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Dual-Action Molecule Design Concentrates Cancer Treatment in Tumor Cells to Allow Higher Doses

Written by dari on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (FEB, 6, 2026) — Wistar scientists have combined a promising cancer therapy with a molecule that targets tumors to treat cancer more effectively. The new approach could be a way to deliver treatment directly to tumors at higher doses, while reducing side effects in healthy tissue.

“An Aurora kinase A (AURKA) inhibitor is viewed as a lethal synthetic molecule in cancer therapy, but the problem is you can’t dose it high enough, because then it starts to spill over and target normal cells, causing toxicity,” said coauthor Joseph Salvino, Ph.D. “By using this cancer-targeting approach, we can direct this molecule, which is already in clinical use, to cancer cells, increasing its exposure in the tumor itself.”

Salvino is professor in the Molecular and Cellular Oncogenesis Program at the Ellen and Ronald Caplan Cancer Center, and scientific director of Wistar’s Molecular Screening & Protein Expression Facility.

The new chimeric molecule takes two existing molecules and attaches them together like LEGO blocks to make what’s called a small molecule drug conjugate. One half of the conjugate, an Aurora kinase A (AURKA) inhibitor, works by blocking a protein that controls cell division and helps tumors to grow. While this molecule has shown promise in clinical trials, it’s also caused toxic side effects that limited its use. The second half is a molecule that binds to a protein called HSP90, which cancer cells produce to help them survive stress. By targeting HSP90, which is found at high levels in cancer cells, researchers hoped to show that they could concentrate the compound within the tumor, preferentially over healthy tissue.

In a proof-of-concept study, they demonstrated that the new chimeric molecule successfully binds to both the AURKA and HSP90 proteins. When researchers tested it in cell samples taken from multiple cancer types, including head and neck, lung, and melanoma, they found that it stopped the cancer cells from dividing and replicating, eventually causing the cells to die.

The researchers then tested the new chimeric molecule in preclinical animal models. They found that it concentrated inside the tumors at levels sometimes 10 times higher than when the original AURKA inhibitor was used on its own. The compound also stayed in the tumor for much longer, and was still active 24 hours after being injected, while the original inhibitor was no longer detectable. The compound was also well tolerated in preclinical models, with no significant toxicity.

When the researchers combined the new molecule with another cancer drug, called a WEE1 inhibitor, the two together were even more effective in controlling tumor growth.

“When drugs fail in the clinic, 50% of the time it’s because of poor exposures in the tumor, due to pharmacokinetic problems,” or the body’s ability to absorb or interact with a drug, Salvino explained. “Our approach will take an existing compound and improve its pharmacokinetic properties, enhancing its exposures in the tumor.”

In addition to the cancers tested in the initial study, the new compound should have broad application to many other types of cancer, he added.

Next, researchers plan to apply their approach to different molecules and types of cancer. They also want to develop the new chimeric molecule into a formulation that can be given orally.

Coauthors: Theodore T. Nguyen, Tetyana Bagnyukova, Oleksandra Chkhalo, Kathy Q. Cai, Julia Lamperelli, Shabnam Pirestani, Hossein Borghaei, and Erica A. Golemis of Fox Chase Cancer Center; Nitesh K. Nandwana, Yellamelli V.V. Srikanth, Manish Kumar Mehra, Ravikumar Akunuri, Joel Cassel, and Lily Lu of The Wistar Institute; and Barbara Burtness of Yale University School of Medicine.

Work supported by: National Institutes of Health (NIH) grants R03 CA292552 (E.G. and J.S.), P50 DE030707 (B.B.), P30 CA010815 (Wistar Institute), and S10 OD030245 (J.S.), P30 CA006927 (Fox Chase Cancer Center); Department of Defense (DOD) grant CA201045 / W81XWH2110487 (E.A.G. and B.B.) and by funds from the William Wikoff Smith Charitable Trust (E.A.G.).

Publication information: “NN-01-195, a novel conjugate of HSP90 and AURKA inhibitors effectively targets solid tumors,” Molecular Cancer Therapeutics, 2026. Online publication.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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Wistar Scientists Demonstrate First-Ever Single-Shot HIV Vaccine Neutralization Success

Written by dari on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (TUESDAY, FEB. 3, 2026) — Scientists at The Wistar Institute have developed an HIV vaccine candidate that achieves something never before observed in the field: inducing neutralizing antibodies against HIV after a single immunization in nonhuman primates. The innovative approach, published in Nature Immunology, could significantly shorten and simplify HIV vaccination protocols, making them more accessible worldwide.

The research, led by Amelia Escolano, Ph.D., assistant professor in Wistar’s Vaccine and Immunotherapy Center and the senior author of the study, centers on an engineered HIV envelope protein, WIN332, that challenges scientific assumptions about how to design an effective HIV vaccine.

“By going against one commonly held belief in the field, we achieved low neutralization after a single immunization, which was further increased after one additional booster, something that has never been observed before,” said Escolano. “Usually, HIV vaccination protocols require seven, eight, or even ten injections to start seeing any neutralization. For our immunogen, WIN332, we injected once and already saw some neutralization.”

For years, scientists attempting to engineer HIV vaccines have focused on targeting the virus’s envelope protein, a component of the outermost layer of the virus. Dr. Escolano’s team has engineered a specific region of the envelope protein, called the V3-glycan epitope. Conventional wisdom held that antibodies targeting this region required a particular sugar, N332-glycan, to bind effectively. All previous envelope immunogens were designed to preserve this sugar. Escolano’s team took the unprecedented step of removing the N332-glycan completely to create WIN332.

