(Press-News.org) (Toronto, Friday, May 7, 2021) -- Probing the unique biology of human pancreatic cancer cells in a laboratory has yielded unexpected insights of a weakness that can be used against the cells to kill them.
Led by Princess Margaret Cancer Centre (PM) Scientist Dr. Marianne Koritzinsky, researchers showed that about half of patient-derived pancreatic cancer cell lines are highly dependent or "addicted" to the protein peroxiredoxin 4 (PRDX4), as a result of the altered metabolic state of the cancer cell.
This addiction is vital for the cancer cell's survival, thereby also making it a precise, potential target against the cancer.
Pancreatic cancer is a deadly disease with an overall five-year survival of only eight per cent. Moreover, 36% to 46% of patients who undergo surgery with curative intent develop a recurrence of pancreatic cancer, despite adjuvant chemotherapy.
Research results are published on May 7, 2021 in Science Advances, published by the American Association for the Advancement of Science.
It's been known for decades that cancer cells acquire key changes in their metabolism to support their continuous need for building blocks from nutrients to divide and grow faster, explains Dr. Koritzinsky, who is the senior author of the study, and an Associate Professor in the Departments of Radiation Oncology, Medical Biophysics and the Institute of Medical Science at the University of Toronto.
This latest research reveals that the same metabolic deregulation that fuels cell growth, can create novel vulnerabilities in cancer.
It was previously known that pancreatic cancer cells increased levels of a key metabolite known as NADPH which acts to fuel uncontrolled levels of cell growth. Dr. Koritzinsky discovered that high levels of NADPH in the pancreatic cancer cells created a novel form of oxidative stress and a corresponding requirement for PRDX4 to survive.
Essentially, cancer cells need PRDX4, an antioxidant protein, to destroy the toxic byproducts resulting from the uncontrolled metabolism.
Dr. Koritzinsky showed that targeting PRDX4 in patient-derived cancer cells lines led to toxic accumulation of oxidative stress, resulting in DNA damage, and cell death, and impaired tumour growth in preclinical models. Equally important, loss of PRDX4 had no measurable effect on normal cells.
Taken together, this body of work reveals the potential of targeted therapies to exploit unique metabolic features of cancer cells that are far more specific than, for example, chemotherapy which affects both cancer and normal cells.
"It's not hard to kill cancer cells," says Dr. Koritzinsky, "It's hard to kill cancer cells without harming the cancer patient."
She goes on to explain that targeting a specific protein that is needed by a cancer cell, but not a normal one, opens up a wider therapeutic window, with potentially less toxicity to normal tissue.
For this research, Dr. Koritzinsky teamed up with Dr. Jason Moffat, Professor, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto and PM Senior Scientist/Staff Physician Dr. David Hedley to mine large functional genomics data sets and validate findings in patient-derived tumour cells, including recent samples from Princess Margaret patients.
Through this data set mining, they were able to assess about 20,000 different proteins for a comprehensive picture of which ones are important in helping cancer cells survive. PRDX4 turned out to be key.
Based on these discoveries, Dr. Koritzinsky would like to develop new drugs against PRDX4 that could be tested in preclinical models, and eventually translated to the clinic.
She adds that there may be other ways to take advantage of these new biological insights, including combining this targeted approach with other DNA damaging treatments such as radiotherapy, and establishing biomarkers that can identify the patients who will benefit from PRDX4 targeting.
INFORMATION:
Funding for this research was provided by: the Cancer Research Society/Robert Letterman Memorial Fund, The Terry Fox Foundation/Research Institute, The Princess Margaret Cancer Foundation, the Strategic Training in Translational Radiation Medicine for the 21st Century (STARS21) Program, NIH/NCI, the Ontario Ministry of Health and Princess Margaret Cancer Centre.
Competing interests: Paul C. Boutros is a member of the Scientific Advisory Boards of BioSymetrics Inc. and Intersect Diagnostics Inc. Jason Moffat is a shareholder in Northern Biologics and Pionyr Immunotherapeutics and is an advisor of Century Therapeutics and Aelian Biotechnology. Bradly G.Wouters is a founder, shareholder, and board member for Northern Biologics and a consultant to Versant Ventures. Marianne Koritzinsky is a shareholder in Northern Biologics. None of these associations relate directly to this work.
About Princess Margaret Cancer Centre
Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital, Toronto Rehabilitation Institute and the Michener Institute for Education at UHN. All are research hospitals affiliated with the University of Toronto. For more information: http://www.theprincessmargaret.ca
For media inquiries, please contact:
Alexandra Radkewycz
Senior Public Affairs Advisor
Princess Margaret Cancer Centre, University Health Network
Phone: 416 946 2846
Email: Alexandra.Radkewycz@uhn.ca
Induced bank filtration is a key and well-established approach to provide drinking water supply to populated areas located along rivers or lakes and with limited access to groundwater resources. It is employed in several countries worldwide, with notable examples in Europe, the United States, and parts of Africa. Contamination of surface waters poses a serious threat to attaining drinking water standards. In this context, human pathogenic microorganisms such as some viruses and bacteria, originating from the discharge of wastewater treatment plants, form a major contaminant group. A detailed study at an induced bank filtration site along the Rhine river in Germany has now linked transport of bacteria to seasonal dynamics. Key results of the study show that floods should be ...
