Author: The Wistar Institute

PHILADELPHIA — (Oct. 3, 2019) — A novel anticancer molecule created by researchers at The Wistar Institute showed therapeutic activity in preclinical models of various cancer types. This cell-permeable peptidomimetic was designed to disrupt a newly identified protein complex involving mitochondrial fission factor (MFF) and the voltage-dependent anion channel-1 (VDAC1), which regulates mitochondrial cell death. These results appeared online in the journal Cancer Research.

In a recently published study, the laboratory of Dario C. Altieri, M.D., Wistar president and CEO, director of the Institute’s Cancer Center and the Robert & Penny Fox Distinguished Professor, showed that MFF is highly expressed in cancer and interacts with VDAC1, a key regulator of mitochondrial cell death, to keep tumor cells alive.

“Disruption of the MFF-VDAC1 complex in vitro resulted in killing of cancer cells, pointing us in the direction of a potential therapeutic target,” said Altieri, who is the senior author on the study. “The next step was to create a molecule that could disrupt the protein-protein interaction between MFF and VDAC1 and deliver preclinical anticancer activity without harming normal cells, and we are excited for the clinical potential of this new agent.”

Altieri and collaborators analyzed the structure of the MFF-VDAC1 interface to determine what portions of the MFF protein are required for its interaction with VDAC1. A synthetic peptide designed to contain these MFF regions was able to compete with MFF for binding to VDAC1, disrupting the interaction. As a result, this induced acute mitochondrial dysfunction and consequently cell death.

Treatment with the MFF peptide killed prostate cancer and melanoma cells, including drug-resistant cells, while it did not affect the survival of normal prostate cells and fibroblasts, suggesting that transformed cells are more dependent on the integrity of the MFF-VDAC1 complex than normal cells.

Based on these proof-of-concept studies, researchers then generated a cell-permeable peptidomimetic molecule, or a compound that mimics the inhibitory peptide, to target the complex in vivo for targeted cancer therapy.

This compound was tested in different preclinical settings, both in vitro in 3-D models, using patient-derived lung and breast cancer organoids and glioblastoma neurospheres; and in vivo, using mouse models of prostate cancer cell transplants and patient-derived melanoma transplants (known as PDX models). In all conditions, the peptidomimetic molecule effectively delivered potent anticancer activity. Treatment was well tolerated in mice, with no overt signs of toxicity.

“Targeting protein-protein interaction in mitochondria is a validated therapeutic strategy that has already produced clinically approved cancer treatments,” said Altieri. “We are hopeful that this compound will be translated into a novel anticancer therapy with potential to be effective in multiple cancer types and less prone to drug resistance.”

Co-authors: Jae Ho Seo (first author), Young Chan Chae (co-corresponding author), Andrew V. Kossenkov, Hsin-Yao Tang, Ekta Agarwal, Dmitry I. Gabrilovich, David W. Speicher, Prashanth K. Shastrula,Vito Rebecca, Meenhard Herlyn, Min Xiao, Dylan Fingerman, Alessandra Martorella, and Emmanuel Skordalakes from Wistar; Yu Geon Lee from Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea; Lucia R. Languino from Thomas Jefferson University; Alessandra Maria Storaci, Stefano Ferrero and Valentina Vaira from Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy, and University of Milan, Italy; Gabriella Gaudioso, Manuela Caroli, Davide Tosi, and Massimo Giroda from Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico.

Work supported by: National Institutes of Health (NIH) grants P01 CA140043, R35 CA220446, R50 CA221838 and R50 CA211199 and grants from Fondazione Cariplo, the Italian Minister of Health and the National Research Foundation of Korea. Additional support was provided by the Ulsan National Institute of Science and Technology (UNIST), Korea, and the University of Milan, Italy. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: MFF regulation of mitochondrial cell death is a therapeutic target in cancer, Cancer Research (2019). Online publication.

###

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’s Business Development team is dedicated to accelerating the translation of Wistar discoveries into innovative medicines and healthcare solutions through licensing, start-ups and creative collaborations. wistar.org.

