Author: The Wistar Institute

The Bacteria Whisperer: Bacterial Chatter and Antibiotic Resistance

Written by The Wistar Institute on February 5, 2021. Posted in Featured News.

Antibiotic-resistant bacteria keep Dr. Bonnie Bassler up at night. The Princeton molecular biologist who made groundbreaking discoveries demonstrating that bacteria communicate and orchestrate group behaviors has dedicated her life to unraveling how these tiny, primitive beings exert so much power in the world.

“Microbes are what kill most people on earth,” Bassler said. “Yet the world does not appreciate how vulnerable we are to pathogenic microbes.”

She considers COVID-19 a wakeup-call. We need to study microbes and make arsenals of therapeutics to fight infectious diseases. “The mindset that it’s passé to be working on antibiotics needs to change,” she added.

Bacteria can talk to each other and are capable of collective behaviors

Bassler’s work changes the way we think about bacteria and has opened up new avenues to fight them. We’ve known about the existence of bacteria for 500 years, but scientists thought of them as asocial, single cells. Thanks to Bassler’s research, we now know that bacteria can talk—distinguish self from other and act in groups—behaving like multicellular organisms that collectively assess the surrounding world and manage tasks in unison.

That’s how pathogenic bacteria make us sick and how beneficial bacteria make higher organism life possible.

The human body is inhabited by trillions of bacteria. There are 10 times more bacterial cells than human cells in and on us and, as a consequence, 100 times more bacterial genes than we have human genes. “Our own genomes do not have the capacity to do some of the things bacteria do,” Bassler noted. In essence, these 24/7 partners of ours sort of make us who we are.

How do they do that?

They use a chemical language to communicate and monitor the environment for the presence of other cells, of similar and different species, and they even count how many cells there are in the neighborhood to determine when their population density reaches a critical mass — hence the definition of quorum sensing. Through quorum sensing, it becomes beneficial to enact group behaviors by turning on specific genes in synchrony.

Bassler’s team identified the chemical “words” in the bacterial language and discovered how these molecules mediate bacterial communication to control bacterial behavior. Bassler’s group discovered that each bacterial species has its own chemical language, that is, a private, secret language that only they understand. Bacteria also make another universal molecule that allows cross-species communication, a bacterial Esperanto, as Bassler called it.

Using quorum sensing to make antibiotics

As it turns out, the incredible phenomenon that Bassler described in elegant detail is not restricted to the obscure marine bacteria in which it was first described, but it’s the norm in the bacterial world. One group behavior frequently controlled through quorum sensing is virulence — the collective release of toxins that make the host sick — and another is the ability of bacteria to grow on surfaces and build slimy communities called biofilms, which protect cells from antibiotics and the host immune response.

Based on these discoveries, Bassler and other scientists asked themselves whether they could tinker with quorum sensing to disarm pathogenic bacteria or potentiate the action of beneficial bacteria that populate our microbiome.

“Anti- and pro-quorum sensing strategies already exist in the natural world and have been tried and tested over evolutionary time,” she added. “We can use the strategies bacterial already evolved as inspiration for our studies, bringing them into the lab to refine them.”

Hope for the future

What gives Bassler hope is that scientists are resilient, creative and can come up with new strategies to fight against microbes. Just like how scientists have created vaccines in only a year for the virus that causes COVID-19.

Wistar scientists are doing their part researching innovative antibiotic strategies that attack bacteria on different fronts and harness the power of the host immune system to avoid resistance.

Hopefully, these approaches will give us antibiotics 2.0 to defeat the superbugs that have become resistant to traditional antibiotics and are now threatening global health.

Dr. Bassler gave a fascinating presentation on her research on quorum sensing during a virtual Women & Science event accepting Wistar’s Helen Dean King Award. Watch the video below.

Latest Wistar Discoveries

Written by The Wistar Institute on January 25, 2021. Posted in Featured News.

Despite dramatic progress in cancer therapy, long-term survival is hindered when cancer returns. Tumor cells that escape initial treatment can travel to distant sites in the body and remain hidden there silently for years. If these “dormant” cells reawaken, they divide and give rise to new tumors, often very difficult to treat.

A new study published in Science Translational Medicine by former Wistar professor Dmitry Gabrilovich, Ph.D., and Michela Perego, Ph.D., a research assistant professor in The Wistar Institute Cancer Center, reveals that stress is one factor involved in reawakening dormant cells. They found that stress hormones can activate neutrophils, a type of immune cells, to produce certain special lipids that are in turn responsible for the reawakening dormant tumor cells. Accordingly, they observed higher levels of stress hormones and markers of neutrophil activation in the blood of cancer patients who experience early recurrence compared to patients that have late or no recurrence.

