Skip to main content

Tag: Lieberman

The Wistar Institute Strengthens AI-Driven Drug Discovery with Recruitment of Computational Biophysicist Guangfeng Zhou

Written by dari on . Posted in Press Releases.

PRESS RELEASE
Zhou integrates physics-based modeling, chemistry, biology, and AI to accelerate discovery of new therapeutic leads in the Center for Advanced Therapeutics

PHILADELPHIA — (Aug. 4, 2026) — The Wistar Institute, a world leader in cancer, immunology, and infectious disease research, announces the appointment of Guangfeng Zhou, Ph.D., as assistant professor in the Center for Advanced Therapeutics (CAT). Zhou develops computational methods that combine physics-based molecular modeling with artificial intelligence (AI) to predict how small molecules bind to protein targets. His work transforms atomic-level principles into practical drug-discovery platforms capable of screening ultra-large compound libraries and prioritizing therapeutic leads with greater speed and precision.

“Guangfeng brings expertise in physics-based modeling and AI, and a strong chemistry foundation to the very cutting-edge of drug discovery,” said Paul M. Lieberman, Ph.D., director of the Center for Advanced Therapeutics and Hilary Koprowski, M.D., Endowed Professor. “By applying physics and chemistry theories to AI, he’s building computational tools that will help our scientists ultimately discover new drug compounds and make real-world impact.”

Zhou’s interdisciplinary research reflects an academic path spanning chemistry, biophysics and computation. He received a B.S. in Chemistry from the University of Science and Technology of China and then earned a Ph.D. in Chemistry at Temple University. In graduate school, under the mentorship of Vincent Voelz, Ph.D., he learned scientific programming and applied large-scale, dynamic molecular simulations to study how proteins fold and interact.

Collaborations with experimental labs on computational, drug-discovery “side projects” sharpened his interest in therapeutic design. So, he secured a postdoctoral fellowship at the Institute for Protein Design within the Biochemistry Department at the University of Washington, where he applied his understanding of protein interactions to develop computational methods for designing and discovering novel therapeutic molecules.

“I came to Wistar because of its strong support for early-career scientists and its highly collaborative research environment,” said Zhou. “The Institute’s strong research programs in cancer, immunology and infectious disease align with my goal of building a lab that serves as a collaborative hub. My drug discovery program will aim to develop generalizable methods that can be applied across these areas and across different therapeutic targets, to advance real-world drug discovery. One specific problem I want to solve is to develop AI models, guided by the principles of physics and chemistry, that can “see” a new target that’s outside the model’s training data and still incorporate and obey physical and chemical rules when applied to that target.”

For a printer-friendly version of this release, please click here.

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

Continue reading

The Wistar Institute Announces the Recruitment of Murad Mamedov, Ph.D., to the Center for Advanced Therapeutics

Written by dari on . Posted in Press Releases.

PRESS RELEASE
Brings expertise in unique, unconventional T cells to advance new cancer immunotherapies

PHILADELPHIA — (April 1, 2026) — The Wistar Institute, an international biomedical research leader in cancer, immunology, and infectious disease, is pleased to announce the appointment of Murad Mamedov, Ph.D., as assistant professor in Wistar’s Center for Advanced Therapeutics. Mamedov is an immunologist studying immune stress sensing and the role of human unconventional T cells called gamma-delta T cells in fighting cancer and other diseases.

“We sit at the intersection of Wistar early-stage science and advancing promising discoveries that could be tapped as future therapeutics, so Murad’s gamma-delta T cell knowledge and genome editing toolkit will be crucial for understanding the possibilities of this exciting new area of cancer immunotherapy,” said Paul M. Lieberman, Ph.D., director of the Center for Advanced Therapeutics and Hilary Koprowski, M.D., Endowed Professor.

Mamedov’s extensive T cell biology experience, particularly his studies of unconventional gamma-delta T cells and how they differ from conventional T cells (including killer CD8 T cells and helper CD4 T cells), is important for our understanding of these immune cells’ unique function and crucial to their application in clinical therapeutic settings.

Through the lens of existing targets of gamma-delta T cells, Mamedov wants to understand how the immune system is programmed to recognize cellular stress in cancer cells and other diseased cells under conditions such as lack of nutrients and oxygen, UV radiation, toxin exposure, metabolic aberrations, and viral infection.

Using large-scale, genome editing CRISPR platforms, he also seeks to identify new gamma-delta T cell targets, especially those crucial for the recognition of cancer cells, and how these targets are turned on. Using the same CRISPR editing tools, he wants to engineer human gamma-delta T cells for enhanced detection and killing of tumor cells.

Mamedov received his Ph.D. in Dr. Mark Davis’ lab at Stanford University. Davis’ work is at immunology’s forefront—having published seminal papers on T cell biology since the 1980s. This foundation primed Mamedov’s deep understanding of immunology and shed light on the importance of gamma-delta T cells and their unique protective roles in various diseases. The lab studied T cells across a wide spectrum of diseases, giving Mamedov a different vantage point from which to probe and understand T cell biology.