A single injection of WIN332 induced low but detectable neutralization against HIV within just three weeks—an unprecedented timeline. When the researchers gave a second injection using a related immunogen, neutralization levels increased significantly. This represents a potentially marked improvement over current experimental protocols.

“This immunogen could shorten and simplify vaccination protocols,” said Ignacio Relano-Rodriguez, Ph.D., first author of the study. “If this approach proves successful, we could potentially achieve desired immunity with just three injections. This would make vaccination protocols shorter and more affordable.”

By removing the N332-glycan to create their immunogen, the team also revealed the existence of two distinct types of HIV-neutralizing antibodies that target the V3-glycan region. Type I antibodies represent the previously known class that requires the N332 sugar to bind effectively. Type II antibodies are a new class, identified by this research, that doesn’t require the sugar for binding.

“This discovery potentially expands the toolkit available for developing HIV vaccines that provide broader protection against the diverse HIV strains circulating globally,” Escolano said.

The promising results have attracted attention from major global health organizations to advance WIN332 into human clinical trials. Meanwhile, additional preclinical evaluations are underway, along with the design of subsequent immunogens that could be used in a shortened vaccination series to further enhance neutralization efficiency.

Co-authors: Ignacio Relano-Rodriguez, Jianqiu Du, Zi Jie Lin, Margaret Kerwin, Marta Tarquis-Medina, Eduardo Urbano, Jiayan Cui, Rumi Habib, Colby Agostino, Sukanya Ghosh, Joyce Park, Caroline Boroughs, Niharika Shukla, David B. Weiner, Daniel W. Kulp, and Jesper Pallesen from The Wistar Institute; Meagan Watkins and Ronald S. Veazey from Tulane National Primate Research Center; Peng Zhao and Lance Wells from University of Georgia; Michael S. Seaman from Beth Israel Deaconess Medical Center; Agnes A. Walsh, Mariane B. Melo, and Darrell J. Irvine from Scripps Research Institute; and George M. Shaw and Beatrice H. Hahn from University of Pennsylvania.

Work supported by: National Institute of Allergy and Infectious Diseases (NIAID) grants R00 AI140770-03, P30 AI045008-23, P30 AI045008-24, and R01 AI172627-01A1 to A.E.; Gates Foundation INV-036995 to A.E.; 5 U19 AI166916-03 to J.P. U19 AI166916, BEAT-HIV UM1AI64570, and the a W.W. Smith Charitable Trust Distinguished Professorship in Cancer Research to D.B.W. National Institutes of Health grants R01GM130915 and R01AI157854 to L.W.; National Science Foundation Biofoundry: Glycoscience Research, Education, and Training Grant 2400220 to L.W.; and The Ching Jer Chern Postdoctoral Fellowship to I.R.R.

Publication information: Rapid Elicitation of Neutralizing Asn332-glycan-independent Antibodies to the V3-glycan epitope of HIV-1 Env in Nonhuman Primates, Nature Immunology, 2026. Online publication.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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Wistar Scientists Discover How Gut-Derived Metabolite Acts as Immune “Volume Knob” Via Macrophages

Written by dari on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (JAN. 29, 2026) — Scientists at The Wistar Institute have identified a previously overlooked mediator in the body’s response to life-threatening infections: hippuric acid, a metabolite produced when gut bacteria break down polyphenols from berries, tea, and other plant-based foods. The research reveals that this molecule acts as an immune-system amplifier, boosting the body’s inflammatory defenses during early infection but elevating them to deadly levels when infections progress to sepsis.

Published in Cell Reports, the study demonstrates that elevated hippuric acid levels correlate with increased mortality in sepsis patients, while also uncovering the molecular mechanisms by which this metabolite modifies immune responses. The findings could lead to new approaches for managing severe infections and, potentially, for treating pancreatic cancer.

“Hippuric acid is a metabolite that has historically been seen as a benign byproduct of metabolism and is therefore understudied,” said Rahul S. Shinde, D.V.M., Ph.D., assistant professor in the Molecular and Cellular Oncogenesis Program at the Ellen and Ronald Caplan Cancer Center at The Wistar Institute and senior author of the study. “This paper identifies that it’s not just a passive byproduct. It has bioactive potential to influence the immune system.”

Shinde’s team discovered the bioactive potential of hippuric acid while performing a metabolomic screening on preclinical models infected with E. coli. They found that hippuric acid levels fell 24-fold within 48 hours of infection, suggesting the molecule played an active role in the immune response.

To understand what hippuric acid was doing, the researchers administered it to infected preclinical models. They found that the metabolite acted like a volume dial for inflammation, amplifying the production of pro-inflammatory molecules like IL-12 and IL-6 while suppressing anti-inflammatory signals. Together, these results suggest that a compound once thought to be a passive metabolic byproduct can actively push the immune system toward a dangerous overreaction. When the researchers examined human sepsis patients, they found that those with elevated hippuric acid levels were significantly more likely to die.