These findings suggest that stress hormone levels should be monitored in patients recovering from cancer and that keeping those hormones at bay would be beneficial to prolong remission.

Highly proliferating cancer cells within a tumor often experience severe oxygen and nutrient deprivation. To satisfy their large demands for energy generation and synthesis of molecules, cancer cells evolve to survive and continue growing using whatever nutrient sources available. Acetate is an important one.

The laboratory of Zachary T. Schug, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program, characterized an inhibitor that targets acetate metabolism in cancer cells by blocking the function of the ACSS2 enzyme, which converts acetate into an essential metabolite used by cancer cells to generate energy.

This molecule inhibits tumor growth and causes regression in preclinical studies, demonstrating its promise as a novel therapeutic strategy for solid tumors. Study results were published in Cancer Research.

Up to 60% of ovarian clear cell carcinomas (OCCC) — the type of ovarian cancer that carries the worst prognosis — have mutations that inactivate the ARID1A tumor suppressor gene.

The laboratory of Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, professor and leader of the Immunology, Microenvironment & Metastasis Program, discovered that mutations that inactivate ARID1A increase utilization of the glutamine amino acid, making cancer cells dependent on glutamine metabolism.

In the study, published in Nature Cancer, the team also showed that pharmacologic inhibition of glutamine metabolism may represent an effective therapeutic strategy for ARID1A-mutant ovarian cancer. The inhibitor significantly reduces tumor burden and prolongs survival in OCCC mouse models and mice carrying patient-derived tumor transplants and could become a new strategy to precisely target a specific vulnerability of OCCC cells.

Preclinical models are critical for cancer research. “Humanized” mouse models — mice with a transplanted human immune system — are used to study human-specific characteristics of the tumor microenvironment and the antitumor immune response, and to predict response to therapy.

A team led by Rajasekharan Somasundaram, Ph.D., a member of The Wistar Institute Melanoma Research Center, and Meenhard Herlyn, D.V.M., D.Sc., professor in the Cancer Center and director of The Wistar Institute Melanoma Research Center, engineered an advanced humanized mouse model to produce combinations of human cytokines that result in a more physiologically relevant model system.

Thanks to this model, they examined resistance to immunotherapy in melanoma and revealed a central role for mast cells, which are immune cells that serve as a first line of defense against pathogens.
Researchers also showed that the use of inhibitors able to deplete mast cells can be beneficial to immune checkpoint therapy responses. These finding were published in the journal Nature Communications.

Macrophages are specialized immune cells that eliminate foreign substances, cellular debris and cancer cells. As part of their function to protect the body against pathogens, macrophages play a major role in initiation, maintenance, and resolution of inflammation. Through multiple steps they mature from progenitor cells in the bone marrow and require the concerted action of critical transcription factors that regulate expression of specific genes.

Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program, and his lab discovered that Early Growth Response 1 (EGR1), a protein that turns on and off specific genes during blood cell development, inhibits expression of pro-inflammatory genes in macrophages, blunting their activation and the immune response.

This discovery, published in Science Advances, expands the understanding of how macrophages are activated and deactivated in the inflammatory process, which is critical in many normal and pathological conditions.

Epstein-Barr Virus (EBV) establishes lifelong, latent infection in B lymphocytes, which can contribute to development of different cancer types, including Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC) and Hodgkin’s lymphoma.

The Epstein-Barr Nuclear Antigen 1 (EBNA1) protein serves as an attractive therapeutic target for these cancers because it is expressed in all EBV-associated tumors, performs essential activities for tumorigenesis and there are no similar proteins in the human body.

The laboratory of Paul M. Lieberman, Ph.D., Hilary Koprowski, M.D., Endowed Professor, leader of the Gene Expression & Regulation Program, discovered an enzymatic activity of EBNA1 that was never described before, despite the intense research efforts to characterize this protein.

They found that this EBNA1 function mediates the terminal stage of viral DNA replication.

Published in Cell, this study provides new indications for inhibiting EBNA1 function, opening up fresh avenues for development of therapies to treat EBV-associated cancers.

Immuno-antibiotics: A New Frontier in the Fight Against Antimicrobial Resistance

Written by The Wistar Institute on January 25, 2021. Posted in Featured News.

Have you ever taken antibiotics for a sore throat and ended the treatment as soon as the symptoms disappeared and without finishing the course of medicine? This is a common mistake many of us have made and just one example of the many antibiotic misuses and over-uses that have led to the development and spread of antimicrobial resistance (AMR), one of the greatest threats to human health of our time. And one of the most under-reported.