His postdoctoral fellowship took him to Dr. Alex Marson’s lab at Gladstone Institutes and the University of California, San Francisco, where he used CRISPR molecular scissors to precisely target and rapidly survey the entire human genome for possible targets of gamma-delta T cells. During this time, Mamedov assembled an international collaborative network and made a major discovery of how cancer cells are recognized by the most abundant type of human gamma-delta T cells.

“In the Davis lab we used T cells as the prism through which we looked at various diseases, covering the whole gamut from cancer and multiple sclerosis all the way to my malaria work. Through a chance discovery in one of my experiments, I found myself in the gamma-delta T cell field and have stayed dedicated to understanding and applying these unique cells in human disease,” said Mamedov. “For my postdoc in the Marson lab, I combined my knowledge and passion for these unconventional T cells with CRISPR editing—at the time, a new technology in immunology—and married the two. I set up massively scaled experiments to survey the entire human genome and understand in one experiment what previously would have taken 20,000 experiments. My lab will continue to apply this powerful method to discover T cell targets and how these targets turn on, which we hope will lead to new therapies. I came to Wistar because I felt a strong sense of community and belonging here. Also, the combination of stellar science continuously happening at Wistar for generations, the unique combination of cancer, immunology and infectious disease research, and the opportunities for collaboration within the greater scientific community here in Philadelphia were irresistible.”

Mamedov received a B.S. in biology and philosophy from Georgetown University, where he studied  hepatitis delta virus in Dr. John Casey’s lab. He obtained his Ph.D. in immunology from Stanford University and carried out postdoctoral training at the Gladstone Institutes and the University of California, San Francisco.

For a printer-friendly version of this release, please click here.

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

Continue reading

Pioneering Biologist Dr. Barbara Knowles Returns to Wistar

Written by dari on . Posted in Featured News.

Dr. Barbara B. Knowles’ recent return to The Wistar Institute was timely. The former professor and her family toured Wistar’s newly opened Center for Advanced Therapeutics (CAT). During the visit Dr. Knowles also conferred her blessings on a new $1.5 million endowed professorship carrying her name. The Barbara B. Knowles, Ph.D., Endowed Professorship was made possible by a philanthropic gift from two Wistar Trustees – Sue Dillon, Wistar Board Vice Chair, and Helen Pudlin, former Wistar Board Chair. The permanent endowment supports the recruitment of a cutting-edge, academically excellent research leader to the CAT.

“Barbara’s scientific legacy exemplifies the kind of scientist we want to recruit to Wistar’s Center for Advanced Therapeutics,” said Sue Dillon, “where the unique collaborative environment supports the innovative research needed to solve challenging problems, save lives, and create new and crucial medicines of the future.”

“We are delighted to support this first endowed professorship for the CAT,” said Helen Pudlin. “Named in honor of Barbara Knowles and indicative of her continuous scientific contribution of groundbreaking research, it is more than fitting, and our aim is to bring a new outstanding scientist to the Center.”

Center director Dr. Paul Lieberman accompanied Dr. Knowles, her husband, fellow retired Wistar professor Dr. Davor Solter, and her two adult children Amanda and Jared Knowles, through the state-of-the-art space built to translate Wistar biomedical research into new future cures.

Seeded by a $30 million philanthropic gift, the CAT will recruit and grow a team to identify clinically attractive assets. Through advanced computational biochemistry, AI, high-tech instrumentation & robotics, Wistar scientists can steward and advance promising discoveries with the end goal of future medicines.

The renown geneticist’s return was a special opportunity to revisit old Wistar haunts and relive the scientific career that established her as a pioneering researcher and major contributor to pluripotent stem cell development. The “HepG2” liver cell line she created is still widely used in biomedical research, biotech and pharmaceutical development around the world. Dr. Knowles also developed important monoclonal antibodies against embryonic stem cell markers that, for the past four decades, have been the critical reagents to identify pluripotent stem cells.

Dr. Knowles was first recruited in the late 1960s by then-director Dr. Hilary Koprowski.

Dr. Knowles did her graduate work and then postdoctoral fellowship at the University of California, Berkeley, working in Drosophila genetics but she did not want to work with fruit flies for the rest of her life. Dr. Koprowski offered her a lab manager position saying, “I could do any scientific research that I wanted to in my spare time”. She says, “I wanted to pivot to study human diseases and for me this was the perfect opportunity in a stimulating environment, which became my scientific home.” Three years later, and pregnant with her first child, Dr. Knowles had developed several therapeutic strategies she wanted to follow but didn’t have enough time to do her own science and also continue running the Koprowski lab. “So, I finished writing up the papers from my thesis and more recent somatic cell hybrid work and just continued writing grant proposals for independent funding at Wistar.”

And she won, in spades.

Surrounded by so many great scientists at Wistar and being an integral part of a dynamic, environment, Barbara collaborated with many researchers at Wistar, including her husband Dr. Davor Solter, and followed her interests in immunology, embryology and cancer to develop cell therapies. She probed the use of somatic cells as a possible enzyme therapy, and explored immunotherapeutic approaches to control SV40 Tumor antigen-induced tumors in pre-clinical models, and then paved the way for developing human pluripotent stem cell therapeutics.