Through a series of experiments using cultured immune cells, genetically modified preclinical models, and advanced molecular profiling techniques, Shinde’s team uncovered how hippuric acid amplifies inflammation. The metabolite works by enhancing an immune signaling pathway involving Toll-like receptor (TLR) and MyD88 proteins, which act as the immune system’s early warning system for detecting pathogens. Hippuric acid makes these immune system detectors more sensitive and boosts the phosphorylation of key signaling proteins like IRAK4 and NF-κB, amplifying the inflammatory cascade once it’s begun. (Notably, the effects of hippuric acid require activation of the MyD88 signaling protein. In preclinical models lacking MyD88, hippuric acid had no impact on inflammatory responses.)

The researchers also discovered that by triggering TLR signaling, hippuric acid causes macrophages to produce more cholesterol and remodel their lipid composition—changes that further sustain their inflammatory state. When the team blocked cholesterol synthesis using drugs like fluvastatin, the pro-inflammatory effects of hippuric acid disappeared, demonstrating that lipid metabolism is integral to the metabolite’s immune-boosting function.

“It’s a chain of events,” said Shinde. “Hippuric acid is acting via the TLR/MyD88 pathway and promoting the inflammatory signal, inflammatory responses go up, and then genes that are part of lipid remodeling in macrophages get activated, contributing to inflammation.”

While significant for sepsis patients, whose survival may improve from monitoring or modulating hippuric acid levels, these findings could have even broader potential for cancer treatment. Shinde’s lab focuses on pancreatic cancer, one of the deadliest malignancies with a five-year survival rate of just 13%. In solid tumors like pancreatic cancer, macrophages often become immunosuppressive, creating a protective shield around cancer cells that prevents T cells from attacking them. Shinde and his team are investigating whether these macrophages can be reprogrammed to be immunostimulatory instead of immunosuppressive.

“We want to get them to become immunostimulatory so that instead of making a shield, they kick T cells into action to attack cancer cells,” Shinde said. “My lab is particularly interested in whether we can harness microbial metabolites like hippuric acid to do that job. We’d love to take a natural approach where we balance the diet and microbiome in patients with cancer to change macrophage behavior.”

The team is conducting preliminary studies in preclinical models of pancreatic cancer and investigating how hippuric acid affects TLR signaling and cholesterol metabolism in tumor-associated macrophages. They are also working to understand the long-term effects of hippuric acid exposure through diet on baseline immune function.

“We want to understand the impact of hippuric acid levels on a chronic basis. If somebody eats blueberries and a polyphenol-rich diet, is it helpful over the long term or not?” said Shinde. “These things really shape health outcomes.”

Co-authors: Gauri Mirji, Sajad Ahmad Bhat, Mohamed El Sayed, Sarah Kim Reiser, Siva Pushpa Gavara, Ying Ye, Taito Miyamoto, Wujuan Zhang, Qin Liu, Aaron R. Goldman, Andrew Kossenkov, Nan Zhang, and Joel Cassel from Wistar; Peter Vogel from St. Jude Children’s Research Hospital.

Work supported by: National Institutes of Health grants R37 CA280869 and R21 CA259240; a Margaret Q. Landenberger Research Foundation grant award; the 2022 Pancreatic Cancer Action Network Career Development Award, grant number 22-20-SHIN (to R.S.S.), NIAID K99 AI151198; The Wistar Institute Cancer Center Support Grant (CCSG) P30 CA010815; and NIH instrument award S10 OD023586.

Publication information: Aromatic Microbial Metabolite Hippuric Acid Potentiates Pro-Inflammatory Responses in Macrophages Via TLR-MyD88 Signaling and Lipid Remodeling, Cell Reports, 2026. Online publication.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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The Wistar Institute Announces the Recruitment of Jianliang Xu, Ph.D., to the HIV Cure and Viral Diseases Center

Written by dari on . Posted in Press Releases.

PRESS RELEASE

Xu specializes in antibody research & engineers nanobodies—tiny, effective tools
against HIV & emerging pandemics

PHILADELPHIA — (Jan 13, 2026) — The Wistar Institute, an international biomedical research leader in cancer, immunology, and infectious disease, is pleased to announce the recruitment of Jianliang Xu, Ph.D., to Wistar’s HIV Cure and Viral Diseases Center. Xu is a molecular biologist, trained in fundamental immunology, specializing in antibody and nanobody engineering. Xu engineers antibodies and nanobodies (smaller versions of antibodies) through binding and fusing them to create chimeric molecules—hybrids made from two sources—or nanobody cocktails that are new, enhanced, cutting-edge tools which can be rapidly deployed drug development or diagnostic technologies for HIV and emerging pathogens.

As a Ph.D. student, Xu explored genes and their function in cancer. After reading a paper on activation-induced deaminase (AID) in cancer, he became interested in how this enzyme, essential for building antibody diversity, could be linked to cancer. Xu would reach out to the discoverer of the molecule — Kyoto University professor Dr. Tasuku Honjo (2018 Nobel Laureate in Physiology or Medicine), switch fields from cancer to antibodies, and join Dr. Honjo’s lab as a postdoctoral fellow.

“In Japan I was working on very basic science, doing fundamental, deep dives into antibodies—pursuing how the immune system produces such a diversity of antibodies that can recognize pathogens, and how our body can create stronger binding, more specific antibodies over time,” said Xu. “Understanding these core abilities laid the foundation for my interest in the translational side of antibody research and my focus on a branch of antibody study, which is nanobody development. I am interested in creating nanobody countermeasures against HIV, SARS-CoV-2, respiratory syncytial virus (RSV), and dangerous viruses like Hantavirus and Henipavirus.”

Xu’s research at Wistar will uncover possibilities for HIV and infectious disease, including translating antibodies into future immunotherapies.

