Tag: Lieberman

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.

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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.

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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.

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PHILADELPHIA — (May 28, 2024) — The Wistar Institute’s Paul M. Lieberman, Ph.D., and lab team led by senior staff scientist and first author, Samantha Soldan, Ph.D., have demonstrated how B cells infected with the Epstein-Barr virus (EBV) can contribute to a pathogenic, inflammatory phenotype that contributes to multiple sclerosis (MS); the group has also shown how these problematic B cells can be selectively targeted in a way that reduces the damaging autoimmune response of multiple sclerosis. The lab’s findings were published in Nature Microbiology in the paper, “Multiple sclerosis patient derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease.”

EBV — a usually inactive, or latent, herpesvirus — affects most of the human population; more than 90% of people carry the virus as a passive, typically symptomless infection. However, EBV infection has been linked to several diseases, including MS: an incurable, chronic autoimmune disease that causes the body’s immune system to attack the myelin sheath of neurons in the brain and nervous system. Because myelin sheathing facilitates fast nervous system signaling (the fatty insulation of myelin along a neuron’s axon allows electrical impulses to travel through neuronal networks faster), its degradation can cause a wide variety of symptoms in both type and severity that may include motor control disruption, sensory issues, and speech difficulties.

Though researchers know that EBV can contribute to the development of MS, the exact mechanisms by which it does so aren’t completely understood. The Lieberman lab, in seeking to understand how EBV contributes to the development of MS, collaborated with Steven Jacobson, Ph.D., of the Neuroimmunology Branch at the National Institute of Neurological Disorders and Stroke, who contributed cell line samples from patients. The research team analyzed spontaneous lymphoblastoid cell line (SLCL) cell samples from a healthy control group; a group of patients with active MS (as opposed to so-called stable MS; the disease is characterized by unpredictable periods of flare-ups and eased symptoms); and a group of patients with stable MS.

B cells are crucial cells of the immune system that help regulate the body’s immune responses; they have also been implicated in autoimmune conditions due to their role as mediators of which biological signals warrant immune response. And B cells, when infected with EBV, become immortalized — that is, the cells are no longer constrained by senescence, so they can continue to divide an indefinite number of times — as “lymphoblastoid cell lines,” or LCLs. This immortalized B cell state can occur spontaneously within the body as a result of EBV infection, which is how the Lieberman lab was able to extract immortalized SLCL samples for study from the different patient groups.

Having obtained the matched samples, Dr. Lieberman and his team conducted genetic analyses of the SLCLs and confirmed that the MS-positive sample groups showed greater expression of genes associated with lytic EBV (“lytic” describes when latent viruses like EBV become active); they also saw increased inflammatory signaling and expression of the FOXP1 protein, the latter of which was shown to promote lytic EBV gene expression. As a whole, the group’s findings suggested a mechanism of lytic EBV in MS that promoted inflammation and disease.

Diving further, Lieberman’s group tested several antiviral compounds on all SLCL groups and found that one, TAF, reduced lytic EBV gene expression without killing the cells. TAF also significantly reduced the expression of inflammatory cytokines like IL-6 in the SLCLs from the patients with active MS. Finally, when cultured SLCLs from active MS, stable MS, and controls were administered TAF in the presence of antiviral T cells, the T cell response (a major factor in the autoimmune dysfunction of MS) was reduced in SLCLs from patients with MS but not reduced in the control SLCLs — an indication that TAF treatment has potential as a selectively cytotoxic anti-lytic treatment for MS.

“Our work with these SLCLs shows that the problematic inflammation signaling from lytic EBV can be selectively targeted in a way that demonstrably reduces damaging immune responses,” said Dr. Lieberman. “We’re excited about expanding this concept further; we have the potential to see whether TAF or other inhibitors of EBV might be a viable treatment for multiple sclerosis that can stop the autoimmune damage without causing wide-ranging and dangerous cell death.”

Co-authors: Samantha S. Soldan, Chenhe Su, Leena Yoon, Toshitha Kannan, Urvi Zankharia, Rishi J. Patel, Jayaraju Dheekollu, Olga Vladimirova, Jack Dowling, Natalie Brown, Andrew Kossenkov, Daniel E. Schäffer, Noam Auslander, and Paul M. Lieberman of The Wistar Institute; Maria Chiara Monaco and Steven Jacobson of the Neuroimmunology Branch at the National Institute of Neurological Disorders and Stroke; Jack Dowling and Simon Thebault of the Perelman School of Medicine; Annaliese Clauze, Frances Andrada, and Joan Ohayon of the Neuroimmunology Clinic at the National Institute of Neurological Disorders and Stroke; and Andries Feder and Paul J. Planet of the Children’s Hospital of Philadelphia.

Work supported by: This work was supported by grants from the National Institutes of Health (R01 CA093606, R01 AI153508, R01DE017336 to PML, the Wistar Cancer Center Core Grant P30 CA010815), and the Department of Defense (HT9425-23-1-1049 Log#MS220073). The funders had no role in study design; data collection and analysis; decision to publish; or preparation of the manuscript.

Publication information: “Multiple sclerosis patient derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease,” from Nature Microbiology

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