Dr. Knowles went on to become Director of Research at The Jackson Laboratory, Deputy Director of the Jax Cancer Center and founded the Graduate School in Biomedical Sciences at the University of Maine. After retiring from The Jackson Laboratory and the Max Planck Institute for Immunobiology and Epigenetics respectively, Barbara and Dr. Solter were appointed Research Directors in Singapore at A*STAR’s Institute for Molecular Biology, where they finished up and published select aspects of their scientific work, while expanding Biomedical Science in this entrepreneurial Southeast Asian country.

“I became a scientist at Wistar. I had the time to think and interact with wonderful creative people. And that is it.”

And that is everything.

Wistar Opens the Doors to its New Center for Advanced Therapeutics

Written by evan on . Posted in Featured News.

After more than a year of construction, the Center for Advanced Therapeutics (CAT) opened its doors to a crowd of more than 100 eager guests, launching a new phase in Wistar’s drive to translate research discoveries into new potential medicines.

In his opening remarks, Wistar president and CEO Dr. Dario Altieri highlighted Wistar’s long record of advancing science. “Wistar has an institutional culture where we seek innovation and risk taking, we prize collaboration and partnership, and we reward excellence. That culture is alive today in the opening of the Center for Advanced Therapeutics.”

Dr. Paul Lieberman, an expert in the field of Epstein-Barr virus (EBV) research as well as other viruses that cause cancer, is the Center’s founding director and leads the drug discovery process to advance Wistar’s early-stage research toward therapeutic potential.

The CAT will bring together the expertise of Wistar scientists in biology, chemistry, and artificial intelligence (AI) to pursue new foundational discoveries. Members of the CAT will work closely with the public and private sectors to accelerate translating those discoveries into new treatments and therapies.

Known as the “Valley of Death,” the gap between the foundational research that Wistar performs and real-world clinical applications can be a long, arduous, and costly journey. That CAT is designed to bridge that gap by connecting academics, industry, investors, and other collaborators to help expedite bringing those discoveries to fruition.

“The goal of the Center for Advanced Therapeutics will be to find our academic champions who do their basic research and collaborate with the expertise necessary to advance their discoveries into clinical implementation,” said Lieberman during the event. “Ultimately, the CAT will build a community of academic, industry, nonprofit, and government partners committed to advancing medical breakthroughs.”

The renovated 12,000 square foot space was made possible by an anonymous $30 million donation, a $1 million grant from the Pew Charitable Trusts, and a $2 million Redevelopment Assistance Capital Program (RACP) grant from the Commonwealth of Pennsylvania.

Pennsylvania State Representative Kerry Benningoff, founder and chairman of the bipartisan Cancer Caucus, spoke of his personal experience with cancer and emphasized the critical need for research as a path to curing cancer and other diseases. “In Pennsylvania alone, 600 children are diagnosed with cancer every year. That why this investment, and this research, is so important.”

Rick Horowitz, Chair of the Wistar Board of Trustees, echoed the value of foundational research. “Human life is precious, and the quest to improve the quality and length of life is a noble one,” he stressed. “Here at Wistar, rest assured, we’re going to continue to grow, thrive and advance the state of scientific knowledge.”

The event concluded with a ribbon cutting and tour of the new lab and administrative space, including a virtual reality (VR) demonstration that showcased structure-based design and visualized drug interactions.

View a photo gallery of the event here.

The Wistar Institute Launches Center for Advanced Therapeutics to Accelerate Scientific Innovation into Future Medicines

Written by dari on . Posted in Drug Discovery, Press Releases.

PRESS RELEASE
Cutting-edge research, technology & public-private collaboration elicits therapeutic potential

PHILADELPHIA — (Sept. 17, 2025) — The Wistar Institute announces the opening of its new Center for Advanced Therapeutics (CAT) to harness the power of Wistar science and speed creation of new drugs and therapies for human health. The CAT is led by Paul Lieberman, Ph.D., and capitalizes on a history of groundbreaking Wistar research in cancer, immunology and infectious disease.

“Despite the enormous progress of the last few years in combating cancer and other major diseases, there remains an urgent need for greater innovation, collaboration and public-private partnership to bring the next generation of molecular, personalized therapies to all,” said Dario Altieri, M.D., Wistar president and CEO, director of the Ellen and Ronald Caplan Cancer Center and Robert and Penny Fox Distinguished Professor. “This can only come from the type of rigorous, paradigm-shifting and transformational research that Wistar is known for worldwide, and this new Center, under Paul’s leadership, will function as a unique catalyst for multidisciplinary collaboration and freedom to discover, translating new insights of disease mechanisms into promising therapeutics.”

Spearheaded by Lieberman, a leading expert in the field of Epstein-Barr virus (EBV) research as well as other viruses that cause cancer, the vision of the Center is to identify new, early-stage biomedical research discoveries and support the genesis and trajectory of innovations as successful potential medicines.

“The goal is to create something new and impactful at Wistar,” said Lieberman, director of the Center for Advanced Therapeutics and Hilary Koprowski, M.D., Endowed Professor. “The Center brings together a multi-disciplinary team of chemists, biologists and development partners to identify new opportunities for therapeutic intervention through an accelerated pipeline of biology to chemistry to clinically relevant technologies that improve patient care and enhance human health. We need all these pieces to bridge the divide in the ’Valley of Death’ that is drug development.”