“I came to Wistar for the strong HIV research and innovative collaborative team science approach,” he said. “I develop nanobodies to neutralize HIV, but I can see this expanding to eradicating infected cells that are “sleeping” latently in HIV viral reservoirs. At Wistar they engineer CAR-T cells and natural killer (NK) cells to have the same advantages of recognizing and killing HIV-infected cells and these are strategies that combine with my expertise.”

“Jianliang’s deep expertise and ability to engineer custom-designed antibodies with therapeutic potential are indispensable to our goal of developing novel antiviral strategies, including an HIV cure,” said Luis J. Montaner, D.V.M., D.Phil., Wistar executive vice president, director of the HIV Cure and Viral Diseases Center, and Herbert Kean, M.D. Family Professor. “Xu’s program will not only drive progress in uncovering the hidden HIV reservoir by designing unique tools to find and eliminate infected cells, but will also deliver a powerful platform that can be rapidly directed against emerging viral threats.”

Xu obtained a Ph.D. in Biochemistry and Molecular Biology from Nanjing University in China. He carried out postdoctoral training at Kyoto University in Japan and the National Institutes of Health in Bethesda, Maryland. Prior to Wistar, Dr. Xu was assistant professor of Biology at Georgia State University.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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The Wistar Institute Receives Exceptional Rating in Renewal of its Cancer Center Support Grant

Written by evan on . Posted in Press Releases.

PRESS RELEASE

The State’s only National Cancer Institute-designated Basic Cancer Center, this is the third consecutive “Exceptional” rating for the for the
Ellen and Ronald Caplan Cancer Center

PHILADELPHIA — (Dec. 16, 2025) — The National Cancer Institute (NCI) rated The Wistar Institute’s Ellen and Ronald Caplan Cancer Center as “exceptional” for the third time in a row during the renewal of its Cancer Center Support Grant (CCSG). The grant provides $16.3 million over the next five years to the NCI-designated Basic Cancer Center, which was the first to receive the designation in 1972.

The “exceptional” rating is the highest rating offered by the NCI. The review process praised Wistar’s strong, collaborative cancer research programs and scientific leadership, state-of-the-art core research facilities, and award-winning education and workforce training programs. Further contributing to its “exceptional” status are the productive partnership with ChristianaCare’s Helen F. Graham Cancer Center, which bridges science and clinical medicine, and the transformational opportunities presented by Wistar’s Hubert J.P. Schoemaker Education and Training Center, forging the next generation of cancer scientists.

Wistar was one of the first organizations in the nation to receive the NCI designation in 1972, following the signing of the National Cancer Act, and has maintained the status uninterrupted since that time. Now in its 57th year, the NCI-designated, Ellen and Ronald Caplan Cancer Center continues to demonstrate scientific excellence, groundbreaking contributions in basic and translational cancer research, and strong collaborations with clinical and academic institutions. These achievements were validated through a rigorous, competitive peer-review process, underscoring the Center’s leadership in advancing innovative approaches to cancer prevention, diagnosis, and treatment.

“Receiving an exceptional rating for the third consecutive time is a tremendous honor,” said Dario C. Altieri, M.D., Wistar Institute president and CEO, director of the Ellen and Ronald Caplan Cancer Center, and Robert and Penny Fox Distinguished Professor. “This is the highest distinction awarded by the NCI, and it reflects the unwavering commitment of our extraordinary team. Every day, our researchers push the boundaries of science to confront some of the world’s most challenging health issues—working collaboratively within Wistar and globally with our peers. With the launch of our new Center for Advanced Therapeutics, we are poised to accelerate the translation of groundbreaking discoveries into treatments and cures that will make a lasting impact on human health.”

The Center for Advanced Therapeutics opened in September 2025 to identify new, early-stage biomedical research discoveries and translate those innovations into successful potential medicines. Led by Dr. Paul Lieberman, Hilary Koprowski, M.D., Endowed Professor, the Center leverages the expertise of top Wistar scientists in biology, chemistry & AI to capitalize on new areas of investigation and expand vital collaborations across public-private sectors, integrating expertise and technology to reduce the burden of human disease.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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The Wistar Institute Announces Recruitment of Vincent Wu to Join Vaccine & Immunotherapy Center as Caspar Wistar Fellow

Written by dari on . Posted in Press Releases.

PRESS RELEASE
Interdisciplinary scientist brings expertise in molecular biology and bioinformatics to study HIV reservoir, where dormant virus hides

PHILADELPHIA — (Dec. 3, 2025) — The Wistar Institute, an international biomedical research leader in cancer, immunology, and infectious disease, is pleased to announce the recruitment of Vincent Wu, Ph.D., to Wistar’s Vaccine & Immunotherapy Center (VIC) as a Caspar Wistar Fellow.

Wu studied HIV-2 as an undergraduate and though still early in his career comes to Wistar with a decade of research in HIV biology—its life cycle and where it hides, and in immunology—understanding what is the body’s immune response to HIV infection and how the HIV virus persists. As a postdoctoral fellow in the University of Pennsylvania lab of Dr. Michael Betts, Wu honed his skills at the lab bench conducting experiments using single cell profiling methods to better understand cell phenotypes during HIV infection. Then at the computer, he uses specialized computational tools and algorithms to process and interpret the raw data.

