence tomography and machine learning for rapid, accurate test

Endometrial cancer is the most common gynecologic cancer, with more than 69,000 cases diagnosed in the U.S. in 2025 and increasing up to 3% annually. Diagnosis requires an often painful and invasive biopsy that carries a risk of false negatives. A multidisciplinary research team at Washington University in St. Louis and Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, is looking to a fast, safe and noninvasive imaging method combined with machine learning for an accurate detection and diagnosis of precancerous lesions and early cancers.

The team, led by Quing Zhu, PhD, the Edwin H. Murty Professor of Engineering in the McKelvey School of Engineering at Washington University in St. Louis, conducted an initial investigation using optical coherence tomography (OCT), which detects differences in how tissue reflects light and acquires high-resolution 3D images with a depth of up to 1 to 2 millimeters. With a custom catheter probe developed in Zhu’s lab, the team took images of the entire endometrial cavity in less than three minutes, creating an optical biopsy. It is the first catheter-based, 3D OCT imaging study that integrated optical functional, structural and radiomic features for endometrial assessment. Results of the research were published in npj Imaging June 3, 2026.

To obtain images from patient tissues, the team collaborated with WashU Medicine physicians led by Lindsay Kuroki, MD, MSCI, associate professor of obstetrics & gynecology, and Ian Hagemann, MD, PhD, professor of pathology & immunology and of obstetrics & gynecology. They, along with Zhu, are research members at Siteman Cancer Center, where Kuroki also treats patients. The team acquired OCT images from 57 post-hysterectomy uteri in 2025. Of these, 34 contained high-risk precancerous lesions or early-stage cancers.

The 3D OCT images provided a close view of tissue microstructure and optical properties, revealing clear differences among normal endometrium, benign endometrium, high-risk precancerous lesions, and endometrial cancer at different stages.

First authors Sanskar Thakur, a doctoral student in Zhu’s lab, and Yixiao Lin, who earned a doctorate in biomedical engineering from WashU in 2025, developed an imaging feature extraction pipeline and a machine learning model to categorize the results into two groups of normal and benign, and pre-cancer and cancer using 26 extracted imaging features. Their model achieved an exploratory sensitivity of 94% and specificity of 87%.

“Current endometrial biopsy practice has an estimated false-negative rate of about 10% (approximately 90% sensitivity), largely due to sampling limitations and interpretive variability,” Zhu said. “With our three-dimensional OCT imaging system combined with machine learning, we can image the entire endometrial cavity in 2 to 3 seconds and may have a potential to achieve higher sensitivity than random biopsy sampling.”

“There is currently no reliable screening for endometrial cancer,” said coauthor David Mutch, the Ira C. and Judith Gall Professor and vice chair of obstetrics & gynecology at WashU Medicine, a Siteman research member and principal investigator of the National Cancer Institute-funded Route 66 Endometrial Cancer Specialized Program of Research Excellence (SPORE) grant. “This technology, developed by Dr. Zhu and her colleagues, should allow us to better screen for this cancer and at a minimum catch it much earlier in its development,” Mutch added. “This is really novel, cutting-edge technology.”

Going forward, Zhu said the team plans to evaluate the catheter in live patients to demonstrate the translational potential of the AI-assisted OCT technology.

Thakur S, Lin Y, Xu J, Nie H, Badwan S, Wang L, Sanders BE, Thaker PH, Hagemann AR, McCourt CK, Khabele DM, Powell MA, Mutch DG, Kuroki LM, Hagemann IS, Zhu Q. Optical coherence tomography enables optical biopsy of endometrial tissue for early cancer detection. npj Imaging, June 3, 2026, https://doi.org/10.1038/s44303-026-00160-z.

This work was funded by the Developmental Research Program (DRP) of the NCI Route 66 Endometrial Cancer SPORE (5P50CA265793-03). Partial support for this work was provided by the NCI (R01CA237664) and the NIBIB (R01EB034398).

Targeting Tumor Metabolism to Fight Cancer

Cancer cells are ravenous eaters. Gary Patti is trying to turn their hunger against them.

By their nature, cancer cells have different nutritional needs than healthy cells.



“Cancer cells have a distinct metabolism,” said Gary J. Patti, PhD, the Michael and Tana Powell Professor of Chemistry and a professor of genetics and medicine at WashU Medicine and a research member at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.