Almost a century after the discovery of penicillin, an estimated 700,000 people die each year due to antibiotic-resistant infections such as tuberculosis and malaria, a number that could reach 10 million by 2050.

Because of the widespread use of antibiotics in agriculture and intensive farming to promote growth and prevent disease, more resistant bacteria are transferred to people and escape into the environment.

Without effective antibiotics, routine medical procedures could become risky, common bacterial diseases that used to be easily treatable are turning into serious threats, and others we considered long gone are coming back from the past.

Just imagine life in the pre-antibiotic era where a simple infection from a cut could kill you.

Not to mention the economic burden to patients and the health care system. In 2006, hospital-acquired sepsis and pneumonia cost the U.S. health care system more than $8 billion. If the AMR crisis is not solved by 2050, the estimated cost to the global economy will run into $100 trillion.

In the last two decades, only a few new antibiotics have been approved for clinical use and resistant bacteria have already emerged against these new drugs. The number of new molecules in the pipeline has been on the rise since 2014, but to stop resistant bacteria in their tracks we need creative, out-of-the-box solutions that are less likely to be circumvented.

The lab of Dr. Farokh Dotiwala at The Wistar Institute Vaccine & Immunotherapy Center recently reported a landmark discovery that could lead to the development of a new class of antibiotics, built on the idea that if we attack bacteria on multiple fronts, they are less likely to find a way out and become resistant.

Nature, one of the highest impact scientific journals, published the study and then highlighted it with a commentary in Nature News & Views, a scientific forum that discusses influential and broad-interest studies, as a highly promising proof of concept for an innovative strategy for tackling the emergence of drug resistance.

World Health Organization leaders “tweeted” about the importance of immuno-antibiotics to their more than million followers.

Dotiwala and his team reasoned that vaccines are much less likely to give rise to resistance because they work by enlisting the body’s immune response rather than just directly killing the pathogens (like traditional antibiotics do). So, they researched an antibacterial strategy that could also harness an immune response.

The new compounds, named immuno-antibiotics, kill bacteria by blocking a metabolic pathway that is essential for them to grow and survive. Though at the same time, these drugs potently activate a subset of T cells involved in immune responses to a wide variety of viral and bacterial infections, adding a second line of attack.

When tested on patient-derived, drug-resistant bacteria and in preclinical models of infection, immuno-antibiotics outperformed the current best-in-class antibiotics.

Creating a synergy between the direct killing of antibiotics and the natural power of the immune system, immuno-antibiotics have the potential to represent a milestone in the fight against AMR.

In Severe COVID-19, What Happens in the Gut Doesn’t Stay in the Gut

Written by The Wistar Institute on January 25, 2021. Posted in Featured News.

Shortly after the pandemic began, when doctors and scientists knew little to nothing about the novel coronavirus that has been sweeping across the globe for almost a year now, one thing became clear quickly: people who get severely ill or die of COVID-19 experience generalized inflammation and extensive damage to their lungs and often to other vital organs, sometimes leading to multi-organ failure.

Fast forward a few months. The amount of knowledge has grown exponentially and scientists are now unraveling the factors that determine whether SARS-CoV-2 infection will be mild, or even asymptomatic, or cause severe illness and possibly become fatal.

The Wistar lab of Dr. Mohamed Abdel-Mohsen is one of the first to investigate the link between SARS-CoV-2 infection, inflammation and gut integrity, based on previous knowledge from other respiratory conditions.

Dr. Abdel-Mohsen and team are dissecting the so-called “gut-lung” axis, whereby a disruption of the normal crosstalk between gut microbiota and the lungs contributes to the severity of respiratory diseases.

We tend to think of the lungs and the gut as two unrelated, distant organs. It takes some effort to understand their interaction and the influence microorganisms that colonize the intestine can have on the lungs.

Let’s break it down. Conditions that damage the intestinal wall and cause it to become abnormally permeable allow gut-resident microbes and their products to translocate into the blood stream and reach the lungs. This has a pro-inflammatory effect on the whole body — and the lungs in particular. Other lung-associated diseases, including asthma and acute respiratory distress syndrome, are known to disrupt gut integrity and cause a similar translocation of inflammatory molecules.

Now, Wistar scientists are testing this hypothesis, as it might be the case in COVID-19 as well. A vicious cycle may become established whereby SARS-CoV-2 infection in the lungs causes a generalized inflammation that results in breakdown of the gut barrier, which causes microbial translocation that in turns hastens inflammation and lung injury.

