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Dr. Maureen Murphy with two PhD students in her Wistar lab

Wistar Scientists Identify a Gene Signature to Assess Cancer Risk

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

PHILADELPHIA — (FEBRUARY, 6, 2023) — In a paper published in PNAS, Maureen Murphy, Ph.D., Deputy Director of Wistar’s Ellen and Ronald Caplan Cancer Center and Ira Brind Professor and Program Leader in the Molecular & Cellular Oncogenesis Program, and team have identified a gene signature that accurately predicts the functioning of P53 variants, important information to assessing cancer risk and optimizing choices for cancer therapeutics.

“There are so many genetic variants of P53,” explained Murphy. “A lot of P53 variants are classified as having uncertain significance with current methods of testing. This does not help people determine whether they have increased cancer risk. The signature we identified does.”

The Murphy lab monitored differences in activity in mutant and normal p53 proteins to determine any genetic markers that would flag if a p53 variant is functioning less than normal. In collaboration with Andrew Kossenkov, Ph.D., assistant professor in Wistar’s Vaccine and Immunotherapy Center, the research team used machine learning to identify a gene signature that consistently and accurately predicted the difference between a normal functioning or benign p53 and a lower functioning variant of the protein.

This knowledge could be used to screen individuals with genetic variants of p53 and better inform them of their cancer risk and response to therapy. Murphy intends to continue this work with the goal of turning the gene signature into a blood-based genetic test someone could take to learn about their p53 status.

“The promise of this research is personalized medicine,” Murphy elaborated. “This work could not have happened in any other place except Wistar where our environment is so collaborative and cutting edge.”

Co-authors: Jessica C. Leung, Julia I-Ju Leu, Alexandra Indeglia, Toshitha Kannan, Nicole L. Clarke, Nicole A. Kirven1, Harsh Dweep, David Garlick, Thibaut Barnoud, Andrew V. Kossenkov, Donna L. George

Work supported by: Research support for this study was provided by NIH grants CA102184 (PI 385 Murphy) and CA238611 (PI Murphy). J.C. Leung received support from T32 CA009171-43 and 386 the Wistar Accelerator Postdoctoral Award; A. Indeglia was supported in part from T32 387 GM008216. T.B. was supported through R00 CA241367.

Publication Information: Common activities and predictive gene signature identified for genetic hypomorphs of TP53. PNAS, 2023. Online publication.

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The Wistar Institute, the first independent, nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a culture of biomedical collaboration and innovation. Wistar scientists are focused on solving some of the world’s most challenging and important problems in the field of cancer, infectious disease, and immunology. Wistar has been producing groundbreaking advances in world health for more than a century. Consistent with its legacy of leadership in biomedical research and a track record of life-saving contributions in immunology and cell biology, Wistar scientists’ early-stage discoveries shorten the path from bench to bedside. wistar.org

Wistar Scientists Study Ferroptosis to Improve Cancer Treatments

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

What clues can a cell’s death reveal for immunotherapies for treating cancer and other diseases?

Wistar scientists Dr. Yulia Nefedova, associate professor in the Immunology, Microenvironment & Metastasis Program in the Ellen and Ronald Caplan Cancer Center, and Dr. Maureen Murphy, Ira Brind Professor and program leader of the Molecular & Cellular Oncogenesis Program in the Ellen and Ronald Caplan Cancer Center, are studying a recently identified form of cell death called ferroptosis and how to harness this knowledge to improve care for cancer patients.

Ferroptosis cloaks cancer from the immune system

In a recently published Nature paper, Dr. Nefedova and collaborators reported that ferroptosis occurs in immune cells called neutrophils in the tumor microenvironment. Ferroptosis of neutrophils suppress the immune system and actually aid cancer cells in escaping death. Specifically, neutrophils dying from ferroptosis inhibit one of the most powerful natural enemies cancer has – T cells. T cells are a critical line of defense in the human immune system because they are programmed to attack cancer cells.

“Understanding the mechanisms that mediate immune suppressive activity of neutrophils in the tumor microenvironment is critical to improve the anti-tumor response and efficacy of immunotherapies,” explained Nefedova.

The study demonstrated that systemically or selectively blocking ferroptosis in neutrophils significantly delayed tumor growth and increased host sensitivity to a type of cancer treatment called immune checkpoint inhibitors. Nefedova shared, “Our study identified a new therapeutic approach that could be further explored as a treatment option for cancer patients – especially those who are poorly responding to the existing immunotherapies.”