WASHINGTON, D.C. - Peer reviewed by medical experts that included three U.S. government senior scientists and published in the American Journal of Therapeutics, the research is the most comprehensive review of the available data taken from clinical, in vitro, animal, and real-world studies. Led by the Front Line COVID-19 Critical Care Alliance (FLCCC), a group of medical and scientific experts reviewed published peer-reviewed studies, manuscripts, expert meta-analyses, and epidemiological analyses of regions with ivermectin distribution efforts all showing that ...
The two meters of -stretched- DNA contained in human cells are continuously twisting and untwisting to give access to genetic information: when a gene is expressed to generate a protein, the two strands of DNA are separated to give access to all the machinery necessary for this expression, resulting in an excessive accumulation of coiling that needs to be resolved later. The paper that has now been published by the team led by Felipe Cortés, head of the DNA Topology and Breaks Group at the Spanish National Cancer Research Centre (CNIO), in collaboration with Silvia Jimeno González, professor at the University of Seville ...
Neonatal hypothermia -- which occurs when an infant's core body temperature falls below the normal range needed to maintain health -- contributes to approximately one million deaths each year, and countless cases of stunted growth, almost exclusively in low- and middle-income countries. To address this common but preventable condition, researchers from Boston Children's Hospital, engineers at Lawrence Berkeley National Laboratory, and colleagues in Rwanda developed the Dream Warmer, a low cost, reusable non-electric infant warmer to prevent and treat hypothermia. A new study from the team shows that infants who received treatment with the warmer had only an 11 percent rate of ...
A new experiment shows that the more energy consumed by a clock, the more accurate its timekeeping.
Clocks pervade every aspect of life, from the atomic clocks that underlie satellite navigation to the cellular clocks inside our bodies. All of them consume energy and release heat. A kitchen clock, for example, does this by using up its battery. Generally the most accurate clocks require the most energy, which hints at a fundamental connection between energy consumption and accuracy. This is what an international team of scientists from Lancaster, Oxford, and Vienna set out to test.
To do this, they built a particularly simple clock, consisting of a vibrating ultra-thin membrane, tens of nanometers ...
A research team from the Skoltech Center for Design, Manufacturing and Materials (CDMM) studied the effects of processing additives - aluminum hydroxide and zinc stearate - on the polymerization kinetics of thermosets used in pultrusion. The research was published in the Journal of Composite Materials.
Fiber-reinforced plastic (FRP) structural elements that have obvious advantages over conventional materials, such as steel, wood, and concrete, are widely used in civil, marine and road construction. FRP structures are manufactured using the pultrusion process, in which polymerization is achieved by continuously pulling ...
A new University of Iowa study challenges the idea that gray matter (the neurons that form the cerebral cortex) is more important than white matter (the myelin covered axons that physically connect neuronal regions) when it comes to cognitive health and function. The findings may help neurologists better predict the long-term effects of strokes and other forms of traumatic brain injury.
"The most unexpected aspect of our findings was that damage to gray matter hubs of the brain that are really interconnected with other regions didn't really tell us much about how poorly people would do on cognitive tests after brain damage. On the other hand, people with damage to the densest white matter connections did much worse on those tests," explains Justin Reber, PhD, ...
Training the artificial intelligence models that underpin web search engines, power smart assistants and enable driverless cars, consumes megawatts of energy and generates worrying carbon dioxide emissions. But new ways of training these models are proven to be greener.
Artificial intelligence models are used increasingly widely in today's world. Many carry out natural language processing tasks - such as language translation, predictive text and email spam filters. They are also used to empower smart assistants such as Siri and Alexa to 'talk' to us, and to operate driverless cars.
But to function ...
To observe the swift neuronal signals in a fish brain, scientists have started to use a technique called light-field microscopy, which makes it possible to image such fast biological processes in 3D. But the images are often lacking in quality, and it takes hours or days for massive amounts of data to be converted into 3D volumes and movies.
Now, EMBL scientists have combined artificial intelligence (AI) algorithms with two cutting-edge microscopy techniques - an advance that shortens the time for image processing from days to mere seconds, while ensuring that the resulting images are crisp and accurate. The findings are published in Nature Methods.
"Ultimately, we were able to take 'the best of both worlds' in this approach," says Nils Wagner, one of the paper's two lead ...
PHILADELPHIA-- A gene called GAS2 plays a key role in normal hearing, and its absence causes severe hearing loss, according to a study led by researchers in the Perelman School of Medicine at the University of Pennsylvania.
The researchers, whose findings are published online today in Developmental Cell, discovered that the protein encoded by GAS2 is crucial for maintaining the structural stiffness of support cells in the inner ear that normally help amplify incoming sound waves. They showed that inner ear support cells lacking functional GAS2 lose their amplifier abilities, causing severe hearing ...