PHILADELPHIA — (October 1, 2019) — The National Institutes of Health (NIH) today announced that Zachary T. Schug, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program at The Wistar Institute, was awarded the prestigious NIH Director’s New Innovator Award in support of his research on the link between a high sugar/fat diet, alcohol use and cancer.

Obesity and heavy drinking are on the rise in the U.S. and represent two of the most significant risk factors for cancer. This grant, totaling $2,679,000 given over five years, will advance Schug’s research on the molecular mechanisms underlying this connection.

NIH Director’s Awards for High-Risk, High-Reward Research are given to exceptionally creative scientists and were launched to support innovative approaches to major challenges in biomedical and behavioral research that call for high-risk, high-impact proposals.

“Each year, I look forward to seeing the creative approaches these researchers take to solve tough problems in biomedical and behavioral research,” said NIH Director Francis S. Collins, M.D., Ph.D. “I am confident the 2019 cohort of awardees has the potential to advance our mission of enhancing health through their groundbreaking studies.”

The New Innovator Award is focused on funding dynamic and talented early career investigators who are within 10 years of their final degree.

“Zachary’s research has the ambitious goal of unraveling the diet-induced metabolic and epigenetic changes that underlie tumor growth and progression, and may have important clinical implications,” said Dario C. Altieri, M.D., Wistar’s president and CEO, director of the Wistar Cancer Center and the Robert and Penny Fox Distinguished Professor. “Because of its high impact, this work embodies the type of research the NIH plans to support with this award.”

Both alcohol and high-fructose-containing foods cause production of high amounts of a chemical called acetate, which is used by cancer cells to fuel growth and progression. Acetate is critical for numerous metabolic functions including energy production and lipid synthesis and represents a key intracellular signaling molecule used for modification of protein function and modulation of gene expression.

Schug seeks to elucidate how diet and alcohol consumption influence acetate metabolism and, as a consequence, how they impact gene expression in cancer. He will additionally study the contributing role played by the bacteria that reside in the gut, also known as the microbiota, which are the major producers of acetate in the body. The information gained through this study may provide the basis for novel therapies and will deepen our understanding of the links between alcohol use, obesity and cancer.

The High-Risk, High-Reward Research Program is part of the NIH Common Fund that supports high-risk, unconventional endeavors with the potential for extraordinary impact on high-priority emerging scientific questions. In 2019, NIH Director’s Awards provided approximately $263 million to be given over five years.

Grant information: Director’s New Innovator Award 1DP2CA249950-01, The multifaceted role of acetate in cancer.

###

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.

PHILADELPHIA – September 25, 2019 – The Wistar Institute, a global leader in cancer, immunology and infectious disease research, has selected Integral Molecular, Inc. as the first industry partner for its Biomedical Research Technician (BRT) Apprenticeship. This industry-academia relationship continues Integral Molecular’s dedication to community partnership, economic development, and job creation in the city of Philadelphia.

Wistar’s BRT Apprenticeship, the first-ever registered, nontraditional apprenticeship program for biomedical research ratified by the Pennsylvania Department of Labor & Industry, offers a career pathway to fill in-demand jobs within Philadelphia’s fast-growing biotechnology industry. It is an extension of Wistar’s Biomedical Technician Training (BTT) Program, which has helped students from the Community College of Philadelphia gain valuable hands-on laboratory experience and jobs in the life sciences for the past 20 years.

Participants in Wistar’s BRT Apprenticeship gain critical skills to facilitate experimental procedures, manage a laboratory, conduct data analysis on experiments, and learn other valuable laboratory techniques.

“For the past two years, Wistar’s BRT Apprenticeship has fostered the next generation of biomedical researchers in Philadelphia by creating a career pathway,” said William Wunner, Ph.D., director of Academic Affairs and director of Outreach Education and Technology Training at Wistar. “With its focus on cutting-edge antibody technologies, Integral Molecular is the ideal setting for our students to acquire marketable skills in the biotechnology industry.”