“These two camps, the molecular biology side and the bioinformatics side—wet lab and dry lab—speak very different languages and sometimes a lot is lost in translation when trying to convey findings or requests with each other,” said Wu. “From my own hybrid experiences, I envision my lab to be akin to a ‘Rosetta Stone’ where we create a holistic, synergistic relationship between the two languages that enables us to generate wet lab data and then directly analyze it to draw conclusions and act upon the research findings”

One of the big scientific questions he wants to answer concerns the HIV reservoir.

“The reservoir is a very critical aspect of any possible cure strategy, but unfortunately, it’s not a single, homogenous mixture of cells and there’s no unique signature to them that we know of,” said Wu. “What is the HIV reservoir composed of, what regulates it, and how does it dynamically change over time and upon different interventions? The methods for single cell profiling are so important because we can more properly disentangle noise from signals and get a clearer picture of the reservoir and how it changes over time”

Another project in which he sees collaboration is “shock and kill” strategy. Here Wu targets HIV integrated DNA to wake up the viral reservoir so once-dormant HIV cells are visible to immune therapies.

“In collaboration with leaders in the field, we have had some exciting data with mRNA-LNP based, latency-reversal agent (LRA) strategies as a design that can induce the aforementioned shock. Developing this further would pair well with collaborations that include Wistar’s Dr. Dan Claiborne and Dr. Amelia Escolano. We could shock using HIV DNA specific platforms that are delivered by mRNA-LNPs to wake up the reservoir and then use immunotherapies like Claiborne’s CAR-T cells and Escolano’s bNAbs.”

“Dr. Wu’s research integrates his approach to hands-on single cell biology with computational analysis for data interpretation. This combination of approaches places him at the cutting-edge of where the field is evolving,” said David Weiner, Ph.D. Wistar executive vice president, director of the Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Distinguished Professor in Cancer Research. “This is a key area in advancing cancer and immunology research, and Dr. Wu has significant interest from collaborators in his multiplexed single-cell profiling program. He advances our Center’s interest in determining populations that are responding to immunization and engaging protective immunity for prevention as well as for immunotherapy. Dr. Wu’s tools are of broad interest to members of Wistar’s Center for Advanced Therapeutics and the HIV Cure and Viral Diseases Center as well as playing a major role working with researchers here in the VIC.”

Wu is a member of the Caspar Wistar Fellows Program, which fast-tracks the most promising, early-career scientists to pursue creative, out-of-the box biomedical research for the benefit of humanity. He will receive support from the Institute to expand his laboratory and work toward building a mature research program.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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Wistar Scientists Reveal Why Anti-estrogen Therapy Fails in Ovarian Cancer—And How to Make It Work

Written by dari on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (Nov. 11, 2025) — Scientists at The Wistar Institute have solved a longstanding puzzle in ovarian cancer treatment: why anti-estrogen therapy often fails even when tumors express the hormone receptor that should make them responsive. The study reveals that mutant p53, which occurs in 96% of high-grade serous ovarian cancers, blocks estrogen signaling, which drives treatment resistance. The researchers also identified a potential therapeutic strategy that relies on a drug already being explored in clinical trials.

“This discovery fundamentally changes how we think about hormone therapy resistance in ovarian cancer,” said Maureen Murphy, Ph.D., deputy director of the Ellen and Ronald Caplan Cancer Center, Ira Brind Professor, program leader of the Molecular and Cellular Oncogenesis Program at The Wistar Institute, and senior author of the study. “We’ve not only uncovered why these treatments fail but also identified a clear path to making them work. For patients with specific p53 variants, we can potentially combine FDA-approved drugs to overcome resistance.”

High-grade serous ovarian cancer is particularly deadly, with an 80% relapse rate after initial chemotherapy and a predicted death toll of 13,000 women per year in the United States alone. While nearly three quarters of these tumors express estrogen receptors—suggesting they should respond to hormone-blocking drugs—clinical trials of these therapies have shown a clinical benefit rate of only 41%.

Murphy’s investigation into this discrepancy began with an unexpected discovery during her previous work on genetic variants of p53 found in people of African descent. When her team analyzed blood samples from carriers of these variants, they found that estrogen-responsive genes showed dampened activity—a clue that led her team to explore the p53-estrogen receptor connection.

In the lab’s most recent study, published in Genes and Development, the team discovered that the mutant p53 protein binds to estrogen receptors, disrupting an important hormone signaling pathway. When this happens, the tumor becomes resistant to hormone treatments.

Thanks to collaborations with key consortium partners such as the Helen F. Graham Cancer Center & Research Institute, Murphy’s team was able to obtain human ovarian cancer cells and patient tissue samples to test whether silencing mutant p53 restored hormone therapy sensitivity. Their hypothesis proved correct: When mutated p53 was silenced, previously resistant tumors responded to treatment. Together with Ronny Drapkin at the University of Pennsylvania, they confirmed these findings in even the earliest stages of ovarian cancer.

“The most exciting part came when we tested a compound called rezatapopt,” Murphy said. “This drug can refold a specific variant form of p53—called Y220C—back into its normal shape. When we combined rezatapopt with hormone therapy, tumors with this mutation became much more sensitive to treatment.”

Rezatapopt is already being tested in clinical trials at Penn and other institutions, meaning this combination approach could be trialed in patients relatively quickly. Furthermore, the findings may have broader implications for other hormone-driven cancers. For instance, the work provides a potential explanation for why endocrine therapy sometimes fails in breast cancer patients with p53 mutations, opening new research directions for improving treatment of that disease, as well.