The fact that SARS-CoV-2 can also infect intestinal cells and directly damage the gut structure and barrier strengthens the scientists’ case.

To test this hypothesis, the Abdel-Mohsen lab is studying blood samples from COVID-19 patients with varying degrees of disease severity and from age-matched healthy individuals and comparing the levels of several biologically active molecules to detect any meaningful shifts.

One type of microbial products that escape from the gut into the blood stream are special enzymes that microbes use to break down the intestinal mucus layer as a source of nutrients. While these enzymes are not harmful in the gut, once in the blood they can alter the sugar molecules present on circulating proteins and antibodies, resulting in enhanced inflammation. These enzymes are among the molecules Dr. Abdel-Mohsen and team are focusing on in their studies.

By shedding light on the link between gut barrier breakdown and COVID-19 pathogenesis, this research might help identify biomarkers for risk of severe disease and pave the way towards new strategies to prevent or reduce the severity of COVID-19.

Dr. Abdel-Mohsen thinks the information acquired through work will be useful to understand some of the health issues experienced by COVID-19 ‘long haulers’. COVID-19 symptoms can persist for months after infection has been cleared and may cause long-term health complications. The team’s preliminary data suggest that the disrupted gut barrier and gut dysfunction observed during severe COVID-19 may persist after recovery from acute disease and play a role in prolonged symptoms.

This research is made possible by urgent funding provided by the National Institutes of Health in response to the COVID-19 crisis.

Wistar Scientists Make Pivotal Discovery on the Mechanism of Epstein-Barr Virus Latent Infection

Written by The Wistar Institute on January 21, 2021. Posted in Press Releases.

PHILADELPHIA — (Jan. 21, 2021) — Researchers at The Wistar Institute have discovered a new enzymatic function of the Epstein-Barr Virus (EBV) protein EBNA1, a critical factor in EBV’s ability to transform human cells and cause cancer. Published in Cell, this study provides new indications for inhibiting EBNA1 function, opening up fresh avenues for development of therapies to treat EBV-associated cancers.

EBV establishes life-long, latent infection in B lymphocytes, which can contribute to development of different cancer types, including Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC) and Hodgkin’s lymphoma.

The Epstein-Barr Nuclear Antigen 1 (EBNA1) serves as an attractive therapeutic target for these cancers because it is expressed in all EBV-associated tumors, performs essential activities for tumorigenesis and there are no similar proteins in the human body.

“We discovered an enzymatic activity of EBNA1 that was never described before, despite the intense research efforts to characterize this protein,” said Paul M. Lieberman, Ph.D., Hilary Koprowski, M.D., Endowed Professor, leader of the Gene Expression & Regulation Program at Wistar, and corresponding author of the study. “We found that EBNA1 has the cryptic ability to cross-link and nick a single strand of DNA at the terminal stage of DNA replication. This may have important implications for other viral and cellular DNA binding proteins that have similar cryptic enzyme-like activities.”

Lieberman and colleagues also found that one specific EBNA1 amino acid called Y518 is essential for this process to occur and, consequently, for viral DNA persistence in the infected cells.

They created a mutant EBNA1 protein in which the critical amino acid was substituted with another and showed that this mutant could not form covalent binding with DNA and perform the endonuclease activity responsible for generating single strand cuts.

In latently infected cells, the EBV genome is maintained as a circular DNA molecule, or episome, that is replicated by cellular enzymes along with the cell’s chromosomes. When the cell divides, the two episomal genomes segregate into the two daughter cells.

While it was known that EBNA1 mediates replication and partitioning of the episome during division of the host cell, the exact mechanism was not clear. The new study sheds light on the process and describes how the newly discovered enzymatic activity of EBNA1 is required to complete replication of the viral genome and maintenance of the episomal form.

“Our findings suggest that one could create small molecules to ‘trap’ the protein bound to DNA and potentially block replication termination and episome maintenance, similar to known inhibitors of topoisomerases,” said Jayaraju Dheekollu, Ph.D., first author on the study and staff scientist in the Lieberman Lab. “Such inhibitors may be used to inhibit EBV-induced transformation and treat EBV-associated malignancies.”

Co-authors: Andreas Wiedmer, Kasirajan Ayyanathan, Julianna S. Deakyne, and Troy E. Messick from The Wistar Institute. K.A. is currently employed at University of Pennsylvania and J.S.D. is currently employed at GlaxoSmithKline.

Work supported by: National Institutes of Health (NIH) grants RO1 CA093606, RO1 423 DE017336, P30 CA010815, and T32 CA09171.