Ferroptosis could be used to kill cancer cells

“Most cell death pathways occur more in tumor cells than normal cells, so we try to exploit them for cancer therapy,” explained Dr. Murphy regarding her recent paper published in the Journal of Biological Chemistry. Some cancer cells have an increased sensitivity to ferroptosis, and this research uncovered not only why, but how these findings can be translated to improve clinical care of cancer patients.

The Murphy lab studies genetic variants of p53, a critical suppressor of cancer that regulates a protein called PLTP (phospholipid transfer protein). In the study, Murphy and team identified that PLTP can control ferroptosis in cells by controlling the ability of cells to sequester lipids into “lipid droplets”. If a cell isolates toxic lipids into droplets, it can prevent these lipids from penetrating the cell membrane and causing cell death by ferroptosis.

“By identifying lipid droplets as critical for ferroptosis, we identify a whole series of drugs that regulate lipid droplets that can now be exploited to combat cancer,” said Murphy. “We are now exploring the possibility that immune cells use ferroptosis to kill cancer cells. This would help identify people who might be less suited to use immunotherapy to combat their cancers and might have to use extended treatment or a different form of therapy.”

Wistar Institute’s Maureen Murphy Named Deputy Director of the Ellen and Ronald Caplan Cancer Center

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

PHILADELPHIA — (JAN. 12, 2023) — Maureen Murphy, Ph.D., has been named Deputy Director of the Ellen and Ronald Caplan Cancer Center at The Wistar Institute. Murphy will guide the growth of the Cancer Center through expanding research initiatives and collaboration, education and training programs, and recruitment to fast-track innovative basic cancer research discoveries into future transformative drugs and therapies.

“I am honored and excited to throw all my energy into achieving Wistar’s strategic goals,” said Murphy, the Ira Brind Endowed Professor. “I look in amazement at Wistar’s progress these past ten years, both scientifically and financially. We have a growing endowment, immense scientific impact, a newly revitalized culture of collaboration, the commitment of our leadership to provide new technology to support ambitious biomedical research, and the spearheading of education programs from high schooler to non-traditional trainee to junior faculty—all under the direction of our president and CEO Dario Altieri.”

In 1972 Wistar became the first NCI-designated Basic Cancer Center in the nation and has continued to be recognized and supported by the NCI. In 2022 Wistar became the first basic NCI-designated Cancer Center to earn the Cancer Center Support Grant Merit Extension.

Dario C. Altieri, M.D., Wistar president & CEO, director of the Ellen and Ronald Caplan Cancer Center and Robert and Penny Fox Distinguished Professor said, “I cannot be more grateful to Maureen for her unwavering commitment, dedication and support of our Institute and Cancer Center, and I very much look forward to working with her to chart our vision for the future of the cancer research enterprise at Wistar in sync with our recently released five-year strategic plan and associated philanthropic campaign.”

Recently, The Wistar Institute embarked on a five-year campaign, a roadmap of Institute priorities in science, education, and strategic collaborations. The Ellen and Ronald Caplan Cancer Center was formally named in 2022 and prioritizes the prevention and treatment of cancer by advancing fundamental high-risk, high-reward basic science into next-generation therapeutics.

Murphy is known for her research on P53, a tumor suppressor gene that is mutated in almost every type of cancer. She studies the impact of genetic variants of p53 on cancer risk and therapy response, with a focus on genetic variants in African-descent populations. Murphy’s research has relevance for understanding ethnic disparities in cancer risk and survival. Her lab also studies the HSP70 protein where Murphy has pioneered pharmacologic targeting of HSP70 for cancer therapy, particularly metastatic melanoma and colorectal cancer.

Murphy holds vital administrative roles promoting Institute stewardship, including program leader of the Molecular & Cellular Oncogenesis Program, associate vice president for Faculty Affairs, and principal investigator of the Training Grant in Cancer Biology, which provides support for top Wistar trainees, and is one of the five longest standing training grants in the history of the National Cancer Institute.

Murphy earned her B.S. degree in biochemistry from Rutgers University and her Ph.D. in molecular biology from the University of Pennsylvania. She conducted postdoctoral research at Princeton University in the laboratory of Arnold J. Levine, Ph.D., a co-discoverer of p53 and a pioneer in the field of tumor suppressor genes and cancer biology. Prior to joining Wistar, Murphy was a professor at the Fox Chase Cancer Center. Murphy joined The Wistar Institute in 2011 and in 2012 became program leader of the Molecular and Cellular Oncogenesis Program. In 2019 she became the Ira Brind Endowed Professor. Murphy is an adjunct professor at Drexel University College of Medicine and The Perelman School of Medicine at the University of Pennsylvania.

