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Wistar Scientists Identify Connection Between Nervous System and Aggressive Prostate Cancer

Written by dari on . Posted in Press Releases, Prostate Cancer.

PRESS RELEASE

PHILADELPHIA — (Sept. 24, 2026) — A new study from The Wistar Institute has found a link between the nervous system and the rapid development of neuroendocrine prostate cancer (NEPC), an aggressive form of the disease. Published in Oncogene, the study found high levels of neuromedin U (NMU), a kind of neurotransmitter, present in prostate cells at the very early phase of NEPC formation, which support tumor progression by blocking the immune response. These findings could present a target for therapy for what is now a virtually untreatable disease.

“We already know that the immune system and cancers communicate with each other, which has led to transformative therapies for cancers that had once been thought of as untreatable,” said Dario C. Altieri, M.D., president & CEO, director of the Ellen and Ronald Caplan Cancer Center and Robert and Penny Fox Distinguished Professor at The Wistar Institute, and senior author on the study. “This study reveals that cancer is also communicating with the nervous system, potentially opening the door to new therapies for cancers that currently lack effective therapeutic options.”

Prostate cancer is typically survivable, with a 98 percent survival rate five years after diagnosis according to the American Cancer Society. But NEPC is a specific type of prostate cancer that is considered immunologically “cold,” meaning it does not respond to currently available treatments, including newer classes of immunotherapy drugs.

NEPC is different because it doesn’t have any T cells, which is one way that our immune system responds to cancer. T cells can also be trained by immunotherapy to more aggressively attack tumor cells.

“But immunotherapy only works if you have immune cells within the tumor,” said Michela Perego, Ph.D., research assistant professor in the Altieri lab and first author of the study. “With NEPC, you can’t target T cells because there are no T cells. We wanted to understand why.”

In a murine model, researchers looked at activity in tissue cells before cancer developed and found an excessive amount of NMU. This neurotransmitter usually does not play a pathological role in the human body, and is a key part of critical functions like regulating blood pressure, stress response and keeping hormones in check. But in NEPC, an overabundance of NMUs effectively block T cell migration to the prostate by activating neutrophils that suppress T cells: NMU-activated neutrophils work for the cancer before the cancer really forms by suppressing T cells that would normally lead the charge to mount an immune response.

Researchers were able to change NPEC in a simulated microenvironment to target NMU for destruction.

“By blocking the communication between the destructive NMUs working for NPEC, we were able to disarm them, and allow the T cells back in,” said Perego. “It reinforced anti-tumor immune response and restored sensitivity to immunotherapy.”

Disrupting this pathway to stop the overproduction of NMU in NEPC could open new avenues for treatment, she added.

“They could turn cold tumors hot, and when used together, make these tumors new targets for immunotherapy and present a new way to approach cancer that has proven nearly impossible to stop or slow down.”

“Neuromedin U turned out to be a lynchpin,” said Altieri. “The tumor uses it to build a shield of protective immune cells around it, and when the signal is removed, the shield comes down. For a cancer with limited options, identifying a target that reopens the door to immunotherapy is something we want to better understand.”

Co-authors: Jozef Madzo, Andrew V. Kossenkov, F. Cansu Atilgan, and Dario C. Altieri of The Wistar Institute; Marcella Tazzari, Maria M. TumideiI, Cristian Lolli and Giorgia Gurioli from the Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”; Francesco Limarzi of the AUSL Romagna; Alessandro Fatatis of the Drexel University College of Medicine; Mary V. Iacocca and Nicholas J. Petrelli of Christiana Care Health; Justine J. Jacobi and David W. Goodrich of the Roswell Park Comprehensive Care Center; and Lucia R. Languino of Thomas Jefferson University.

Work supported by: National Institutes of Health grants CA234162 (DWG) and the Prostate Cancer Foundation award 22CHAL13 (DWG).

Publication information: Neuromedin U ‘Innervation’ Reprograms Myeloid Immunosuppression in Neuroendocrine Prostate Cancer, Oncogene, 2026.

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ABOUT THE WISTAR INSTITUTE:

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

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Researchers from The Wistar Institute and ChristianaCare Identify Promising New Therapeutic Target for Pancreatic Cancer

Written by dari on . Posted in Press Releases.

PRESS RELEASE
Study shows that damaged mitochondria leak double-stranded RNA within cancer cells, causing inflammation that fuels cancer growth

PHILADELPHIA — (Apr. 27, 2026) — Scientists at The Wistar Institute and clinical researchers from ChristianaCare’s Helen F. Graham Cancer Center & Research Institute have discovered a vulnerability in pancreatic cancer that could be targeted as a potential therapy. In a new study, published in the Proceedings of the National Academy of Sciences, they show how defective mitochondria within cells spark a process that triggers inflammation. They also show how cancer cells become so dependent on this inflammation to grow that without it, they die.