The Center for Advanced Therapeutics formalizes how Wistar advances drug discovery breakthroughs. The Center will leverage 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 perspectives, expertise and technology to reduce the burden of human disease.

The Center will create opportunities for Wistar investigators to identify innovative starting points and trajectories in the drug discovery process. Five additional principal investigators will be recruited to the new Center over the next two years. Computational chemists and biologists will help to accelerate the design of novel chemical structures and identify key biological targets to more effectively treat cancers and immune disorders.

The CAT will combine top current science, including the Wistar expertise of Joseph Salvino, Ph.D., medicinal chemist focused on discovery and development efforts to validate the “drugability” of small molecule targets; Troy Messick, Ph.D., a structural biologist advancing small molecule programs from preclinical research through clinical trials; Samantha Soldan, Ph.D., who leads preclinical multiple sclerosis research and will spearhead research expansion into autoimmune diseases; and Heather Steinman Ph.D., MBA., Wistar SVP of Business Development, who identifies potential collaborators and synergizes interactions with regional biotech, industry and pharmaceutical organizations.

The Center for Advanced Therapeutics aims to:
• bridge biology and chemistry expertise through recruitment of computational chemists to design chemical structures & use new chemistry innovations to advance Wistar technologies for the next stage of development;
• use artificial intelligence and machine learning to power new approaches for drug discovery and development;
• unite multidisciplinary industry collaborations to turn early-stage discoveries into future medicine; and
• expand the study of early-stage autoimmune diseases, an area that complements Wistar cancer biology and viral disease knowledge.

Wistar received a $30M gift from an anonymous donor – the largest in Institute history – to establish and build the Center for Advanced Therapeutics. The Pew Charitable Trusts awarded a $1 million grant to support Wistar’s appointment of Lieberman as director of the Center for Advanced Therapeutics as well as recruitment of new staff.

The CAT occupies 12,000 square feet of newly renovated space in The Wistar Institute’s signature campus at 3601 Spruce Street. This is the second major Wistar Center to open in 2025. The first was the HIV Cure and Viral Diseases Center at Wistar’s Market Street campus, with more than 25,000 square feet dedicated to laboratory and office space and the first expansion beyond the building’s original footprint in Wistar’s 130+year history.

For a printer-friendly version of this release, please click here.

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

Continue reading

Wistar Institute Scientists Identify New Strategy to Fight Cancer Caused by Epstein-Barr Virus

Written by The Wistar Institute on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (March 10, 2025) — The Wistar Institute’s Paul M. Lieberman, Ph.D. and lab identified and tested a new method for targeting certain cancers caused by Epstein-Barr Virus (EBV), in the paper, “USP7 inhibitors destabilize EBNA1 and suppress EBV tumorigenesis,” from Journal of Medical Virology.

“This work sheds valuable new light on how we can potentially treat cancer caused by EBV,” said Dr. Lieberman, the Ellen and Ronald Caplan Cancer Center’s Hilary Koprowski, M.D., Endowed Professor. “Our research shows that targeting USP7 effectively stops EBV-positive cell growth in preclinical models. Considering that several USP7 inhibitors not only exist but are also approved by the FDA, there is a clear path forward for further translational research that aims to get USP7 inhibitors ready for use in patients as part of a strategy to fight EBV-positive cancers.”

EBV is a herpesvirus that infects more than 90% of people throughout the world. Usually, people experience no symptoms from this virus, although one notable exception is mononucleosis, a disease with flu-like symptoms caused by EBV infection. Latent EBV infection has been shown to cause certain conditions like multiple sclerosis and cancers like gastric cancer and some lymphomas.

EBNA1 is one of the most important genes in EBV cancers. Present in every EBV-positive tumor, EBNA1 is critical to the virus’ ability to sustain prolonged, latent infection, and in EBV-positive cancers, the gene facilitates tumor growth.

By showing that USP7 inhibition is effective against EBV-positive cancers in preclinical testing, the Lieberman lab has paved the way for more research on this strategy for both EBV-positive cancers and beyond. Because USP7’s relationship with EBV is similar to its relationship with other herpesviruses that can cause cancers of their own, USP7 inhibition may have comparable efficacy against non-EBV herpesvirus cancers.

“Our work on USP7 inhibitors has exciting implications for disrupting the harmful effects of Epstein-Barr Virus,” said the paper’s first author, Christopher Chen. “We look forward to seeing how this research can be taken further with more investigation.”

Co-authors: Christopher Chen1, Kush Addepalli2, Samantha S. Soldan1, Leonardo Josue Castro- Munoz1, Sarah Preston-Alp1, Rishi J. Patel2, Coltin J. Albitz1, Hsin-Yao Tang1, Italo Tempera1, and Paul M. Lieberman1

1The Wistar Institute, Philadelphia, Pennsylvania 19104

2University of Pennsylvania, Philadelphia, Pennsylvania 19104

Work supported by: This work was supported by National Institutes of Health grants R01CA259171, P01 CA269043, R01 AI153508, P30CA010815, T32CA009171, R01 DE017336, R01 AI153508, R01 CA140652, R01 CA093606, R01 CA259171-02S1, R50 CA221838, and T32 CA009171.

Publication information: “USP7 inhibitors destabilize EBNA1 and suppress EBV tumorigenesis,” from Journal of Medical Virology.