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The Wistar Institute, the first independent, nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a highly enabled culture of biomedical collaboration and innovation, to solve some of the world’s most challenging and important problems in the field of cancer, immunology, and infectious diseases, and produce groundbreaking advances in world health. Consistent with a pioneering legacy of leadership in not-for-profit biomedical research and a track record of life-saving contributions in immunology and cell biology, Wistar scientists pursue novel and courageous research paths to life science discovery, and to accelerate the impact of early-stage discoveries by shortening the path from bench to bedside. wistar.org

Dr. Maureen Murphy examines data with her students.

Dr. Maureen Murphy: Scientist and Teacher

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

Wistar offers the perfect blend of qualities for cancer researchers to thrive.

Challenging science paired with a social cause is the winning formula that propels Dr. Maureen Murphy in her quest to cure cancer. A researcher for over 25 years, Murphy leads research projects on the genetics of the tumor suppressor protein p53 with the goal of improving and personalizing cancer therapies for understudied populations who often have the highest cancer burden, particularly those of African and Ashkenazi Jewish descent. She also serves as a mentor, actively guiding scientists as they navigate the joys and challenges of scientific research. Grit and kindness, she says, is what she searches for when adding talent to her team.

Murphy and her lab thrive in Wistar’s highly collaborative environment, a space that actively rejects scientific ivory towers and welcomes those with curious minds and innovative imaginations. Wistar science pushes forward the frontiers of research in pursuit of knowledge to combat and eradicate cancer. This National Breast Cancer Awareness Month, we spoke with Dr. Murphy, Ira Brind Professor and program leader of the Molecular & Cellular Oncogenesis Program of the Ellen and Ronald Caplan Cancer Center, on her breast cancer research, mentorship, and motivations to understand – and ultimately cure – the disease.

As a breast cancer researcher, what are some of the most significant accomplishments in managing and treating breast cancer in your opinion? Put another way, why should breast cancer patients feel more hopeful today than – say – 10 years ago?

The five-year survival rate for breast cancer has improved dramatically in the last two to three decades – possibly more than any other cancer. I find three most promising things: first is the development of more sensitive ways to detect breast cancer early (including the new revelations about the difficulty for a standard mammogram to detect cancer in women with dense breasts, like Katie Couric … and like me); second is the power of patient advocacy groups and other organizations whose fundraising really powers the research and the patients; third is the discovery of therapies for breast cancer that are not as toxic to the body as the conventional chemotherapy that used to be standard. This allows for more effective therapy that is tolerated better by the body.

What attracted you to focus on cancer research?

When I was a kid, I realized I had more energy than most people. At a young age, I knew I was going to have to choose a career where I could apply all my energy – and as Austrian poet Rilke says, “scrape the bottom of my soul”– at the problem. I could not have chosen a more worthy or more fulfilling cause. I think what most people don’t realize is that, as a scientist, you are not just performing experiments. You are teaching. You are giving young people opportunities. You are always mentoring and caring for people and making the world a better place with your efforts. Can you imagine a better thing to which to devote your life?

As a scientist, what drew you to be a Wistar researcher?

I realized that the most important thing about the place I worked at was the leader – the President/CEO. This had to be someone with three things: good leadership skills – someone able to get people to work together; someone with vision ¬– what aspects were going to be critical for the success of the cancer center; and finally, great science from the leader’s laboratory itself – science that impressed and even daunted me. I found this trifecta exceedingly rare. Most cancer center directors had one while some had two. Exceedingly few had all three. I held out for a job where the leader had all three, and I’ve been thrilled to be here every single day.

What role do your posts docs and students play in advancing treatments and/or a cure?

They have the most important role! They are on the ‘front lines’ of the battle, coming up with questions and new hypotheses to test. Can we screen for chemotherapeutic drugs that kill tumors with particular genetic mutations? Can we screen for drugs that improve the efficacy of immune methods to kill cancer?

My job is to teach them how to ask that question in the best way, whether it be the simplest way, sometimes the most informative way, and often, the most cost-saving way. People do not understand how much money it takes to do all the research to move drugs into the clinic, so cost-effectiveness means you get more information out of your research dollars. Sometimes, I hear postdocs and students asking each other how they would answer a particular science question. Then, I hear one of my trainees say, “Yes that’s a good experiment, but do you realize how much it would cost?” and I smile.

Good job, Grasshopper.

Any advice for others interested in a career in cancer research?

My advice is to get into a lab as soon as you can. Do a one-day visit to a lab. Then work in a lab over spring break. Then work in a lab over the summer in a paid internship. The more research you do, the more you will fall in love with it. Imagine a job where you get to figure out how nature works, what God is thinking, and at the same time know that your work will one day benefit the lives of others. I can’t imagine anything better.