The discovery is exciting because it suggests that blocking the pathway, called TLR3/TRAF6, could be a promising new therapeutic target for pancreatic cancer, said senior author Dario Altieri, M.D., president and CEO of The Wistar Institute, director of the Ellen and Ronald Caplan Cancer Center, and Robert and Penny Fox Distinguished Professor. It’s the first time this mechanism has been identified as playing a role in cancer, he said.

“It’s been known that mitochondria could release double-stranded RNA and generate inflammation, but not in cancer, and not as a cancer driver,” Altieri explained. “Similarly, this pair of molecules, TLR3 and TRAF6, were known to act as a sensor for double-stranded RNA, but again, not in cancer. So this could be a therapeutic target for pancreatic cancer, where we are in desperate need of therapeutic targets, but perhaps also for other types of cancers.”

“For pancreatic cancer patients, options remain far too limited and the prognosis far too often devastating,” said coauthor Nicholas Petrelli, M.D., director of the Cawley Center for Translational Cancer Research at ChristianaCare’s Helen F. Graham Cancer Center & Research Institute. “What makes this finding so exciting is that it points us toward a genuine vulnerability in the cancer itself — one we may be able to exploit therapeutically.”

Pancreatic cancer is one of the most aggressive and deadly forms of cancer, with few treatment options. It remains highly resistant to treatment and is typically discovered late, when it’s already at the metastatic stage. Most patients have a very poor prognosis.

Mitochondria are organelles found within cells that convert nutrients into energy. Previous studies showed that many tumor cells have mitochondria that are low in an important structural protein called Mic60. These mitochondria are severely damaged but remain present in the cell. Researchers found that these “ghost mitochondria” became powerful signaling hubs for inflammation, but they didn’t understand why.

The new study helps solve that mystery.

Normal, healthy mitochondria are sealed inside a membrane. But the team found that in the mitochondria lacking Mic60, that membrane becomes defective and starts to leak. Double-stranded RNA drains out of the mitochondria into the surrounding cell. The cell’s internal warning system mistakes this for a sign that the cell is infected.

Researchers found two proteins that act as sensors, detecting the double-stranded RNA and activating a massive inflammatory response, Altieri said. The cancer cells then use this inflammation to grow.

Importantly, the team also found that the cancer becomes so “addicted” to inflammation that it comes to depend on it not just for growth, but survival. When they used drugs to block the sensor proteins, the cancer cells died, while healthy cells survived. In a murine model, this approach caused pancreatic cancer tumors to stop growing.

Altieri said the discovery was a surprise.

“The idea that the reduction of a structural protein could play a role in the damaged mitochondria becoming hubs for stress response signaling, which would translate to a very potent inflammatory response — that was totally unexpected,” he said. “We had no idea that this was a possibility.”

Next, researchers want to learn more about how Mic60 damages the mitochondria’s membrane to release double-stranded RNA, starting the inflammation process — and if this mechanism can be stopped. They also want to continue investigating and developing a TLR3/TRAF6 inhibitor as a potential cancer therapy.

Work supported by: National Institutes of Health (NIH) grants R35 CA220446, R50 CA221838, and R50 CA211199; the Cotswold Foundation; National Cancer Institute grant P30 CA10815.

Publication information: Mitochondrial Double-Stranded RNA Fuels Pancreatic Cancer Growth Via RIG-I/TLR3 Inflammation, Proceedings of the National Academy of Sciences, 2026. Online publication.

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 THE HELEN F. GRAHAM CANCER CENTER & RESEARCH INSTITUTE
The Helen F. Graham Cancer Center & Research Institute, a National Cancer Institute Community Oncology Research Program, is part of the ChristianaCare, one of the country’s most dynamic health systems, centered on improving health outcomes, making high-quality care more accessible and lowering health care costs. With more than 245,000 patient visits last year, the Graham Cancer Center is recognized as a national model for multidisciplinary cancer care and a top enroller in U.S. clinical research trials. In conjunction with the Gene Editing Institute, the Cawley Center for Translational Cancer Research, the Tissue Procurement Center, statewide High-Risk Family Cancer Registry and collaborations with world-renowned scientists at facilities such as The Wistar Institute in Philadelphia, scientists are opening new avenues to more quickly translate cancer science into cancer medicine. For more information, visit christianacare.org/cancer.

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The Wistar Institute Announces Dr. Dario Altieri Leadership Transition

Written by dari on . Posted in Press Releases.