Murphy’s team is now working to expand their findings to other variant forms of p53. They’re also developing more precise methods to identify which patients would benefit most from p53-targeted combination treatments.

“Our ultimate goal is to transform this from a laboratory discovery into a clinical tool that helps patients,” Murphy said. “We’ve shown the scientific principle works—now we need to translate that into treatment protocols that oncologists can use to help their patients.”

Co-authors: Chunlei Shao, Alexandra Indeglia, Maya Foster, Kaitlyn Casey, Jessica Leung, Bryant Duong, Noam Auslander, Nan Zhang, and Maureen E. Murphy from The Wistar Institute; Shirin R. Modarai and Jennifer Sims-Mourtada from the Helen F. Graham Cancer Center & Research Institute; Julia I-Ju Leu and Ronny Drapkin from Perelman School of Medicine, University of Pennsylvania; Anne-Marie Mes-Masson from Centre de recherche du Centre hospitalier de l’Université de Montréal et Institut du cancer de Montréal, Université de Montréal; and Benjamin G. Bitler from University of Colorado Anschutz Medical Campus.

Work supported by: National Health Institutes (NIH) grants CA102184 and CA266075 (M.E.M.); funds from the Elaine M. Ominsky, Ph.D. Breast Cancer Research Endowed Fund (M.E.M.); Department of Defense grant HT94252410206 (N.Z.); the V Foundation for Cancer Research grant V2024-026 (N.Z.); and National Cancer Institute grant P50CA228991 (R.D.).

Publication information: Mutant p53 Binds and Controls Estrogen Receptor Activity to Drive Endocrine Resistance in Ovarian Cancer, Genes and Development, 2025. Online publication.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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The Wistar Institute Appoints Two New Members to its Board of Trustees

Written by evan on . Posted in Press Releases.

PRESS RELEASE
Wistar welcomes David Krupnick and Elliot Menschik, M.D., Ph.D.

PHILADELPHIA — (Oct. 30, 2025) — The Wistar Institute, a global leader in biomedical research in cancer, immunology and infectious disease, is pleased to welcome two new members to its Board of Trustees. David Krupnick and Elliot Menschik, M.D., Ph.D., will join the current board in offering strategic counsel to the Institute as it undergoes a period of significant growth and expansion.

“With the opening of Wistar’s Center for Advanced Therapeutics and the HIV Cure and Viral Diseases Center, we are ideally positioned to further our record of advancing discoveries that have the opportunity to solve some of the world’s most pressing health issues,” said Dario C. Altieri, M.D., Wistar Institute president and CEO, director of the Ellen and Ronald Caplan Cancer Center, and Robert and Penny Fox Distinguished Professor. “David and Elliot’s background and expertise in business development, strategy, and, in particular, the biotech industry all dovetail well with our strategy to accelerate the advancement of our foundational research discoveries into new potential treatments and cures.”

David Krupnick joins with a range of expertise in investing and corporate management. He is currently President and CEO of Webb Medical, a Philadelphia-based medical device manufacturer, where he has helped modernize operations, expand customer base, and increase revenue and profitability. Prior to Webb Medical, David spent more than eight years at Morgan Stanley, where he served as a Vice President across roles in Leverage Finance and Corporate Strategy, including post-merger integration for the Wealth and Institutional Divisions. He is also an active angel investor and advisor, with investments in more than 20 early-stage companies across sectors.

Krupnick is a graduate of Brown University and lives in Philadelphia with his wife and three young children.

Elliot Menschik, M.D., Ph.D. has created, built, and led multiple investor-backed startups in digital health, molecular diagnostics, biomanufacturing, and drug development. He is currently an entrepreneur-in-residence at Amazon where he earlier led its global cloud computing arm Amazon Web Services and worked with investors and their portfolio companies across healthcare, life sciences, and AI/ML. He has previously been a venture capitalist, coached over 100 startup founders, and taught 500+ Penn science and engineering students how to bring technology innovations to market.

Dr. Menschik received his bachelor’s and master’s degrees in electrical and computer engineering from The Johns Hopkins University, and his M.D. and Ph.D. in Neuroscience from the University of Pennsylvania School of Medicine.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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First-in-Human Study of DNA Antibody Replicas Generate Efficient and Long-Lasting Biologic Production of Human Antiviral Antibodies

Written by dari on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (Oct.21, 2025) — A multidisciplinary team of scientists led by The Wistar Institute, including Perelman School of Medicine at the University of Pennsylvania, AstraZeneca and Inovio Pharmaceuticals, published today in Nature Medicine a breakthrough in biologic antibody production that happens directly in human subjects in this encouraging first clinical trial of its kind.

Funded by the Defense Advanced Research Projects Agency and Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, researchers have demonstrated that designed DNA cassettes (small genetic elements) through direct delivery instruct human tissues to produce, assemble, and secrete functional human monoclonal antibodies that persist in the bloodstream for more than a year. Detailed studies of these expressed antibodies show they function effectively, bind correctly to their specific viral target and are well tolerated by the host, an important outcome.

The DNA “cassettes” were designed to mimic native human antibodies in sequence and assembly upon delivery. The two antibodies were detected in 100% of evaluable participants, with serum concentrations reaching a peak of 1.61 µg/mL—a level comparable to some FDA-approved biologic therapies. Sustained antibody expression was observed in all participants during the 72 weeks of follow-up, supporting this novel approach to disease protection and treatment.