Integral Molecular has been a strong supporter of Wistar’s BTT Program over the years, providing training sites for students to gain real-world experience in a laboratory setting.

Wistar’s non-traditional BRT Apprenticeship is supported by Philadelphia Works, Inc., the city’s Workforce Development Board, under the governance of the Pennsylvania Department of Labor & Industry. Learn more: wistar.org/education-training

About Integral Molecular
Integral Molecular is the industry leader in membrane protein antibody discovery, with a pipeline of therapeutic antibodies against GPCRs, ion channels, transporters, and immuno-oncology targets. Built on the company’s extensive experience optimizing membrane proteins, this platform enables the isolation, characterization, and engineering of MAbs against otherwise intractable targets. Integral Molecular discovers antibodies for partners in parallel with independent work developing antibodies for licensing. The company currently has therapeutic programs focused on cancer, pain, immunity, and metabolic disorders.

About The Wistar Institute
The Wistar Institute is an international leader in biomedical research with special expertise in cancer and 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.

For More Information, Please Contact:
Integral Molecular, Inc.
Benjamin Doranz
President & CEO
215-966-6061
info@integralmolecular.com

The Wistar Institute
Darien Sutton
Media Relations and Communications Manager
215-898-3988
dsutton@wistar.org

PHILADELPHIA — (September 24, 2019) — The Wistar Institute was awarded two major grants totaling more than $12 million from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health, to fund an international multidisciplinary clinical research consortium spearheaded by Wistar’s HIV Research Program. The consortium, including several partner institutions in the U.S. and abroad, will investigate the impact of opioid use disorder (OUD) and medications for opioid use disorder (MOUDs) on immune recovery in response to antiretroviral therapy (ART) in HIV-infected people.

“We have uncovered a potential link between substance abuse, HIV infection and MOUDs that may determine health outcomes only if the right medication is chosen,” said study leader Luis J. Montaner, D.V.M., D.Phil., the Herbert Kean, M.D., Family Professor and director of the HIV-1 Immunopathogenesis Laboratory at Wistar’s Vaccine & Immunotherapy Center.

Both HIV infection and chronic opioid exposure are associated with immune activation, which leads to T-cell depletion and progression to acquired immunodeficiency syndrome (AIDS).
OUD is commonly treated with drugs that either activate (agonists) or block (antagonists) the opioid receptor. “Yet, we have a very limited understanding of how the medications we use to treat OUD impact disease progression and the response to ART in people living with HIV,” commented Montaner.

The overarching goal of this research is to investigate the role of opioid receptor involvement in modulating the levels of immune activation, and the effects of different classes of MOUDs, in people living with HIV. Effectively controlling immune activation after ART in persons taking MOUDS can directly impact health and mortality.

The NIDA support of this initiative will fund two clinical studies:

• The first grant provides $8,373,891 over five years for an international trial conducted among the U.S., Vietnam and France, in collaboration with the Vietnam Ministry of Health, the Perelman School of Medicine at the University of Pennsylvania, the Institute of Applied Medicine and Epidemiology (a French-led initiative to expand access to HIV/hepatitis prevention and treatment services), and the Pasteur Institute.

The goal of this three-arm randomized trial, conducted in Vietnam and co-led by Montaner and David Metzger, Ph.D., a research professor and director of the HIV Prevention Research Division at the Perelman School of Medicine at the University of Pennsylvania, is to evaluate the impact of long-term opioid receptor stimulation or blockage with MOUDs on immune reconstitution in HIV-infected people who inject drugs and are initiating ART. Early preliminary data suggest that chronic opioid receptor engagement by an opioid receptor agonist while on ART may result in increased immune activation and inflammation associated with increased levels of persistent HIV, when compared to a full opioid receptor antagonist. To verify this hypothesis, the study will assess recovery outcomes and adherence to therapy 48 weeks after initiation of ART in 225 participants with OUD who receive either methadone (opioid receptor agonist), extended-release naltrexone (antagonist) or buprenorphine (partial agonist).