PRESS RELEASE
Board of Trustees conducting president & CEO search process

PHILADELPHIA — (Jan. 26, 2026) — The Wistar Institute, a biomedical research leader in cancer, immunology and infectious disease, announces Dario C. Altieri, M.D., Wistar’s president and CEO, director of the Ellen and Ronald Caplan Cancer Center, and Robert and Penny Fox Distinguished Professor, will step down from his leadership role effective December 2026. In the interim, the Board of Trustees will undertake a comprehensive national search process to identify his successor.

During Dr. Altieri’s distinguished tenure of more than 11 years as president and CEO and over 16 years as director of the Ellen and Ronald Caplan Cancer Center, he has led the Institute through a period of significant growth and scientific innovation resulting in unprecedented expansion. Through his leadership, the Institute quadrupled its annual budget to greater than $100 million, tripled the organization’s endowment to $277 million, guided the Cancer Center’s designation as a National Cancer Institute (NCI) Basic Cancer Center – the only such one in Pennsylvania to be renewed three times with the highest possible “Exceptional” rating, doubled the scientific footprint of the Institute with the creation of two new research Centers (Center for Advanced Therapeutics and HIV Cure and Viral Diseases), grew the scientific staff from 30 independent labs to 41, and supported the first, non-traditional, life science apprenticeship program recognized by the Commonwealth of Pennsylvania.

“It has been the utmost privilege to work alongside the incredibly talented and dedicated scientists and staff at The Wistar Institute and our Board of Trustees,” says Dr. Altieri. “I am proud of the unprecedented success that Wistar experienced during this time and look forward to dedicating my time to the values of work that have defined me since I was a medical student: laboratory research, teaching and mentoring.”

A native of Milan, Italy, Dr. Altieri joined Wistar in 2010 as director of its National Cancer Institute-designated Cancer Center and chief scientific officer. He assumed the role of president and chief executive officer in 2015. Dr. Altieri’s research focuses on fundamental and translational cancer biology with emphasis on mechanisms of tumor progression and therapeutic resistance. He is the author/co-author of more than 260 publications and named inventor for 13 patents. Dr. Altieri is a former director of the UMass Memorial Cancer Center and founding chair of its Department of Cancer Biology.

“On behalf of Wistar’s Board of Trustees, I want to thank Dario for his many years of dedication to Wistar and his energetic, visionary leadership, which will have an enduring impact on Wistar and the life science community at large,” said Rick Horowitz, Wistar Board of Trustees Chair. “Due in large part to Dario’s efforts, Wistar is exceptionally well positioned for continued growth and success. We look forward to his support and guidance in facilitating this leadership transition.”

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ABOUT THE WISTAR INSTITUTE:

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

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Wistar Institute Researchers Identify Parkinson-related Protein’s Role in Cancer and T Cell Activation

Written by dari on . Posted in Press Releases.

PRESS RELEASE
Wistar’s Altieri lab uncovered the protein’s powerful influence on immune response to tumors

PHILADELPHIA — (September 17th, 2024) — The Wistar Institute’s President and CEO, Dario C. Altieri, M.D., and team have demonstrated the role of Parkin — a protein implicated in Parkinson’s disease — in the body’s innate immune response to cancer. Parkin is not expressed in several cancers. Dr. Altieri and his team engineered cancer cells to re-express Parkin and found that Parkin contributes to the production of interferons, which activate and attract T cells to fight the tumor. The lab’s findings were published in The Journal of Clinical Investigation in the paper, “Parkin activates innate immunity and promotes anti-tumor immune responses.”

“Parkin has only recently been implicated for its role in cancer, so our study adds to the knowledge base being formed around that role. We are the first to demonstrate its dual role in suppressing tumor traits while activating innate immunity,” said Altieri, president and CEO, director of the Ellen and Ronald Caplan Cancer Center and the Robert & Penny Fox Distinguished Professor at The Wistar Institute.

Parkin is well known for its role in breaking down damaged and excess proteins, and the loss of Parkin expression due to genetic mutation in the PRKN gene is most commonly associated with Parkinson’s disease. However, Parkin can also be epigenetically silenced in cancer and has been implicated in several types, including lung, ovarian, and breast cancer.

Epigenetic silencing occurs when physical changes to the genome prevent certain genes from being turned into proteins or expressed. In the case of Parkin, cancers epigenetically silence the gene through DNA methylation, a process that attaches methyl molecules to DNA. To better understand the interplay between Parkin and cancer cells, Altieri, and an international team of collaborators began by reintroducing Parkin into tumor cells in vitro and in vivo.

They found that in the presence of Parkin, interferons — a group of cytokine proteins that aid in immune responses to threats — were produced as a result of Parkin activation. The team followed up with an in vivo experiment where they restored PRKN expression in mice by using the approved demethylating agent decitabine, which removes the gene-silencing methyl groups from DNA. The drug treatment worked to restore Parkin expression and slow down tumor growth.