Learn more about Wistar’s Postdoctoral Training Program.

National Institutes of Health Funding Powers Wistar Science in 2020

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

Approaching the end of the year, Wistar takes stock of its federal funding performance.

During the 2020 fiscal year of the National Institutes of Health (NIH) — the U.S. government agency that supports biomedical research, it funded Wistar research by granting more than $43M in existing and newly awarded grants.

“Our ability to attract and maintain federal funding is vital for the success of our enterprise and speaks volumes to the quality of the science being pursued at Wistar,” said Dario C. Altieri, M.D., president and CEO, director of the Institute’s Cancer Center and the Robert & Penny Fox Distinguished Professor. “NIH grants fuel some of our largest and most ambitious research projects and our collaborative efforts and support our Cancer Center, a powerhouse of discoveries and advanced technologies in the region.”

The NIH is made up of 27 Institutes and Centers, each with a specific research focus on particular diseases or body systems, working together to support the nation’s research efforts. The vast majority of Wistar’s active grants are administered by the National Cancer Institute (NCI), reflecting Wistar’s vast commitment to cancer research. The second largest pool of grants comes from the National Institute of Allergy and Infectious Diseases, which supports basic and applied research on infectious, immunologic and allergic diseases, powering Wistar investigations into HIV, Epstein-Barr Virus, antimicrobial resistant bacteria, and tuberculosis.

Highlights from newly awarded grants include:

  • Two large grants over four and five years, respectively, to Mohamed Abdel-Mohsen, Ph.D., assistant professor in The Wistar Institute Vaccine & Immunotherapy Center, for his glycoimmunology research in HIV. Glycoimmunology is an emerging field focused on the role of sugar molecules present at the surface of our cells, also referred to as glycans or carbohydrates, in mediating immune responses.

    The new funding will support Abdel-Mohsen’s work investigating the role of altered host sugar repertoire, or glycome, in gut and brain inflammation and cognitive disorders in HIV. This research aims to discover new mechanisms that could be targeted to prevent or treat chronic inflammation that persists in individuals living with HIV despite antiretroviral therapy.

    Applying a similar research paradigm, Abdel-Mohsen obtained additional funding to expand his research to COVID-19. He seeks to understand the integrity of the intestinal barrier in inflammation and COVID-19 pathogenesis. SARS-CoV-2 infection alters the structure of the gut wall making it more permeable to intestinal microbes that can then enter and circulate in the blood. This may lead to a loss of anti-inflammatory circulating carbohydrate molecules in the body, which results in inflammation and worse disease outcomes. This research will lay the groundwork for developing novel biomarkers for disease risk and therapeutic interventions for the COVID-19-induced cytokine storm to prevent severe outcomes and death.
  • A five-year grant to Qing Chen, M.D., Ph.D., assistant professor in The Wistar Institute Cancer Center, for her studies on brain metastasis, which causes an increasingly heavy clinical burden due to its rising incidence and the limited efficacy of existing therapies. Chen is investigating the interaction between cancer cells and the surrounding brain cells to identify key mechanisms that could be targeted to disrupt this interaction and the cancer’s ability to grow in the brain, and eventually provide more effective therapies for cancer patients.
  • A five-year grant awarded to Maureen Murphy, Ph.D., Ira Brind Professor and program leader in The Wistar Institute Cancer Center, to further her studies on the p53 protein, a master regulator of numerous functions in the cell and frequently mutated in cancer. In particular, the Murphy lab is interested in the effects of specific genetic variants of p53 on the tumor-promoting ability of the mutant p53 protein. Murphy and her team investigate how these genetic variants affect the cancer risk in different populations, and this research has important implications for informing personalized medicine approaches.
  • A five-year grant to Rugang Zhang, Ph.D., professor and deputy director of The Wistar Institute Cancer Center, that enables the Zhang lab to study the mechanisms that allow a small number of “dormant” tumor cells to persist in the body after therapy. These cells can awaken from dormancy and start proliferating to give rise to metastases even years after the onset of the primary tumor. Elucidating the underlying mechanisms of tumor dormancy is crucial to achieve cancer eradication.
  • Two NIH Pathway to Independence Awards bestowed to staff scientists Thibaut Barnoud and Sergey Karakashev, both working in Wistar Institute Cancer Center labs. This prestigious and highly sought-after award supports outstanding postdoctoral researchers in their transition from mentored training to and independent faculty position and boosts the awardees’ competitiveness in the job market

The information on dollar amounts disclosed in this blog is publicly available and has been obtained through the NIH Research Portfolio Online Reporting Tools (RePORT).