Publication information: Cell Cycle-Dependent EBNA1-DNA Cross-Linking Promotes Replication Termination at oriP and Viral Episome Maintenance, Cell (2021). Online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Dr. Alessandro Gardini, flanked by two lab members

New Insights Into the Control of Inflammation

Written by The Wistar Institute on January 13, 2021. Posted in Press Releases.

PHILADELPHIA — (Jan. 13, 2021) — Scientists at The Wistar Institute discovered that Early Growth Response 1 (EGR1), a protein that turns on and off specific genes during blood cell development, inhibits expression of pro-inflammatory genes in macrophages. As part of their function to protect the body against pathogens, macrophages play a major role in initiation, maintenance, and resolution of inflammation. The discovery expands the understanding of how macrophages are set off and deactivated in the inflammatory process, which is critical in many normal and pathological conditions. These findings were published online in the journal Science Advances.

“By deepening the understanding of the role of EGR1, we shed light on the fundamental process of macrophage maturation, which is required for many aspects of the immune response including inflammation,” said Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program at The Wistar Institute and senior author on the study. “Our data suggest EGR1 acts as a master regulator of inflammation in macrophages.”

Macrophages are specialized immune cells that eliminate foreign substances, cellular debris and cancer cells. Their multi-step maturation from progenitor cells in the bone marrow requires the concerted action of critical transcription factors that regulate expression of specific genes. EGR1 is one of these factors but its function remained elusive.

In response to tissue damage and infection, white blood cells of the immune system called monocytes can leave the bloodstream and infiltrate tissues, where they undergo an elaborate developmental program and mature into macrophages. Macrophages have the ability to “eat” pathogens, promote inflammation and elicit pathogen-specific immune responses.

The molecular mechanisms underlying this maturation process are not well defined. The same set of transcription factors acting in early monocyte development were thought to be involved in the conversion of monocytes to macrophages.

Gardini and colleagues used a model to recreate differentiation of monocytes to macrophages in vitro and performed a systematic genomic analysis of the role of EGR1 in this process. They found that EGR1 binds to different DNA regulatory regions in late-differentiating macrophages as opposed to progenitor cells differentiating into monocytes.

The lab previously uncovered a mechanism whereby EGR1 regulates gene expression in monocytes and macrophages by interacting with enhancers. These are short regulatory DNA sequences that, when bound by specific transcription factors, augment the expression of the associated genes.

In the new study, researchers found that EGR1 represses inflammatory enhancers in developing and mature macrophages, blunting their activation and the immune response.

“Our results suggest that the role of EGR1 in modulating inflammation may extend beyond development of blood cells and be relevant to the control of inflammation in health and disease conditions,” said Avery Zucco, Ph.D., a postdoctoral researcher in the Gardini lab and co-first author of the study.

Co-authors: Marco Trizzino (co-first author), Sandra Deliard, Fang Wang, Elisa Barbieri, Filippo
Veglia, and Dmitry Gabrilovich from Wistar.

Work supported by: National Institutes of Health (NIH) grants R01 HL141326 and T32 CA009171; grants from the American Cancer Society (RSG-18-157-01-DMC) and The G. Harold and Leila Y. Mathers Foundation. Support for The Wistar Institute facilities was provided by Cancer Center Support Grant P30 CA010815.

Publication information: EGR1 is a gatekeeper of inflammatory enhancers in human macrophages, Science Advances (2021). Online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Wistar Researchers Develop New Humanized Mouse Model That Provides Insight Into Immunotherapy Resistance

Written by The Wistar Institute on January 12, 2021. Posted in Press Releases.

PHILADELPHIA — (Jan. 12, 2021) — Scientists at The Wistar Institute have created an advanced humanized immune system mouse model that allows them to examine resistance to immune checkpoint blockade therapies in melanoma. It has revealed a central role for mast cells. These findings were published today in the journal Nature Communications.

Checkpoint inhibitors revolutionized therapeutic options for advanced melanoma. However, only a fraction of patients respond to this treatment and some relapse due to reemergence of therapy-resistant lesions.

“To better understand why some cancers do not respond or become resistant to checkpoint therapies, we need more preclinical models that mimic the human tumor immune environment,” said Rajasekharan Somasundaram, Ph.D., a member of The Wistar Institute Melanoma Research Center, who is the first and corresponding author of the paper.

Due to critical differences in the murine and human immune systems, mouse models do not allow the study of immune mechanisms that are uniquely human. “Humanized” mouse models are widely used to mimic the human immune system in mice.