By stimulating the production of interferons — a key element of immune response — the team found that Parkin’s interferon-signaling effects ultimately recruited anti-cancer T cells, which slowed tumor growth. To confirm this mechanism, the researchers expressed Parkin but cancelled interferon signaling, and then they expressed Parkin in immunocompromised mice. In both instances, the tumor-suppression effect was eliminated, even while Parkin was expressed — ultimately proving that the immune system’s anti-cancer response mediates the role Parkin plays in tumor reduction.

“We are excited to uncover a new mechanism of crosstalk between the immune system and tumor cells because we can only cure what we know,” said Michela Perego, Ph.D., the paper’s first author. “By reactivating Parkin, it may be possible to develop new treatment options and boost the immune system’s ability to fight cancer.”

Co-authors: Michela Perego, Minjeong Yeon, Ekta Agarwal, Andrew T. Milcarek, Irene Bertolini, Jagadish C. Ghosh1, Hsin-Yao Tang, Andrew V. Kossenkov, Sarah Preston-Alp, Italo Tempera, Noam Auslander, and Dario C. Altieri from The Wistar Institute; Chiara Camisaschi from IRCCS Humanitas Research Hospital; Nathalie Grandvaux from Centre de Recherche du Centre Hospitalier de l’Université de Montréal, and Marcus Ruscetti from University of Massachusetts Chan Medical School.

Work supported by: National Institutes of Health (NIH) grants R35 CA220446 and R01 CA286080 (D.C.A.), P01 CA269043 (I.T.), T32 CA009171 (S.P.-A.), R50 CA221838 (H.Y.T), and R50 CA211199 (A.V.K.). Wistar Shared Resources are supported by P30 CA010815. The Thermo Q-Exactive HF-X mass spectrometer was purchased with NIH grant S10 OD023586.

Publication information: “Parkin Activates Innate Immunity and Promotes Anti-tumor Immune Responses,” The Journal of Clinical Investigation.

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ABOUT THE WISTAR INSTITUTE:

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

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(left) Wistar CEO Dr. Dario Altieri and (right) Dr. Andrew Kossenkov

Wistar Scientists Identify Link Between Mitochondria and Pancreatic Cancer Risk

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

PRESS RELEASE
The mitochondria is a key energy-producing component of the human cell that plays an important role in cancer cell metabolism.

PHILADELPHIA — (Oct. 12, 2022) — In a research paper published in PLOS ONE, Dario C. Altieri, M.D., president and chief executive officer, director of the Ellen and Ronald Caplan Cancer Center, and the Robert and Penny Fox Distinguished Professor at The Wistar Institute, alongside national and international collaborators, distinguish a specific gene signature indicative of mitochondrial reprogramming in tumors that correlates with poor patient outcome.

“To the best of our knowledge, this is the first time that a gene signature of mitochondrial dysfunction is linked to aggressive cancer subtypes, treatment resistance and, unfortunately low patient survival rates. Although our work has focused on the mitochondrial protein Mic60 in this response, we know that dysfunctional mitochondria are commonly generated during tumor growth, suggesting that this is a general trait in cancer,” says Altieri.

This paper stemmed from past research investigating the role of the protein Mic60 in tumor cell proliferation, motility, and metastases. Mic60, also called mitofilin or inner membrane mitochondrial protein (IMMT), is a key protein that is essential to the structure of mitochondria and thus has a downstream impact on mitochondrial functions and tumor metabolism.

Andrew Kossenkov, Ph.D., first author on the paper, assistant professor in Wistar’s Gene Expression and Regulation program and scientific director of the Institute’s Bioinformatics Facility, shares, “After original findings on the strong association of Mic60 in low levels in cancer tissues, we were curious if we could identify a small panel of Mic60 downstream genes of specific functions and if the Mic60-low gene panel signature has clinical relevance – i.e., if it is associated with clinical data like survival, cancer sub-types, response to treatment, etc. – and we did.”

Armed with this knowledge, the team – along with collaborators from Canada, Italy, and across the United States – analyzed tumor cells from three independent patient cohorts with pancreatic ductal adenocarcinoma (PDAC). They showed that an 11-gene Mic60-low signature is associated with aggressive disease, local inflammation, treatment failure, and shortened survival – ultimately demonstrating the clinical relevance of protein. Therefore, the Mic60-low gene signature may be used as a simple tool or biomarker to estimate cancer risk for PDAC and potentially other types of cancer, including glioblastoma.

“Gene signatures can be used to gain insight into specific tumor qualities,” Kossenkov explains. “If extensively developed, tested, and validated, this [Mic60-low gene signature] can be a potential simple point-of-service molecular tool for pancreatic cancer prognosis or stratification of patient risks and prediction of treatment response.”