“While FIH studies require cautious interpretation, and rigorous validation, the long-term expression of biologic antibodies with demonstrated fidelity and functionality in all volunteers without induction of anti-drug antibodies represents an important development for the biologics field.” said David B. Weiner, Ph.D., Executive Vice President of The Wistar Institute, director of Wistar’s Vaccine & Immunotherapy Center, W.W. Smith Charitable Trust Distinguished Professor in Cancer Research, and senior author of the study.

As the FDA and other regulatory agencies have requested solutions for the complex biologic production of cell based medicines, this study supports that direct delivery of highly focused DNA, which is already utilized as the seeds to create the cell lines that produce biologics in laboratories, could eliminate steps and excipients in biologic production moving to direct patient production by using the native human biologic production process in their cells.

Traditional antibody or biologics face limitations: They can be expensive to manufacture, store, and distribute; are made in laboratories utilizing many excipients that are time-consuming to approve; and provide only temporary protection lasting weeks to months. During the COVID-19 pandemic, these challenges became particularly apparent when, by the time several antibody treatments were developed, approved, and distributed, they had been rendered ineffective due to the rapid development of viral escape.

In the clinical trial, led by Pablo Tebas, M.D., a professor of Infectious Diseases at Penn and the study’s lead clinical investigator, forty-four healthy adults received between one and four doses of synthetic plasmids encoding two COVID-19 neutralizing antibodies. Thirty-nine out of thirty-nine evaluable participants showed detectable levels of DMAbs produced in vivo up to 72 weeks later. Additionally, no anti-drug antibodies (ADAs) were detected in any participant throughout the duration of the study—a significant advantage over other delivery methods.

“For the first time, we’ve shown that the human body itself can be turned into a factory to safely produce long-lasting, fully functional antibodies,” said Tebas. “This approach could simplify biologic therapies, lower costs, and extend protection for patients who need it most. In our study we were able to give up to four doses in some subjects, in total >200 administrations in the cohort, and did not observe the development of ADAs. We hypothesize that the design of the antibody constructs with high fidelity to normal human antibodies, the lack of foreign proteins or other components that may trigger the immune system, the consistency of antibody production by their own cells,and the targeted delivery of the DNA plasmids into muscle cells by INOVIO’s CELLECTRA delivery system without the use of chemical adjuvants, lipid nanoparticles or viral vectors, contributed to this positive outcome. These among others remain areas for continued investigation by the team.” 

One important application of this approach is for persons who cannot benefit from or take traditional vaccines for various reasons. These could include cancer survivors, transplant recipients, and persons with certain autoimmune diseases, for example. The study reported sustained antibody expression after a single dose. This could reduce the cost of therapy and patient experience through lowering the number of treatments, potentially eliminating expenses associated with protein biologic production and infusion.  

Tebas also emphasized that the approach proved to be generally well-tolerated. Most side effects were limited to mild, temporary injection site reactions typical of any intramuscular injection. This was the primary objective of the clinical trial.

“Our sample size was limited, and we looked at up to 72 weeks of expression and tested a limited set of formulations, said Tebas.” We are excited to share our findings to bring more eyes to this study and further advance the field.”

This study represents the value of deep collaboration, a hallmark of Wistar research to address complex biologic issues. Weiner, Tebas, and their respective labs have collaborated for years on developing first-in-human trials of novel DNA immunogens and vaccines. In this study, Weiner and The Wistar Institute provided the foundational DNA platform technology, while Tebas and Penn used their extensive experience to guide the clinical process and regulatory navigation. They both have collaborations in the DNA space with Inovio Pharmaceuticals, which developed the specialized CELLECTRA® delivery system and oversaw production of the DNA plasmids, and with AstraZeneca which shared its antibody designs and expertise in biologic development. This project received extensive support and guidance through the U.S. Defense Advanced Research Projects Agency, which funded the project through its reduction to practice focus.

“It was an honor to work together with this exceptional team whose combined skills and dedication to bring new creative solutions for patients benefit underpin this project’s important findings.” said Weiner.

The implications of these findings extend far beyond COVID-19. Weiner suggests that this platform could potentially deliver long-acting treatments for cancer, autoimmune diseases, and other conditions currently requiring frequent clinic visits for antibody infusions. It could be particularly valuable for immunocompromised patients who don’t respond well to traditional vaccines, offering them extended protection through their now own cells antibody production. The approach could also be a viable delivery method for long-term hormone medications like GLP-1s or for enzyme replacement diseases, as well as multicomponent gene editing approaches for inherited disease applications.

“This proof-of-concept in some ways strengthens concepts for biologics delivery,” Weiner said. “We’ve shown that the DNA antibody replicas can reliably deliver to human cells to produce complex biological molecules with high fidelity and are well tolerated. The platform’s simplicity, scalability, and independence from cold storage potentially offer advantages for patient equity and accessible treatments.”

Co-authors: Amanda Baer, Maria Caturla, Chungdhak Tsang, and Knashawn Morales from the University of Pennsylvania; Ami Patel, Elizabeth M. Parzych, Sukanya Ghosh, Mansi Purwar, Nicole Bedanova, and Jesper Pallesen from The Wistar Institute; Joseph T. Agnes, Dinah Amante, Paul D. Fisher, Laurent Humeau, and Trevor R. F. Smith from Inovio Pharmaceuticals; Joseph R. Francica, Paul Leon, and Mark Esser from AstraZeneca.