Understanding those differences could open new possibilities for tracking and ultimately defeating the disease. That’s why Patti and others at Siteman Cancer Center are turning their attention to a relatively new frontier of research: Cancer metabolomics, the comprehensive study of the small molecules that cancer cells either consume or produce as they attempt to grow and multiply.

Earlier this year, Patti and co-author Joe Rowles, a postdoctoral researcher in the Department of Chemistry and molecular oncology trainee in Siteman Cancer Center’s Cancer Biology Pathway program, explored the latest research and most pressing questions in cancer metabolism in Nature Reviews Cancer.

Patti is an internationally recognized leader in mass spectrometry, a technology that makes it possible to identify and quantify specific molecules in a sample. With more than 20 mass spectrometers in his ultra-clean lab, Patti has the power to track even the tiniest of changes in the levels of cancer metabolites — small molecules involved in cellular metabolism. The challenge is determining which of those molecules can be targeted in the fight against cancer.

“The fact that cancer cells run distinct metabolic programs gives us two big opportunities,” Patti said. Metabolites could be used as markers to identify tumors, he explained. More importantly, a deeper understanding of cancer metabolism might lead to new drugs or dietary strategies that slow tumor growth while sparing healthy cells.

Tracking the metabolic needs of cancer cells is no simple task. For one thing, cancerous cells can act very differently depending on the context. “A cancer cell in a lab dish might use completely different nutrients than the same cell that’s growing in a mouse or a human,” Patti said. “One of the defining attributes of cancer cells is that they are very flexible.”

The complexity of tumors also poses a challenge. “A lung tumor, for example, might have dozens of cell types, and they aren’t all malignant,” Patti said. “Some of them, like immune cells, can actually be helpful.” It’s hard to zero in on the metabolites associated with the cancer cells and not with the other parts of the tumor, he explained, and it’s challenging to find a healthy comparison sample for experiments. “There’s no such thing as a healthy tumor.”

Patti and his team are collaborating with WashU Medicine researchers and fellow Siteman research members — including David Mutch, MD, a professor of obstetrics and gynecology, and Yin Cao, ScD, MPH, an associate professor of surgery and of medicine — to address these challenges.

In ongoing experiments, they’re using isotopically labeled glucose to track the dynamics of tumor metabolism in patients. “WashU is a great place to do this kind of work, because the medical school has been a pioneer in developing innovative clinical tests using isotopes,” Patti said.

In many cases, it’s a cancer cell’s appetite that really sets it apart from healthy cells. “They generally consume many of the same things that healthy cells consume,” Patti said. “They just do it much faster.”

Still, a closer look at metabolomics data could lead to new dietary strategies to prevent and control cancers. “I’m very enthusiastic about the idea that we can leverage diet to improve the lives of cancer patients,” Patti said. To reach that point, metabolomics studies will have to expand to thousands of people with different diets, genetic profiles, and overall lifestyles. “We’ll need tons of data points to try to figure out how all of these different things are connected,” he said.

In 2024, Patti and co-authors reported in Nature that fructose — a sugar found in high-fructose corn syrup — can indirectly fuel tumor growth in mouse models of melanoma, breast cancer, and cervical cancer. Metabolomics studies found that the tumors were especially fond of a fructose product created in the liver.

The finding underscores the importance of close examination of the metabolic and nutritional pathways that allow cancer cells to flourish. “If you take cancer cells and put them in a dish and give them fructose, they won’t use it,” Patti said. “But if you have a tumor and you eat tons of fructose, it makes the tumor grow, in some cases, four or five times faster.”

Patti is especially alarmed by the growing rates of cancer among young people, a surge that has yet to be fully explained. “Cancers are still fairly rare in that age group, but they’re becoming increasingly common,” Patti said. “It’s happening so quickly that it can’t be caused by genetics alone. There must be a lifestyle factor, and it might come down to diet.”

Cancer metabolomics may seem like a niche area of research, but the insights could ultimately tip the fight against cancer to our advantage. “It is not a new idea to fight cancer with dietary modifications, but it’s too complicated to design interventions based on simple studies of cancer cells alone in isolation,” Patti said. “We are excited that metabolomics data from human patients can provide the knowledge needed to sort out the complexity.”

Above all, Patti noted, cancer cells are greedy. And their greed could ultimately be their undoing.

Siteman Cancer Center Shares the Latest in Medical Oncology, Screening Innovation and Translational Science at ASCO

WashU Medicine physician-scientists and others affiliated with Siteman will share findings from multi-institutional studies they lead and will present on health equity, mentorship and more at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.