“While the broad applicability of this new Mic60-low gene signature certainly awaits further confirmation in larger patient populations, we hope that this simple, easily implementable molecular tool will be of help in the clinic to stratify patients at higher risk of severe and progressive disease,” Altieri details.

Regarding future directions, Kossenkov suggests that studying broader datasets with extensive clinical information not limited to pancreatic cancer, but also other malignancies can help demonstrate the applicability of the 11gene Mic60-low signature in estimating cancer risks.

Co-authors: Andrew V. Kossenkov, Andrew Milcarek, Jagadish C. Ghosh, Michela Perego from The Wistar Institute; Faiyaz Notta, Gun-Ho Jang, Julie M. Wilson from Ontario Institute for Cancer Research; Steven Gallinger from University Health Network Toronto and Mount Sinai Hospital; Daniel Cui Zhou, Li Ding from Washington University in St. Louis; Annamaria Morotti, Marco Locatelli, Valentina Vaira from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan; Marie E. Robert from Yale University.

Work supported by: This work was supported by National Institutes of Health (NIH) grants P01 CA140043 and R35 CA220446 (D.C.A.) and R50 CA211199 (A.V.K.). The COMPASS study was conducted with the support of the Ontario Institute through funding provided by the Government of Ontario.

Publication Information: Mitochondrial Fitness and Cancer Risk. PLOS ONE, 2022. Online publication.

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ABOUT THE WISTAR INSTITUTE:

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

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Human crowd forming an awareness ribbon symbol above human hands on white background.

Fighting Breast Cancer Disparities Through Collaboration

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

A decade-long collaboration between Wistar and ChristianaCare is leading to new discoveries and better treatment for triple-negative breast cancer patients.

Dario C. Altieri, M.D., president, CEO, and director of the Ellen and Ronald Caplan Cancer Center at The Wistar Institute, and Nicholas J. Petrelli, M.D., Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute at ChristianaCare, formed a collaboration between the two institutions that would expedite the pipeline of cancer interventions from bench to bedside.

“We had the patients, and they had the world-class science,” said Petrelli. “We felt that this was a great opportunity between an NCI-designated, basic science research center and an NCI community cancer center. This relationship is unique in cancer research.”

This collaboration has yielded more than a dozen translational cancer research papers to date and advanced research discoveries made in Wistar labs into early clinical trials at ChristianaCare. One of the newest projects to come from this collaboration is a population health study on treating triple-negative breast cancer.

RESEARCHING TRIPLE-NEGATIVE BREAST CANCER

Triple-negative breast cancer is an aggressive form of breast cancer with few treatment options. It’s more than twice as common in Black women as in white women, and Black women have a 40% higher mortality rate [1, 2]. These factors are what led Zachary Schug, Ph.D., an assistant professor in the Molecular and Cellular Oncogenesis Program at Wistar’s Ellen and Ronald Caplan Cancer Center; Jennifer Sims-Mourtada, Ph.D., lead scientist and director of Translational Breast Cancer Research at ChristianaCare’s Helen F. Graham Center & Research Institute; and Scott Siegel, Ph.D., MHCDS, director of population health research at ChristianaCare to join forces.

Siegel says, “Disparities in breast cancer are the result of multiple interacting factors operating at different scales, so if we’re going to do something meaningful, we can’t take a silo-based approach and focus on one key variable. We really do need to look across this spectrum.”

ALCOHOL AND BREAST CANCER

Schug, Sims-Mourtada, and Siegel share three intersecting research interests: breast cancer, health disparities, and investigating the connection between alcohol and cancer – truly the linking factor in the context of this project.

As a molecular and cellular biologist, Schug examines the problem of alcohol and breast cancer at the “smallest” level of the three researchers. His research has shown that breast tumors feed on a breakdown product of alcohol called acetate, which they use to grow and fight the body’s immune responses. How and why the breast cancer cells use acetate in this way are questions Schug continues to pursue. However, it’s important for him to make his work clinically meaningful as quickly as possible.

“Instead of just focusing on individual tumor cells and trying to do things at a molecular level, we wanted to ask more broad questions,” Schug explains, “and that’s where Scott and Jen come in with what they’re doing.”

GENETICS AND ALCOHOL METABOLISM

Sims-Mourtada is a translational breast cancer researcher who studies how gene expression regulates and alters the progression of breast cancer. Her work intersects neatly with Schug’s because she is investigating whether race-based differences at the genetic level affect how many alcohol-metabolizing enzymes are produced in breast cancer stem cells.

