Tag: Kossenkov

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 February 6, 2023. 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.

###

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

(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 October 12, 2022. Posted in Press Releases.

PHILADELPHIA — (OCTOBER 12, 2022) — The mitochondria is a key energy-producing component of the human cell that plays an important role in cancer cell metabolism. 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.

###

The Wistar Institute 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.

(left) Dr. Louise Showe works with a young scientist in the lab. (right) Dr. Andrew Kossenkov

Powering Cancer Research

Written by The Wistar Institute on October 4, 2021. Posted in Featured News.

Wistar’s scientific accomplishments could not be achieved without the support of our donors who recognize our research strengths, share our vision and are committed to tackling disease, improving human health and answering the most pressing scientific questions.

Dr. Jerry Francesco’s support is behind the latest developments in the cancer research of Dr. Louise Showe, professor in the Molecular & Cellular Oncogenesis Program of The Wistar Institute Cancer Center.

Dr. Showe is helping advance the development of a blood-based test to detect cancer at an early stage in nonsmokers with no family history of lung cancer as well as people with an increased risk, as early detection makes a difference for this most hard-to-treat cancer. Dr. Francesco learned about Dr. Showe’s work in 2019, and since then has been an essential part of making a lung cancer early diagnosis test a reality.

“The potential of this project to develop a clinical, non-invasive test based on blood gene expression is incredible,” said Showe. “There are a number of possibilities for the project including using this test to diagnose lung cancer in at-risk populations. It could also be used as a follow up test after treatment to monitor cancer recurrence. And further along in development, it could even be a test for screening the general population to help in early detection.”

Dr. Showe collaborates closely with Dr. Andrew Kossenkov, assistant professor in the Vaccine & Immunotherapy Center and member of the Gene Expression & Regulation Program. In 2007, Dr. Kossenkov started as a postdoctoral fellow in the Showe lab where the lung cancer diagnostic project quickly became his main focus for years to come. Dr. Kossenkov is now the scientific director of the Bioinformatics Facility.

“This is a very exciting project of great proportion and importance with the final goal of making a non-invasive lung cancer diagnosis from blood,” said Kossenkov. “Besides great clinical down-the-road impact, it was a technically and logistically complex endeavor, and we had to go through multiple iterations and approaches during the span of the project. That was and continues to be an exciting time and helped me to increase my expertise in the field tremendously.”

Because of donors like Dr. Francesco, Wistar scientists see the fruits of their research move forward in directions that are visionary and out of the box. Philanthropic support also gives researchers a leg up to gather the data needed to apply for large federal grants.

Wistar’s Science Discovery Fund connects philanthropists and scientists together to solve some of the biggest issues in cancer and infectious disease. It is the vehicle through which the donor community can learn about and support the highest-risk, potentially high-reward research taking place. Side by side with researchers, they move discoveries into future diagnostics or drug targets that help scientists translate basic discoveries into next-generation vaccines and medicines.

We spoke to Dr. Francesco about Dr. Showe’s work and his contributions that helped her advance a lung cancer diagnostic for one of the most common causes of cancer deaths in men and women worldwide,1 accounting for 2.1 million new cases and 1.8 million deaths in 2018.2 Twenty percent of those U.S. deaths were nonsmokers who may have smoked less than 100 cigarettes in their lifetime or might have been genetically predisposed or driven by a molecular abnormality or change.

Dr. Francesco wants people to know that Wistar scientists are a highly committed team that possesses a broad range of scientific interests and cutting-edge expertise, with an aim toward practical solutions to disease.

“I think Wistar research is the finest in the country, if not the world,” said Dr. Francesco. “Dr. Showe’s research is of immense interest because of the sad state of affairs in early diagnosis of lung cancer and for the hope of developing simple and readily available tests for this terrible disease. I only wish such tests were available for my beloved wife Lucille who passed from lung cancer. I hope that my philanthropy will help speed the early diagnosis of lung cancer so that eventually such tests can be used by family physicians in their practice. I am happy to play a small role in this project.”

Sources:

1 World Health Organization Cancer Fact Sheet, 2018
2 Source: Yale Medicine;