Wistar’s new humanized mouse model relies upon transplanted human stem cells and tissues that have been uniquely engineered to produce combinations of human cytokines that result in a more physiologically relevant model system for evaluating new immuno-oncology therapies and effective treatments targeting the tumor microenvironment.

“Our novel humanized mouse model has a longer life span and allowed us to study treatment responses to immunotherapies after human tumor transplant,” said Somasundaram, who was part of a Wistar team led by Meenhard Herlyn, D.V.M., D.Sc., professor in The Wistar Institute Cancer Center, director of The Wistar Institute Melanoma Research Center, and a co-senior author on the study.

Researchers transplanted human metastatic melanoma cell lines into their humanized mouse model and treated them with anti-PD-1 antibody therapy. By studying immune cell infiltration into the tumors, Somasundaram and colleagues observed an abundance of infiltrated mast cells in anti-PD-1-treated tumors. Mast cells are an immune cell found throughout the body, especially in the skin and mucosa, where they serve as a first line of defense against pathogens. In samples from melanoma patients receiving immune checkpoint therapies, the team saw the same higher abundance of mast cells in non-responding tumors.

The authors showed that combining anti-PD-1 therapy with small molecule inhibitors able to deplete mast cells caused complete regression of tumors in mice and prolonged survival in comparison with mice receiving either treatment. Importantly, mice that reached remission did not show any signs of recurrence for four weeks after cessation of therapy and developed memory T cell response against melanoma tumors.

“Our results suggest that mast cells are associated with resistance to anti-PD-1 therapy, and that depleting mast cells is beneficial to immune checkpoint therapy responses,” said Herlyn. “This warrants further investigation into the development of new combined immunotherapy approaches with small molecule inhibitors for the treatment of melanoma patients.”

Co-authors: Thomas Connelly, Robin Choi, Hyeree Choi, Anastasia Samarkina, Ling Li, Elizabeth Gregorio, Yeqing Chen, Mohamed Abdel-Mohsen, Marilda Beqiri, Meaghan Kiernan, Michela Perego, Fang Wang, Min Xiao, Denitsa Hristova, Joshua Wang, Mizuho Fukunaga-Kalabis, Clemens Krepler, Fang Ping-Chen, Xiang Y. Zhou, Alexis Gutierrez, Frederick Keeney, James Hayden, Brian J. Gavin, David Weiner, Luis J. Montaner, Qin Liu, and Dmitry Gabrilovich (now at AstraZeneca) from Wistar; Rohit Thakur, Elizabeth M Burton, Michael A. Davies, Michael T. Tetzlaff, and Jennifer A. Wargo from MD Anderson Cancer Center, Houston, Texas; Xiaowei Xu, Alex Huang, Anthony Secreto, Gwenn Danet-Desnoyers, Daniel Traum, Klaus H. Kaestner, and Alex Huang from University of Pennsylvania; Johannes Griss from Medical University of Vienna, Vienna, Austria; Lukas Peiffer and Jürgen Becker from University of Duisburg-Essen, Essen, Germany.

Work supported by: National Institutes of Health (NIH) grants P50 CA174523 and U54 CA224070; Department of Defense Peer Reviewed Cancer Research Program grants WX1XWH-16-1-0119 (CA150619), W81XWH-16-1-0120 and W81XWH-16-1-0121; Additional support was provided by the University of Texas MD Anderson Cancer Center Melanoma Moon shot Program and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Support for The Wistar Institute facilities was provided by Cancer Center Support Grant P30 CA010815.

Publication information: “Tumor-infiltrating mast cells are associated with therapy resistance to anti-PD-1”, Nature Communications (2020). Online publication.

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Wistar Scientists Target an Alternative Fuel Source of Cancer Cells as a Therapeutic Approach for Breast Cancer

Written by The Wistar Institute on January 7, 2021. Posted in Press Releases.

PHILADELPHIA — (Jan. 7, 2021) — Scientists at The Wistar Institute characterized an inhibitor that targets acetate metabolism in cancer cells. Cancer cells use acetate metabolism to support tumor growth in conditions of low nutrient and oxygen availability. This molecule caused tumor growth inhibition and regression in preclinical studies, demonstrating the promise of this approach as a novel therapeutic strategy for solid tumors. Study results were published today in Cancer Research, a journal of the American Association for Cancer Research.

Highly proliferating cancer cells within a tumor often experience severe oxygen and nutrient deprivation. Over time, to satisfy their large metabolic demands for energy generation and synthesis of macromolecules, cancer cells adapt and evolve to survive and continue growing using different nutrient sources. The changes that accompany this metabolic rewiring represent a critical barrier to cancer treatment.