“We have some data that show that a certain isoform of enzyme is overexpressed in tumors from Black women, and a possible reason for this could be some kind of genetic factor,” said Sims-Mourtada. Specifically, there are reports from alcohol use disorder research suggesting the existence of tiny genetic variations called single nucleotide polymorphisms (SNPs) that may be involved in alcohol metabolism. Sims-Mourtada is working on identifying SNPs that might cause an alcohol-metabolizing gene to become overactive or underactive in individuals of differing races which, combined with the individual’s alcohol use, could increase tumor growth.

ALCOHOL-RELATED ENVIRONMENTS AND BEHAVIORS

Siegel looks at the problem of triple-negative breast cancer at a population level. His research focuses on identifying modifiable risk factors for cancer—i.e., whether people’s cancers can be affected by where they live and what they do.

“My contribution to this project is to collect behavioral data on patients. Then we can relate these variables to the processes Jennifer and Zach are looking at, including the enzymes that metabolize alcohol and ultimately the metabolites,” said Siegel.

In examining prevalence of triple-negative breast cancer within ChristianaCare’s home state of Delaware, he found that the areas that have the highest rates of this cancer also have the highest rates of alcohol use disorder and the highest density of alcohol retail stores. The collaboration will help to dig into the biology and genetics that may belie this correlation.

THE RESEARCH PROJECT

The researchers plan to recruit 1,000 women with breast cancer, 500 Black and 500 white. They will biopsy the women’s tumors, which Sims-Mourtada will use to examine differences in gene expression by race. They will also take blood, which Schug will analyze for levels of ethanol and acetate in order to assess the patient’s drinking level, as well as nutrients to get a sense of the patient’s diet. Finally, the researchers will collect extensive patient reported data – including lifestyle, environmental, and socioeconomic factors – which Siegel will assess to determine how the patient’s behaviors and environment relate to what is happening inside their body.

“I think it’s a unique approach to be looking at this multi-level analysis. We’re not just taking into consideration the neighborhood or the behavior, but how those influence what actually happens biologically and genetically,” said Sims-Mourtada.

IMPACTING PATIENTS, PROVIDERS, AND COMMUNITIES

At a patient level, the researchers are hoping to identify biomarkers that would not only indicate risk of developing triple-negative breast cancer but also help detect the cancer sooner than is currently possible via conventional methods.

“Triple-negative breast cancer may start earlier in life before mammography is recommended or develop between screenings. To be able to do a blood test the way one could do a cholesterol test for heart disease, maybe we can see cancer developing sooner,” said Siegel.

The researchers also want to uncover risk factors that healthcare providers can use to educate patients and steer them toward behaviors that match their individual risk level. Alcohol consumption won’t necessarily increase cancer risk for everyone. But it will for some, and those individuals should be informed. With just gentle nudges from a physician, simple changes in alcohol consumption could save lives by reducing the probability of breast cancer in certain high-risk individuals.

At a community level, identifying where rates of risk for triple-negative cancer are highest could mean more targeted outreach. To be able to use public health resources in the areas where they could make the biggest impact could amplify effects on many lives.

A LASTING COLLABORATION

Wistar and ChristianaCare’s joint efforts have repeatedly yielded a two-way benefit: basic scientists learn directly from clinicians about the issues clinicians are seeing at the bedside, and the clinicians learn from the scientists about the challenges scientists face as they are trying
to solve problems in the quest for therapeutic solutions.

“We will be publishing in basic science journals, but we will also be changing how we practice in the cancer center, potentially how we do our community outreach, and possibly prevent loss of life as a result of this research,” said Siegel.

“It really has been a special marriage made in heaven,” said Petrelli, “and I see it continuing for a long time.”

SOURCES

  1. McCarthy, A. M., Friebel-Klingner, T., Ehsan, S., He, W., Welch, M., Chen, J., Kontos, D., Domchek, S. M., Conant, E. F., Semine, A., Hughes, K., Bardia, A., Lehman, C., & Armstrong, K. (2021). Relationship of established risk factors with breast cancer subtypes. Cancer Medicine, 10(18), 6456–6467. https://doi.org/10.1002/cam4.4158
  2. Cancer of the Breast (Female) – Cancer Stat Facts. Chart Death Rate per 100,000 Persons by Race/Ethnicity: Female Breast Cancer. (2018). SEER. https://seer.cancer.gov/statfacts/html/breast.html

Taking on Cancer

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

Philadelphia Business Journal senior health reporter John George hosted Taking on Cancer, a two-panel discussion that kicked off with perspectives from local research leaders at the helm of world-class research institutes and health care systems. It was followed by the innovative go-getters behind health care startups in the region. The intimate event took place in the high ceiling, music venue City Winery in Philadelphia’s Center City.