For a printer-friendly version of this release, please click here.

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

Continue reading

Scientists at The Wistar Institute and Stanford University Report Encouraging Results on First-in-Human Clinical Trial for an Investigational Drug to Treat Epstein-Barr Virus Cancer

Written by dari on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (January 20, 2025) — In newly reported clinical trial results, The Wistar Institute and Stanford University have successfully tested an investigational drug for the treatment of Epstein-Barr Virus (EBV)-positive nasopharyngeal cancer (NPC) in humans. The drug VK-2019 was tested in a first-in-human clinical trial by a research team led by Wistar research associate professor Troy Messick, Ph.D., and Stanford professor of medicine A. Dimitrios Colevas, M.D. VK-2019 was discovered and developed at The Wistar Institute in the Lieberman lab.

Findings were published in the paper, “First-in-Human clinical trial of a small molecule EBNA1 inhibitor, VK-2019, in patients with Epstein-Barr positive nasopharyngeal cancer, with pharmacokinetic and pharmacodynamic studies,” in the journal Clinical Cancer Research, a journal of the American Association for Cancer Research.

“It is very encouraging that the drug is well-tolerated in patients with advanced cases of NPC,” said Dr. Messick. “Now that the safety of the drug has been tested, we are well prepared to advance VK-2019 to further testing, including in other cancers or diseases that are caused by EBV.”

In a cohort of 23 participants with cases of NPC that had exhausted all available treatment options, the clinical trial team administered oral doses of VK-2019 that increased from 60 to 1800 milligrams. Even at high doses, most patients tolerated the drug well with only minor side effects. Only one adverse event deemed attributable to VK-2019 was reported, which was successfully reversed.

Analysis of a limited number of patient biopsies before and during treatment with VK-2019 showed that levels of viral DNA could be reduced.  One patient showed an anti-tumor response, even at this early stage of clinical testing with the drug’s yet-to-be-optimized dosing schedule.

Armed with robust evidence that even high doses of VK-2019 are safe for cancer patients, the researchers plan to expand the number of participants in clinical trials to evaluate the drug’s clinical efficacy against cancer.

“The results of the trial indicate a robust safety profile for VK-2019 in NPC patients,” said Dr. Colevas. “Now knowing the drug’s safety, we should be able to conduct trials with larger numbers of participants to better understand and optimize its pharmacological properties to fight cancer.”

Working alongside Paul M. Lieberman, Ph.D., Wistar Hillary Koprowski, M.D., Endowed Professor, Dr. Messick co-invented the small-molecule VK-2019 for clinical testing. Dr. Paul Lieberman, an expert in EBV and its role in causing diseases, discovered EBNA1’s potential as a clinical target for treating EBV-associated conditions. Preclinical testing from the Lieberman lab has demonstrated that VK-2019 blocks the ability of the virus to replicate and thereby significantly inhibits the growth of tumors dependent on EBV.

More than 90% of people globally carry EBV. After an initial infection, EBV persists typically in a latent form without symptoms, but researchers have found that latent EBV infection can cause certain cancers, particularly nasopharyngeal cancer (NPC). NPC, in its more advanced stages, can often be fatal despite treatment.

Co-authors: A. Dimitrios Colevas1, Zahra Talebi2, Elizabeth Winters1, Caroline Even3, Victor Ho-Fun Lee4, Maura L. Gillison5, Saad A. Khan1, Rong Lu1, Benjamin A. Pinsky1, Samantha S. Soldan6, Olga Vladmirova6, Paul M. Lieberman6, and Troy E. Messick6

1 Stanford University

2 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University

3 Gustave Roussy Cancer Centre

4 The University of Hong Kong

5 University of Texas MD Anderson Cancer Center

6 The Wistar Institute

Work supported by: This research was funded by National Institutes of Health grants R01CA235633, R01CA259171, P30CA006973, UL1TR003098, S10OD020091, UL1TR003098, and P30CA124435. Cullinan Therapeutics, Inc. also provided funding support. Additional support was provided by The Steven R. Sommer Fund and The Hrebec Head & Neck Cancer Research Fund.

Clinical Trial information: The clinical trials are registered on clinicaltrials.gov under NCT04925544 and NCT03682055.

Publication information: “First-in-Human clinical trial of a small molecule EBNA1 inhibitor, VK-2019, in patients with Epstein-Barr positive nasopharyngeal cancer, with pharmacokinetic and pharmacodynamic studies,” from Clinical Cancer Research.

For a printer-friendly version of this release, please click here.

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

Continue reading

Mono, Multiple Sclerosis, and Cells That Live Forever: Wistar’s Dr. Paul Lieberman on Progress in EBV Research

Written by The Wistar Institute on . Posted in Featured News.

Paul M. Lieberman, Ph.D., is leader of the Genome Regulation and Cell Signaling Program at the Ellen and Ronald Caplan Cancer Center. He studies how certain viruses, such as Epstein-Barr virus, establish a long-term latent infection that can lead to cancer or autoimmune disorders.

Why did you choose to focus your research on EBV?

I became interested in EBV during my graduate student introduction to virology. Someone explained that this virus is very good at immortalizing cells, and I became intrigued by the concept of immortalization.