The laboratory of Zachary T. Schug, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program at The Wistar Institute Cancer Center, studies the metabolic changes that arise during tumor progression to identify targets that can be exploited for new effective cancer treatments.

In particular, they focus on the role of acetate metabolism. They and others have identified acetate as an important alternative nutrient source for cancer cells and discovered that the ACSS2 enzyme, which converts acetate into acetyl-CoA, is crucial for tumor growth under nutrient stress conditions. Acetyl-CoA is an essential metabolite used by cancer cells for many fundamental cellular processes and to generate energy.

“We wanted to verify whether pharmacological inhibition of ACSS2 could prevent tumor growth and offer a significant therapeutic opportunity for cancers that rely on acetate for fuel,” said Schug, who is the lead author of the study.

In a collaboration with Joseph Salvino, Ph.D., professor in The Wistar Institute Cancer Center and a medicinal chemistry expert, Schug and colleagues synthesized and tested an inhibitor of the ACSS2 enzyme and showed that this molecule, called VY-3-135, is potent and highly specific in blocking the function of ACSS2 in breast cancer cell lines. Importantly, VY-3-135 treatment was able to inhibit acetate metabolism in tumors in vivo and caused marked inhibition of tumor growth in preclinical breast cancer models with high ACSS2 levels.

“Multiple studies have now shown that ACSS2 is essential in a wide variety of cancers, suggesting that acetate metabolism plays a near universal role in cancer and supports the promise of ACSS2 inhibitors for cancer treatment,” said Katelyn D. Miller, Ph.D., postdoctoral fellow in the Schug lab and first author of the study.

“We look forward to furthering our studies and creating safe, potent ACSS2 inhibitors for translation into the clinic,” added Schug.

Co-authors: Katherine Pniewski, Caroline E. Perry, Sara Papp, Joshua D. Shaffer, Jessica C. Casciano, Tomas M. Aramburu, Yellamelli V.V. Srikanth, Joel Cassel, Emmanuel Skordalakes, Andrew V. Kossenkov, and Joseph M. Salvino from Wistar; Jesse N.Velasco-Silva from University of Utah.

Work supported by: National Institutes of Health grants NIH Director’s New Innovator Award DP2 CA249950-01 and T32 CA009171; grants from the W.W. Smith Charitable Trust, Susan G. Komen®, and the V Foundation for Cancer Research. Support for The Wistar Institute facilities was provided by Cancer Center Support Grant P30 CA010815. The Wistar Proteomic and Metabolomic Facility is supported in part by NIH grants R50 CA221838 24 and S10 OD023586.

Publication information: Targeting of ACSS2 with a transition state mimetic inhibits triple negative breast cancer growth, Cancer Research (2021). Online publication.

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Coronavirus COVID-19 SARS-CoV-2 Concept Image.

DARPA and JPEO-CBRND Award $37.6M to The Wistar Institute and Collaborators at INOVIO, AstraZeneca, Penn, & Indiana University to Develop Innovative COVID-19 Treatment

Written by The Wistar Institute on December 15, 2020. Posted in Press Releases.

PHILADELPHIA — (Dec. 15, 2020) — A team of scientists from The Wistar Institute, INOVIO, AstraZeneca, the Perelman School of Medicine at the University of Pennsylvania, and Indiana University has received a $37.6 million award over two years from the Defense Advanced Research Projects Agency (DARPA) and the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) for rapid preclinical development and translational studies of DNA-encoded monoclonal antibodies (DMAbs) as countermeasures for COVID-19.

DMAbs, unlike conventional therapeutic antibodies, are administered as genetic blueprints that instruct the patient’s body to build its own highly specific antibodies against pathogens, such as bacteria and viruses, and as immunotherapeutics for cancer. Conceptually DMAbs have advantages over traditional monoclonal antibodies in scale-up and delivery, which would rapidly benefit large populations.

Worldwide, more than 72 million people are infected with SARS-CoV-2 and more than 1.6 million have died. The U.S. outbreak alone has resulted in the hospitalization of over 110,000 people. Sixteen million Americans have been infected, and more than 300,000 have died of COVID-19 since the outbreak began.*

Wistar scientists and their collaborators pioneered the development of DMAb technology as a unique asset to combat the COVID-19 pandemic. In addition to their high specificity for the target, DMAbs have important advantages of rapid manufacturing, low cost of production, and temperature-stable storage and distribution.