Leaders sat shoulder to shoulder to discuss the challenges and changes to cancer research and patient care. The first panel gave perspectives on what the future holds for the region and included Dr. Dario Altieri, Wistar Institute president & CEO, director of the Ellen and Ronald Caplan Caner Center, and the Robert and Penny Distinguished Professor; Dr. Generosa Grana, MD Anderson Cancer Center at Cooper director; Dr. Jonathan Chernoff, Fox Chase Cancer Center director; Dr. Andy Chapman, Jefferson Health’s Sidney Kimmel Cancer Center director; and Dr. Robert Vonderheide, University of Pennsylvania’s Abramson Cancer Center director.

Dr. Altieri represented the panel’s lone basic cancer research center and brought a high-level drug discovery perspective to what John George coined Philadelphia—an “epicenter for cancer research”. Dr. Altieri stated, “We’ve gotten better at public-private partnerships, and we’ve greatly improved the dynamics related to drug discovery and development. We’ve been exploring more and are doing a better job advancing promising new assets, so we are seeing a higher number of success stories.”

The other leaders, representing comprehensive cancer centers that treat patients and conduct research, felt the same – that the last 20 years of cancer research has been a sort of science revolution in our understanding of how genes act together and the hopes of altering or editing them, how to identify and predict cancer risk, and how to treat immune system pathways that were once thought undruggable with emerging drug candidates. In the process, Philadelphia has become central to cell and gene therapy and referenced as “Cellicon Valley”. The region now also supports a teeming cell and gene therapy ecosystem backed by a workforce that understands bioprocessing this “living drug”.

Together, the panel agreed that Philadelphia is poised to be a leading city in the battle against cancer—all due to the innovation of academic institutes coupled with innovative business investment and supporting infrastructure, and the ability to provide delocalized, multidisciplinary care to cancer patients.

As we continue shaping and building this life science ecosystem, Dr. Altieri remarked on the day-to-day challenges of cancer research and what’s to come. “At times, things may not seem to move fast enough, and our work seems incremental, taking only small steps forward. However even those count, as we move away from dogma and assumptions and from the mindset that there are undruggable targets. Discovery through innovation will become more adventurous.”

Dr. Dario Altieri smiles in a Wistar lab

Wistar Scientists Identify Therapeutic Target for Metastatic Cancers

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

Damaged “ghost” mitochondria are found to drive tumor progression.

Metastasis, or the spread of cancer from one place in the body to another, is responsible for more than 90% of all cancer deaths. Therefore, determining how and why this happens is an important part of cancer research. A new collaborative study led by scientists at The Wistar Institute identified one such mechanism thanks to “ghost” mitochondria.

Because they are the “powerhouse” of the cell, mitochondria (a specific organelle inside human cells) are crucial for cell survival, including tumor cells. However, recent research has shown that mitochondria in many human tumors lack an important protein called Mic60. Normally missing a crucial protein is a recipe for disaster, yet these mitochondria and their cells survive.

To determine how this is possible and how it affects tumor cell behavior, Dario C. Altieri, M.D., Wistar president and CEO, director of The Wistar Institute Cancer Center, and the Robert & Penny Fox Distinguished Professor, led a team of researchers in reproducing these types of low-Mic60 tumor cells in mice to enable closer examination. In doing so, they found two things. First, in cells where Mic60 was depleted, all of the mitochondria’s structures and functions were damaged or inhibited.

“They really didn’t produce any energy, which is what mitochondria do,” said Altieri. “That was the idea of calling them ‘ghosts’—because in essence the mitochondria were still there, but they didn’t do anything, or anything good, at least.”

Second, the scientists found that while inferior organelles are usually removed from healthy cells via a quality control process, the ghost mitochondria were not removed from tumor cells. Not only were they not removed, but they helped the cell metastasize.

Given these findings, the scientists speculate that the low-Mic60 tumor cells activate two pathways to stay alive: Akt (related to survival) and GCN2 (related to stress response). Drugs interfering with these pathways could, therefore, help to stop metastasis and kill the cancer.

“The idea would be to eliminate the adaptive responses that these Mic60-low tumors mount to remain alive and viable through a combination targeting of Akt and GCN2,” said Altieri.

The Wistar Institute building

The Wistar Institute Hosts U.S. Department of Commerce Official Making Major Grant Announcements to Strengthen Workforce Pipelines in Philadelphia & Across the Nation

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

Wistar is a finalist of the STEM Talent Challenge to create a new life science workforce training program to address Pennsylvania industry growth and demand for skilled workers.

U.S. Assistant Secretary of Commerce for Economic Development Alejandra Y. Castillo will make a major national grant announcement in support of locally-driven programs that train STEM-capable workforces across the country and create pathways for good-paying STEM jobs in Philadelphia and across the United States at an event on Thursday, January 27, 2022 in Philadelphia.