At the 2026 annual meeting of the American Society of Clinical Oncology (ASCO), WashU Medicine scientists and physician-researchers at Siteman Cancer Center will present on the scale, depth and translational impact of their most recent research in advancing cancer outcomes worldwide.

With presentations representing the continuum of scientific and medical discovery, health equity, mentorship and more, Siteman will share its newest advances that reflect where oncology is headed –— more personalized therapies, smarter screening strategies, multidisciplinary treatment models and deeper understanding of how biology and lived experience intersect in cancer outcomes.

Nearly 45,000 scientists, clinicians and other healthcare professionals, survivors, patients and advocates gather at the conference in Chicago each year to share and discuss the latest breakthroughs. This year’s meeting takes place from May 29-June 2 and will feature key findings from WashU Medicine faculty members, fellows and others associated with Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.

“Siteman Cancer Center is proud to once again take the stage at ASCO, where the brightest minds in oncology gather to push the boundaries of what’s possible,” said Timothy J. Eberlein, MD, director of Siteman, based at Barnes-Jewish Hospital and WashU Medicine in St. Louis. “The research our team brings to this meeting reflects both scientific rigor and an unwavering dedication to patients. This is where ideas become breakthroughs — and breakthroughs become better lives.”

In one of the most anticipated oral abstract sessions at ASCO, Matthew A. Powell, MD, the Ira C. and Judith Gall Professor of Obstetrics and Gynecology at WashU Medicine, will present data from the landmark RUBY trial, which evaluated the addition of dostarlimab to standard chemotherapy with carboplatin and paclitaxel for patients with advanced endometrial cancer. 

Powell, a nationally recognized physician-scientist who treats patients at Siteman Cancer Center, was recently installed as president of the Society of Gynecologic Oncology (SGO). 

WashU Medicine physician-scientists at Siteman also will present key findings in lung cancer: 

  • Ramaswamy Govindan, MD, FASCO, the Anheuser Busch Endowed Chair in Medical Oncology and Associate Chief of Oncology and principal investigator of a Phase III study under the National Cancer Institute’s ALCHEMIST platform, will discuss findings from the trial, which found that erlotinib did not improve overall survival but did improve disease-free survival in resected EGFR-mutant non-small cell lung cancer. 
  • Brendan Heiden, MD, MS, MBA, Assistant Professor of Surgery, will present an analysis of the data of nearly 1 million U.S. veterans that may support a shift in national screening guidelines. 

Additional details of these and other Siteman and WashU-led advances and presentations are below. For a full schedule, click here.

Below are highlighted presentations by WashU Medicine researchers and physician-scientists at Siteman. And be sure to follow us at #ASCO26 on X @SitemanCenter and Bluesky @sitemancenter.bsky.social.

All presentations will be at Chicago’s McCormick Place and available via live stream, if noted, for virtual registrants. All times are CDT.

Friday, May 29

Matthew A. Powell, MD, Ira C. and Judith Gall Professor of Obstetrics and Gynecology, WashU Medicine



Powell will present full data on model-based predictions from the pivotal phase 3 ENGOT-ENG-NSGO/GOG-3031/RUBY trial (NCT03981796) that suggest the potential for cure with dostarlimab-gxly (Jemperli) plus carboplatin and paclitaxel in patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) primary advanced or recurrent endometrial cancer.

Presentation: Long-term survival rates and cure modeling with dostarlimab plus chemotherapy in mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) primary advanced or recurrent endometrial cancer in the ENGOT-EN6-NSGO/GOG-3031/ RUBY trial.  


When: 2:45-2:57 p.m.
Where: Room S100bc + Live Stream



Saturday, May 30

Douglas R. Adkins, MD, Professor of Medicine, WashU Medicine



Adkins will discuss an exploratory analysis of the international KEYNOTE-689 trial (NCT03765918) that found neoadjuvant and adjuvant pembro plus surgery and postoperative [chemo]radiotherapy (SOC) significantly improved event-free survival versus SOC in patients with resectable locally advanced head and neck squamous cell carcinoma.



Poster Presentation: Neoadjuvant and adjuvant pembrolizumab (pembro) plus standard of care (SOC) for resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Efficacy by surgical outcomes in the phase 3 KEYNOTE-689 trial.