The concept of synthetic DMAb technology was originated in the laboratory of David B. Weiner, Ph.D., Wistar executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research. The technology involves the design and delivery of genetic sequences that encode monoclonal antibodies into an optimized DNA platform. This genetic blueprint is then administered to a person so that their own body becomes the production site of highly specific antibodies which, in the case of SARS-CoV-2, target essential parts of the virus. In animal studies, DMAbs have been applied to prevent infection as well as to treat infection.

“We are thrilled that DARPA and JPEO-CBRND have chosen Wistar to assemble this exceptional team to focus on advancing potential DMAb countermeasures for the SARS-CoV-2 crisis,” said Weiner. “Our team combines many different strengths to advance this approach from the bench to the bedside at lightening speed. We have a strong track record of working together to advance DNA-based solutions into the clinic and look forward to advancing these first-in-human studies as a possible risk mitigation approach for COVID-19.”

This paradigm-shifting award supports a unique public-private collaboration, which includes world-class capabilities in synthetic DNA therapeutics and monoclonal antibody technology. Together, with the support of exceptional clinical and translational teams and a global pharmaceutical company, this multidisciplinary approach is uniquely suited to address the unprecedented global health crisis brought about by COVID-19.

The program goal will be to rapidly design, enhance and scale SARS-CoV-2-specific DMAbs, and move them into laboratory and animal model studies. If successful, this will provide the foundation for rigorous, first-in-human clinical trials.

“This partnership broadens the scope and application of our DNA medicines platform across the spectrum of needed COVID-19 treatment modalities and opens the door for faster, more cost effective, and scalable production of monoclonal antibody products for other infectious diseases, cancers and other unmet medical needs,” said J. Joseph Kim, Ph.D., president and CEO of INOVIO. “Working with our partners, we are excited about the potential this offers both for situations requiring immediate clinical response and benefit.”

Mark Esser, VP and Head of Microbial Sciences, AstraZeneca, said, “We are excited to combine capabilities with Wistar and this world-class team to evaluate the potential of these DNA-delivered antibodies to impact the way we can respond to prevent and treat infection.”

“This COVID-19 pandemic presents a unique and immediate challenge to the world, one in which DNA treatments have the potential to move us to a future where COVID-19 is much more manageable,” said Pablo Tebas, M.D., a professor of Infectious Diseases at the Perelman School of Medicine at the University of Pennsylvania. “We are eager to build upon previous DMAb research and put it to the test against COVID-19.”

“We are very excited and honored to be part of this extraordinary team,” said Jesper Pallesen, Ph.D., assistant professor of molecular and cellular biochemistry at Indiana University. “The promise of DMAb technology is huge, and its implementation into our global anti-COVID-19 efforts will leave a resonating and lasting footprint. We are delighted to bring structural biology expertise to the team and to provide atomic-detail evaluation of DMAb technology efficacy mechanisms.”

Wistar, INOVIO, and the University of Pennsylvania with the Department of Defense and the Coalition for Epidemic Preparedness Innovations (CEPI) are in late-stage studies of a synthetic DNA vaccine for COVID-19. Through the collaboration with JPEO-CBRND, this work is supported by the Office of the Assistant Secretary of Defense for Health Affairs with funding from the Defense Health Agency.

Grant information: Synthetic DNA-encoded monoclonal antibodies (DMAbs) targeting COVID-19, 2020-2022.

*Data from the Johns Hopkins Coronavirus Research Center and The COVID Tracking Project at The Atlantic.

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The Wistar Institute is an international leader in biomedical research with special cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

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Dr. Chi Van Dang Ranks in the 2020 Highly Cited Researchers List

Written by The Wistar Institute on November 24, 2020. Posted in Featured News.

Dr. Dang, a world-renowned scientist, medical oncologist, National Academy of Medicine member, and professor in Wistar’s Molecular and Cellular Oncogenesis Program, was selected for the 2020 Highly Cited Researchers list compiled by Clarivate Analytics.

This list includes influential researchers who published multiple highly cited papers that ranked in the top 1% by citation in their field in the year they were published, based on data compiled by the Web of Science global citation database.

Highly cited publications reflect significant peer recognition and identify an author’s considerable, broad influence in one or multiple fields. Being highly cited in the top 1% identifies scientists who have conducted truly pioneering research that opened up new avenues or guided the work of others in the same field.

Dr. Dang, who has appeared in the Highly Cited Researchers list for three years in a row, conducts seminal research focused on cancer cell metabolism that led to the discovery of the central role of the MYC cancer gene.

Ongoing Dang lab interests include the effects of cellular stress on the circadian molecular clock that oversees the body’s natural 24-hour rhythms, the effects of MYC on immunity and exploring the metabolic vulnerabilities of cancer cells to find new ways to treat cancer.