• A second, complementary grant will provide $3,889,138 over five years for mechanistic studies on local persons living with HIV on ART and taking MOUDs. Collaborators on this research are the Perelman School of Medicine at the University of Pennsylvania, Jonathan Lax Treatment Center, and the Icahn School of Medicine at Mount Sinai. The study will assess the preliminary observation that greater myeloid activation and HIV persistence are present in people receiving opioid receptor agonists when compared to people treated with opioid receptor antagonist naltrexone.

Blood and tissue samples from individuals living with HIV who are receiving ART and treatment with different MOUDs will be used to study the mechanisms that regulate persistent immune activation and residual HIV expression.

“We expect the results of this major collaborative effort, which has its hub in Philadelphia, to have broad clinical implications in informing the best pharmacologic strategy for the management of opioid use disease in HIV-infected people starting ART,” said Montaner. “This is directly relevant in light of the opioid epidemic ongoing in our nation and will help ensure that the right medications are used for both HIV and OUD, with the ultimate objective of saving lives in the future.”

###

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.

PHILADELPHIA — (Sept. 18, 2019) — Researchers at The Wistar Institute have described the role of mitochondrial fission factor (MFF) in controlling survival of cancer cells, suggesting the protein could represent a promising therapeutic target. They also found that expression of MFF is regulated by Myc, a ubiquitous mediator of cell proliferation that contributes to development of many cancer types. These results were published online in the journal EBioMedicine.

Mitochondria, the organelles that supply energy to our cells, also control multiple cell death mechanisms and play an intricate role in cancer, which is a field of intense research. In particular, mitochondrial dynamics, a process that orchestrates the size, shape and position of mitochondria within the cell, has been implicated in tumor progression, but, until now, the mechanisms have only been partially elucidated.

“We know that reprogramming of mitochondrial functions is important for cancer development and metastasis,” said senior author on the study Dario C. Altieri, M.D., Wistar president and CEO and director of the Institute’s Cancer Center and the Robert & Penny Fox Distinguished Professor. “Our findings uncover new players and pathways in this process, opening concrete therapeutic opportunities to selectively eliminate tumor cells in patients.”

Altieri’s lab and an international team of collaborators showed that the MFF gene is amplified in prostate cancer patients, correlating with disease relapse and reduced survival. They also observed elevated expression of the MFF protein in a mouse model of prostate cancer and in tissue samples from patients with other cancer types, including lung cancer and multiple myeloma, compared to normal tissues.

Importantly, researchers implicated the Myc oncoprotein, which is commonly amplified in various cancer types and controls mitochondrial reprogramming during tumor progression, as a key driver of MFF expression.

Altieri and colleagues showed that, in cancer, MFF interacts with VDAC1, a mitochondrial regulator of cell death, shutting down its function to keep tumor cells alive. The researchers found that disruption of the MFF-VDAC1 complex activated multiple mechanisms of mitochondrial cell death, inhibiting tumor cell proliferation and reducing tumor growth in a preclinical model.

“In our setting, MFF targeting delivered preclinical anticancer activity,” said Ekta Agarwal, Ph.D., a postdoctoral fellow in the Altieri laboratory and co-first author on the study. “Our data indicate that disruption of the MFF-VDAC1 complex may represent a novel therapeutic strategy that could potentially be effective in a broad array of cancers.”

Co-authors: Jae Ho Seo (co-first author), and Young Chan Chae from Wistar; Yu Geon Lee from Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea; David S. Garlick from Histo-Scientific Research Laboratories, Mount Jackson, VA; Alessandra Maria Storaci, Stefano Ferrero, Umberto Gianelli, and Valentina Vaira from Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy, and University of Milan, Italy; and Gabriella Gaudioso from Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico.

Work supported by: National Institutes of Health (NIH) grants P01 CA140043 and R35 CA220446 and grants from Fondazione Cariplo, the Italian Minister of Health and the National Research Foundation of Korea. Additional support was provided by the Ulsan National Institute of Science and Technology (UNIST), Korea, and the University of Milan, Italy. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer, EBioMedicine (2019). Online publication.

###

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.