WHO:

  • Ms. Alejandra Y. Castillo
    U.S. Assistant Secretary of Commerce for Economic Development
    U.S. Department of Commerce
  • Ms. Mary Gay Scanlon
    U.S. Congresswoman
    Pennsylvania’s 5th District
  • Mr. Jim Kenney
    Mayor
    City of Philadelphia
  • Dr. Dario Altieri
    President & CEO
    The Wistar Institute


WHAT: Major grant announcement in support of locally-driven efforts to strengthen innovation workforce pipelines in Philadelphia and across the United States.

WHEN: Thursday, January 27, 2022; 11 a.m./EST

WHERE: The Wistar Institute; Media are welcome to attend and ask questions virtually.

REGISTRATION: Please use the link below to register: https://register.gotowebinar.com/register/9102191982375060492

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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.

The mission of the U.S. Economic Development Administration (EDA) is to lead the federal economic development agenda by promoting competitiveness and preparing the nation’s regions for growth and success in the worldwide economy. An agency within the U.S. Department of Commerce, EDA makes investments in economically distressed communities in order to create jobs for U.S. workers, promote American innovation, and accelerate long-term sustainable economic growth. To learn more about EDA, visit www.eda.gov.

Fox Chase Cancer Center, The Wistar Institute Announce Opening of Phase 1 Clinical Trial of Anticancer Drug Candidate

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

PHILADELPHIA — (Dec. 2, 2021) — Fox Chase Cancer Center has opened an investigator-initiated, phase 1 clinical trial to evaluate the safety and efficacy of gamitrinib in patients with advanced cancer. Gamitrinib is a first-in-class, mitochondrial-targeted inhibitor of the molecular chaperone heat shock protein-90 (HSP90) that works by inhibiting tumor cell metabolism and survival.

Gamitrinib was developed at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease, and vaccine development, and the two Philadelphia institutions are collaborating to bring this potential new therapy to patients.

The study is a single center, open-label, phase 1 clinical trial of weekly intravenous gamitrinib administration. It is designed to enroll 18 to 36 patients. The primary goal of the study is to determine safety and tolerability. It will be complemented by analyses to determine how gamitrinib is metabolized in humans, assess biochemical evidence of target engagement, and gauge early efficacy signals.

Anthony J. Olszanski, MD, RPh, director of the Phase 1 Development Therapeutics Program and vice chair of clinical research at Fox Chase, is the principal investigator on the gamitrinib trial. “We are excited to share the news that the gamitrinib trial is now open for accrual. We hope to make progress in this very first step toward a promising new treatment for patients with advanced cancer, where there remains a high unmet need for new, effective therapies,” said Olszanski.

“Gamitrinib has had a long and storied journey,” said Dario C. Altieri, MD, Wistar president and CEO, director of The Wistar Institute Cancer Center, and the Robert & Penny Fox Distinguished Professor. His laboratory designed and developed the new drug candidate for clinical use.

“It is a humbling moment to see what started as a research tool advance through preclinical development and now reach our patients. From the start, and continuing to this milestone, this project has embodied our nation’s investment in research solely and continuously supported by competitively awarded public funds,” Altieri said.

“This new trial is important on many levels,” said Jonathan Chernoff, MD, PhD, Cancer Center Director at Fox Chase, which is part of the Temple University Health System. “Delivering anticancer agents inside mitochondria has not previously been brought to the clinic in oncology. It is a highly collaborative, longstanding endeavor across cancer centers here in Philadelphia and delivers considerable innovation for a first-in-human, investigator-initiated clinical trial.”

Known as the powerhouses of the cell for their ability to produce large quantities of cellular energy, mitochondria have been recognized as important tumor drivers, sustaining many critical disease traits. This involves a pool of the HSP90 chaperone that selectively accumulates in the mitochondria of tumor cells and helps in the folding and stability of critical mitochondrial proteins exploited in cancer.

Although conventional HSP90 inhibitors previously tested as cancer drugs failed to accumulate in mitochondria, gamitrinib was designed by the Altieri laboratory to selectively localize to mitochondria, inhibit the function of HSP90, and induce the collapse of mitochondrial metabolism and tumor cell survival.

Funding for the phase 1 clinical trial to evaluate the safety of gamitrinib is being provided by the National Institutes of Health’s National Cancer Institute, the U.S. Army Medical Research and Development Command’s Congressionally Directed Medical Research Program, and Gateway for Cancer Research, a nonprofit organization dedicated to funding meaningful breakthrough treatments and cures for patients worldwide.

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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.

About Fox Chase Cancer Center
The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center, that no one shall be excluded from or denied the benefits of or participation in the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.