EBV is very good at immortalizing otherwise-mortal B lymphocytes, or B-cells, which are a type of white blood cell. If you take a person’s blood and put it in culture, those B-cells will die in a few days. But if you infect the B-cells with EBV, they can live forever. It’s basically what an oncogene can do to a cell — it can take a cell from being normal and short lived to growing forever. I wanted to know: What can make a cell live forever?

Your research works on understanding how cancer-associated viruses persist in a latent state and increase the risk of cancer and autoimmune disorders. What does it mean for a virus to persist in a latent state? Do all viruses do this?

The viruses we study, like EBV, are unique in how they establish a long-term latent infection in cells that will both be long-lived and also can divide. Most viruses do not do this. The majority of viruses, like SARS CoV 2 and flu, don’t stick around. But with all herpesviruses — and EBV is a herpesvirus — the virus finds a place to live in the body for the life of the host. Chickenpox is a good example. You get infected as a child, but the virus lingers in a long-lived neuron and then can reactivate much later and cause shingles.

The viruses we study persist in blood cells, in particular B lymphocytes. The lymphocytes have what are called memory cells, which can live for decades, and the virus finds a place to survive in those long-lived cells. EBV, like other herpesviruses, goes through periodic reactivations. In most healthy individuals, EBV reactivation is asymptomatic because other immune cells like T-cells and natural killer cells do a great job at getting rid of those virally infected cells. Unfortunately, the virus is very good at playing cat and mouse so that the immune system manages to eliminate most of the virus, but not all of it. Then, the virus waits until the immune system is compromised to reemerge or in some cases, cause cancer.

How did scientists connect EBV to multiple sclerosis? And is your lab working on anything regarding this connection?

EBV was originally identified as a “tumor virus” because it was discovered in tumor samples of a rare childhood lymphoma called Burkitt lymphoma that occurred in Central Africa. Sir Tony Epstein, who recently passed away, was responsible for that discovery.

EBV’s ability to immortalize and induce tumors associated with a number of lymphomas has been fairly easy to prove because you can isolate the cancer cells and show that the virus is in those cancer cells. However, the plot thickened when scientists found that EBV also causes mono and many people who are infected with EBV never get cancer.

EBV is now suspected to be associated with autoimmune disease — multiple sclerosis (MS) being one of those. In 2022, Alberto Ascherio, an epidemiologist at Harvard, published a longitudinal study in Science that looked at 10 million blood samples of EBV-positive and EBV-negative individuals over 20 years and found that EBV infection preceded symptoms of MS. Thanks to his work, most scientists are convinced that EBV infection along with complications of mono create something like a 32-fold increase in risk of developing MS. That’s very significant — more than smoking cigarettes increases risk of getting cancer.

The trouble is that, unlike with EBV-infected tumors, sometimes we can find the virus in a patient with MS, but in a lot of cases we can’t. One hypothesis my lab is pursuing is that very few cells are infected with EBV, but it’s enough to cause sufficient inflammation to trigger the disease. However, right now, it’s difficult to definitively show exactly where EBV is in autoimmune disease and what it’s doing. This research is important because it will determine what the best therapeutic will be.

You’re also leading an NCI-funded team of scientists to explore the role of EBV in epithelial cancers. Why study epithelial cancers?

We understand a lot about how EBV infects lymphocytes, but EBV causes on the order of about 150,000 cases of epithelial cancer — meaning nasopharyngeal carcinomas and stomach cancer — every year. And we have very little understanding of why that happens, what the virus is doing in those cancers, or the best ways to treat EBV in that context.

For this program we built a multidisciplinary team that is well-situated to invent new small-molecule drugs and identify the right combination of drugs to treat EBV-epithelial cancers. EBV-infected cancer has allowed us to be very precise because we can target the virus. With this sort of precision medicine, you can reduce a lot of the off-target side effects and resistance issues that you see with other treatments like some of the more severe chemotherapeutics.

What excites you most about where EBV research is headed?

I think we are in the chase for a cure. This opportunity to target EBV across a number of different diseases is what keeps me wanting to get back to work, day after day. If we can eliminate the virus or eliminate the activity of the virus, we can cure a lot of disease.

To support the research of viruses like EBV, donate to Wistar’s Giving Tuesday campaign.

Donate

The Wistar Institute and University of Pennsylvania Scientists Identify Potential Target Gene within Certain HIV Reservoir Cells

Written by dari on . Posted in Press Releases.

PRESS RELEASE
Drs. Lieberman, Collman, and Co-Authors Link RSAD2/Viperin Gene with Certain
Chronically HIV-Infected Cells

PHILADELPHIA — (Oct. 3, 2024) —New findings could lead to different research tactics for scientists investigating a cure for HIV. Results from The Wistar Institute’s Lieberman lab, led by Hilary Koprowski, M.D., Endowed Professor Paul M. Lieberman, Ph.D., and researchers at the Perelman School of Medicine’s Center for AIDS Research and center director Ronald G. Collman, M.D. — have identified the RSAD2/Viperin gene as a potential HIV treatment target within certain HIV reservoir cells. Their results were published in the paper, “HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages,” in the Journal of Virology.