When: 1:30-4:30 p.m.
Where: Hall A



Sunday, May 31

Emily L. Podany, MD, Assistant Professor of Medicine, WashU Medicine



Podany will discuss findings of a multi-institutional study of 851 metastatic breast cancer patients that found that those living in food deserts had distinct tumor DNA profiles — including more RTK/RAS mutations and CCNE1 variants — and significantly shorter survival, particularly among Black patients, highlighting the critical intersection of tumor biology and social determinants of health.



Presentation: Impact of food access and poverty on somatic genomic profiles and clinical outcomes in metastatic breast cancer.


When: 11:42-11:48 a.m.
Where: Hall D1 + Live Stream



Monday, June 1

Ramaswamy Govindan, MD, FASCO, Anheuser Busch Endowed Chair in Medical Oncology and Associate Chief of Oncology, WashU Medicine

Govindan, principal investigator of the Phase III A081105 trial (NCT02193282), will discuss findings from the evaluation of adjuvant erlotinib versus placebo in resected EGFR-mutant non-small cell lung cancer. Among 390 patients, erlotinib did not significantly improve overall survival but did improve disease-free survival. Erlotinib did not significantly improve overall survival but did improve disease-free survival in 390 of 450 patients.

Presentation: Adjuvant erlotinib versus observation after complete resection of EGFRmutant NSCLC: Final overall survival results of Alliance A081105.


When: 1:27-1:39 p.m.
Where: Hall D1 + Live Stream



Brendan Heiden, MD, MS, MBA, Assistant Professor of Surgery, WashU Medicine



Heiden and his fellow researchers analyzed the data of nearly 1 million U.S. veterans to compare tobacco smoking duration (TSD) versus pack-years (TPY) for lung cancer screening eligibility. TSD identified more at-risk individuals, reduced missed diagnoses from 30% to 7.5% and improved equity across racial and sex subgroups — supporting a shift in national screening guidelines toward smoking duration.

Presentation: Redefining lung cancer screening eligibility: Smoking duration vs. pack-years in a national VA cohort of nearly 1 million patients.


When: 2:27-2:39 p.m.
Where: Hall D1 + Live Stream

Dineo Khabele, MD, Mitchell & Elaine Yanow Professor and Chair of OB/GYN, WashU Medicine



Khabele joins other senior leaders in academic oncology to discuss her perspective on career development, including strategic planning and actionable steps for each level.



Presentation: Senior Career Perspective: Gynecologic Oncologist


When: 3:36-3:48 p.m.
Where: Room E350



Tuesday, June 2

Cynthia X. Ma,  MD,  PhD, Professor of Medicine, WashU Medicine



Ma is chair and moderator of this session featuring 11 presenters who will give an overview of their novel research and answer questions during a panel discussion.

Rapid Oral Abstract Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology


When: 9:45-11:15 a.m.
Where: Room E451



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About Siteman Cancer Center

Siteman Cancer Center is one of only a few cancer centers to receive the highest rating of the National Cancer Institute (NCI) — “exceptional.” Comprising the cancer research, prevention and treatment programs of Barnes-Jewish Hospital and WashU Medicine in St. Louis, Siteman treats adults at six locations, including the new Gary C. Werths Building for outpatient care and an inpatient hospital on the Washington University Medical Campus, and partners with St. Louis Children’s Hospital in the treatment of pediatric patients at Siteman Kids. All locations offer patient-focused, multidisciplinary care driven by scientific breakthroughs and powered by WashU Medicine physicians.

Quick Facts

  • Established in 1999, Siteman is recognized as a leading cancer center by its peers and the NCI.
  • Every year, 75,000+ people are treated at Siteman, including 12,000+ who are newly diagnosed.
  • Siteman is powered by 600+ WashU Medicine physicians and scientists focused on the latest in cancer treatment and research.
  • With 9,000+ patients enrolled every year in 1,600+ clinical research studies, including 600+ therapeutic clinical trials, Siteman offers access to investigational therapies not generally available to the public.
  • Siteman has held NCI’s highest rating — “exceptional” — since 2015, based on a rigorous review of its research programs.
  • Siteman is also proud to receive more than $185 million annually for basic and clinical oncology research grants, including $66 million from the NCI, funding 1,400+ research projects. This includes three Specialized Programs of Research Excellence (SPORE) grants, for endometrial, leukemia and pancreatic research.
  • In 2024, WashU faculty at Siteman filed for 198 patents.
  • WashU Medicine has the second-largest research funding portfolio from the National Institutes of Health (NIH) among U.S. medical schools.