Disclaimer: The views, opinions and/or findings expressed are those of the author and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government.

Penn and Dr. Weiner have either received, or may receive in the future, financial consideration related to the licensing of certain Penn intellectual property to INOVIO. Dr. Weiner is a member of the Scientific Advisory Board and Board of Directors for INOVIO.

Work supported by: This work was funded by the Defense Advanced Research Projects Agency and the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) (Award HR0011-21-9-0001 to D.B.W.).

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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Wistar Scientists Discover p53 Can “Read” Cellular Signals to Direct Immune Response, Upending 30 Years of Scientific Consensus

Written by dari on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (Oct. 2, 2025) — Wistar Institute researchers have overturned three decades of scientific thinking about p53, the most important tumor suppressor protein in cancer research. In a study published in Molecular Cell, they reveal for the first time that this critical protein, responsible for halting cell division or initiating cell death, changes its binding sites according to specific cellular signals. The findings challenge the long-held scientific belief that p53 always activated the same set of genes regardless of cellular context or outcome. Instead, researchers discovered that p53 can be directed by the enzyme PADI4 to leave some of its usual binding sites and relocate to genes that generate an immune response to attack tumors.

“For 30 years, we joked that p53 was ‘dumb’ because it couldn’t decide what to do in different situations—it just turned on all its target genes whether the cell needed to die or survive, and the cell decided which activity needed to happen,” said Maureen Murphy, Ph.D., Deputy Director of the Ellen and Ronald Caplan Cancer Center, Ira Brind Professor & Program Leader of the Molecular and Cellular Oncogenesis Program at The Wistar Institute, and senior author of the study.

“This is the first example of p53 actually reading a signal and deciding where on DNA to bind. It’s a completely different mechanism that shows p53 is actually quite smart and, as I suspected, engages the immune system in order to suppress cancer.”

The discovery emerged from Murphy’s decades-long investigation into genetic variants found in families of African descent who develop cancer at accelerated rates but don’t fit typical hereditary cancer patterns. These families carry partially functional versions of p53—called hypomorphic variants—which are understudied and therefore leave patients without clear medical guidance. Murphy and her team hypothesized that studying these semi-functional variants that are associated with cancer, would reveal the key target gene for p53 tumor suppression.

By comparing the function of six p53 hypomorphs to the “normal” or wild-type version of p53, the team identified PADI4 as the only p53 target gene that would typically be activated by wild-type p53 but remained inactive across all six of the hypomorphic variants they tested. They also found that PADI4 doesn’t just respond to commands from p53—it actually directs p53’s behavior through a process called citrullination. When PADI4 citrullinates p53 (adding chemical tags to specific amino acid residues), it fundamentally changes where p53 goes in the cell’s DNA. Instead of binding to its usual genes, the modified p53 relocates to genes associated with ETS transcription factors, which are known to regulate immune response genes. This gives scientists a whole new perspective on p53’s role in responding to cancer.

“P53’s real tumor suppressive role appears to be to alert the immune system to come and eradicate the tumor,” said Murphy.”

The researchers demonstrated this mechanism using advanced genomic techniques, showing that when PADI4 is active, p53 abandons about 30% of its normal binding sites while moving to new locations that activate genes responsible for the interferon response—the cell’s primary antiviral and anti-tumor defense system. To do this, Murphy and her team developed new antibodies specific to citrullinated p53 and used cutting-edge techniques including ChIP-seq and CUT&Tag to map precisely where the modified p53 binds in living cells. They confirmed this mechanism in multiple cell lines and validated it in mouse models.

This discovery has important implications for cancer treatment and diagnosis. Since certain hypomorphic p53 variants cannot properly activate PADI4, these patients may not respond as well to immunotherapies that rely on the body’s natural immune response to fight cancer. Therefore, Murphy suggests, PADI4 could serve as a potential biomarker to help clinicians guide treatment decisions.

“We might be able to predict whether someone will respond to immunotherapy based on their p53 status and PADI4 function. Instead of trying immunotherapy and finding out it doesn’t work, we could direct treatment more precisely from the start. In fact, one of our areas of focus is to identify personalized therapies for people with hypomorphic p53 variants.”

Importantly, this discovery represents more than just a scientific advance. It validates Murphy’s long-held conviction that studying historically underrepresented populations can lead to breakthrough insights. Some families of African descent have the highest cancer burden of any ethnic group, yet their genetic variants have been largely understudied.

“These families are getting cancer in their 30s and 40s, and genetic counselors are telling them ‘sorry, we don’t know if this mutation is really responsible for increasing your cancer risk,’” Murphy said of African descent families with hypomorphic p53 variants.

“By studying people who are marginalized and variants that were being ignored, we ended up discovering a fundamental new mechanism of how the most important tumor suppressor actually works.”

Co-authors: Alexandra Indeglia, Andrea Valdespino, Giulia Pantella, Sarah Offley, Connor Hill, Maya Foster, Kaitlyn Casey, HsinYao Tang, Anneliese M. Faustino, Alessandro Gardini, and Maureen E. Murphy from The Wistar Institute.

Work supported by:National Health Institutes (NIH) grants R01 CA102184 to M.E.M., F31 CA277953 to A.I., and R50 CA221838 to H.Y.T. Wistar shared resources are supported by the Cancer Center Support Grant P30 CA010815.

Publication information: Targeted Citrullination Enables p53 Binding to Non-canonical Sites, Molecular Cell, 2025. Online publication.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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