HIV does not have a cure because there is no known method — yet — for eliminating the virus from the body once infected. Although HIV can be managed with antiretroviral therapy (ART), the virus persists in infected cells throughout the body, called “HIV reservoirs.” Reservoirs not only serve as the main barrier in HIV cure research, which focuses in large part on strategies to destroy these HIV reservoirs, but also contribute to chronic inflammation and comorbidities in people living with HIV.

A certain type of immune cell — myeloid cells, including macrophages and microglia — often serves as an HIV reservoir because, unlike other cells infected with HIV, these cells tend not to be killed by HIV’s viral replication. Due to their comparative longevity as reservoirs and prevalence within the nervous system, HIV-infected macrophages often cause neurocognitive complications in people with HIV that develop even despite antiretroviral treatment (ART).

Lieberman and Collman, joined forces to research the genetics of macrophages that might play a role in maintaining the HIV reservoir status quo. Their investigation revealed a surprising candidate in the gene RSAD2/Viperin — which usually fights viruses. In HIV-infected macrophages, RSAD2/Viperin expression was quite high compared both with controls and HIV-infected CD4+ T cells (the other major type of cell that can become a viral reservoir of HIV).

RSAD2/Viperin is a gene associated with interferon response, and typically, both the gene itself and the interferons that trigger its activation have antiviral effects. However, certain interferons have been found to play paradoxical roles in chronic HIV by enabling the virus’ persistence, and upon finding RSAD2/Viperin’s elevated expression in reservoir macrophages, the researchers hypothesized that the gene must be abetting HIV’s continued presence within these cells.

To test this, the research team used the siRNA method to target and reduce RSAD2/Viperin’s expression in macrophages infected with HIV. Once they reduced the gene’s expression, several measures of HIV’s presence and activity fell, including viral transcripts, p24 protein production, and multinucleated giant cells (another indicator of active viral activity). Reduced RSAD2/Viperin also altered histone modification of HIV genomes — that is, the control of HIV’s latency by chromatin and epigenetic factors. These findings suggest a novel role for RSAD2/Viperin in regulating chromatin that otherwise might suppress HIV replication during latency.

“Looking closely at RSAD2/Viperin in these HIV-infected MDMs, we’ve identified yet another paradox of HIV infection,” said Lieberman, program leader, Genome Regulation and Cell Signaling Program, Ellen and Ronald Caplan Cancer. “Our data show that while, yes, this is an antiviral gene that can come to the body’s defense against the virus at first, it also seems to maintain HIV’s ability to persist as a chronic infection. That makes RSAD2/Viperin a compelling candidate for further research and possible targeting of HIV reservoirs — which is critical to future cure research.”

“We’ve come to understand yet another facet of chronic HIV infection’s complexity,” agreed Collman. “We’re hopeful that these findings will be helpful as the field continues to pursue possible therapeutic interventions that would eliminate the viral reservoir in the search for an HIV cure, or reduce negative consequences of infection that can persist even despite effective therapy, such as neurocognitive decline.”

Co-authors: Urvi Zankharia, Fang Lu, Olga Vladimirova, Bhanu Chandra Karisetty, Jayamanna Wikramasinghe, Andrew Kossenkov, and Paul M. Lieberman of The Wistar Institute; and Yanjie Yi and Ronald G. Collman of The Perelman School of Medicine at The University of Pennsylvania.

Work supported by: NIH grants R6133-133696, P30AI045008, and P30CA010815.

Publication information: “HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages,” from Journal of Virology.

For a printer-friendly version of this release, please click here.

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

ABOUT PENN MEDICINE:

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

The Perelman School of Medicine is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.

The University of Pennsylvania Health System’s patient care facilities stretch from the Susquehanna River in Pennsylvania to the New Jersey shore. These include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Penn Medicine Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff

Continue reading

Breaking Down the Science: Wistar’s New Genome Regulation and Cell Signaling Program in the Ellen and Ronald Caplan Cancer Center

Written by The Wistar Institute on . Posted in Featured News.

Upon the launch of The Wistar Institute’s new Genome Regulation and Cell Signaling Program, we sat down with the Program’s leader — Hilary Koprowski, M.D., Endowed Professor Paul M. Lieberman, Ph.D. — and co-leader, professor Bin Tian, Ph.D., to learn more about their vision for the Program and what it means for the future of cancer research at Wistar.

Tell us about the importance and excitement in this new Caplan Cancer Center Program.

PL: Wistar has been at the forefront of cancer research and discovery for decades. Recent advances in genomic technology and computational biology have inspired us to establish the new Genome Regulation and Cell Signaling (GRCS) Program. This new Program brings together a team of investigators to solve complicated problems underlying cancer causation, including persistent viral infection, immune response to cancer, and cell signaling changes in cancer.

The GRCS Program combines multi-disciplinary expertise to solve these complicated problems from many different angles: from specialists in genome architecture and integrity like Drs. Tempera, Gardini, and Sarma, who focus on the physical structure of our genome, which has very critical ramifications for genetic diseases & cancers; to investigators interested in virus’ infection and cancer causation, like myself, Dr. Tempera, and Dr. Price; to researchers of inflammatory signals in cancer cells and metastasis with Drs. Chen and Altieri; to specialists in computational and informatic techniques like Drs. Madzo, Kossenkov, and Srivastava, who are essential for effective analysis and interpretation of the vast datasets our Program generates.

How does the combination of genome regulation and cell signaling synergize in this new Program?

BT: We want to better understand cancer, so we study how genes are regulated or dysregulated at the genomic level; cell signaling provides the biological context for understanding how genome regulation plays out in response to internal & external cues. Because of recent technological advances, gene regulation can now be studied across the entire genome — not just individual genes or small groups of genes with similar functions, but all the genes throughout the genome. The synergy between genome regulation and cell signaling is holistic.

PL: Genome regulation does not occur in a vacuum. Metabolic and environmental changes trigger signaling between cells, which, in turn, affect how the genome is regulated. How the genome responds to these types of signals is central to the problems in cancer biology and part of the new focus areas of the GCSR Program.

Why is genomics so critical to cancer research?

BT: All aspects of a cancer cell’s growth — from tumor formation, to tumor survival, to interactions with other cells in the tumor microenvironment — involve rewiring of our cells’ gene expression programs. And that is a fundamentally genome-based process — whether it is a physical change of some genome sequences; alternation of how the genome is structured in 3-dimentional space; transcription of DNA into RNA; or post-transcriptional regulations.

PL: Cancer is a disease of the genome: tumors start when the genome is changed in ways that give cancer a foot in the door. Genomics and informatics analyses allow us to understand the specific genetic changes — which, in cancer, are more like genetic injuries — that drive a particular individual’s cancer. Ideally, once you understand the underlying genetic nature of an individual cancer, you can design precision medicines targeted more accurately to a specific disease diagnosis.

What advances has sequencing technology unlocked in this area of cancer research?

BT: In essence, cancer is a genetic disease. And advanced sequencing technologies have enabled us to examine the genome with the resolution of a single nucleotide — the fundamental building block of DNA. Sequencing technologies have evolved to a point where we can even use these tools to understand the dynamics of genome regulation within individual cells or tiny regions in the body. Essentially, we see cancer’s real-time changes far more clearly, which is key to understanding and combatting the disease.

PL: Advances in genomics and sequencing technologies allow us to understand cancer as a personal disease. Each tumor is different, but we can use precision sequencing as a springboard for researching precision medicine. Armed with the latest advances like next-generation and ultra-high-throughput sequencing — methods that allow scientists to accurately assess entire genomic samples and in minute detail — the new Program’s scientists have the tools they need to move the field even further.

In state-of-the-science Wistar labs, our researchers can easily sample an entire genomic state with tools to improve and expand into new areas of application and translation. Our Program members combine these advances with technologies like CRISPR to identify, target, modify, and correct the genetic aberrations that drive cancer and other genetic diseases.

How do cancer researchers deal with the complexity of the different variables at play in cancer? And how will your Program’s approach account for that interconnectivity?

PL: Due to the complexity of biological systems — and cancer being among the most complicated biological problem because of the rapid, chaotic evolution of tumors and their surroundings — it’s quite unlikely that any single person or brain will solve this challenge. New artificial intelligence applications are welcome tools for investigators; by leveraging AI, we can sort through the massive amounts of biological information and identify potential vulnerabilities within cancer’s framework.

We do work in a reductionist mindset — where the entire complex network of information is reduced to one simple example — to identify new targets and pharmacological agents that can impact the whole system. While that might seem at odds with cancer’s enormous complexity, we still need to simplify the complex science of cancer. It’s a give and take: we zoom in to find a specific mechanism at play in cancer, and then we zoom out to see whether targeting that mechanism can work its way through the vast, interconnected complexity of the disease system to produce a therapeutic effect. We cut through the jungle one molecule at a time.

What is your plan for translating your Program’s discoveries into testable therapy strategies?

BT: We have several promising thematic areas for therapeutic intervention, including the emerging area of gene therapies, as well as continued progress in small molecules as drug candidates. So as we make progress on potential therapeutics, we seek to take full advantage of several technologies and investigate how they work together — similar to the multi-pronged approaches the HIV folks are using for disease containment and cure.

We believe in basic science, which pays off in the long run: any discovery and innovation moves the needle in cancer research and future therapeutics.

Five years from now, what do you hope to have achieved through the Program?

BT: We hope to achieve breakthroughs in both basic science research and cancer therapeutics; we can reach these goals because the GCRS Program has faculty with expertise in many cutting-edge and interdisciplinary technologies and is highly collaborative.

PL: The GRCS program has two main goals: advance our knowledge and understanding of the complex mechanisms of genome regulation and cell signaling in cancer; and second, identify new therapeutic targets and strategies to treat cancer and other complex diseases.

We anticipate publications in high-impact journals to highlight breakthroughs in genome regulation and cell signaling, and we also expect to see some of our findings advanced into new therapeutics — small molecules, gene therapies, and vaccines to treat cancer and other diseases — that will reach clinical trials thanks to our continued collaboration between the public and private sectors.

These are broad and ambitious goals, but they are achievable. With an excellent diversity of scientific expertise and supported by the most advanced technologies available from Wistar’s Shared Resources facilities, the GCRS Program is positioned to find answers to some of the most pressing questions in cancer biology.