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TORONTO, Dec. 03, 2024 (GLOBE NEWSWIRE) -- Brain Cancer Canada is pleased to announce a $100,000 pediatric research grant awarded to Dr. Cynthia Hawkins, neuropathologist-scientist, and her team at the Hospital for Sick Children targeting Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma, a highly aggressive type of brain tumour that primarily occurs in children, with a survival rate of less than 1%. The project, “Synthetic Peptides Targeting METTL13 as a Novel Therapeutic for Diffuse Midline Glioma”, aims to develop new chemical moieties capable of crossing the blood-brain barrier (BBB), which remains a significant challenge in treating these types of tumours. Hawkins and her team believe that synthetic peptides designed to inhibit METTL13 can significantly reduce its methylation activity on EEF1A1, thereby impeding the synthesis of proteins essential for oncogenesis in DIPG/DMG. By targeting this specific enzymatic interaction, these peptides will disrupt the downstream onco-proteomic pathways, leading to reduced DIPG/DMG cell growth and viability. Dr. Hawkins describes the project aims and support from BCC, “DIPG/DMG is a devastating disease and the #1 cause of cancer-related death in children. For over 15 years our lab has been dedicated to understanding what drives DIPG/DMG and using this information to test new potential therapies. Through new technology that allowed us to look for how proteins are modified in DIPG/DMG cells, we uncovered a new pathway that these cells rely on to survive. With help from Brain Cancer Canada, and community driven fundraisers, notably Kayge Fighters Foundation, the DIPG community, and a Brain Cancer Canada donation match, we will test novel peptides for their ability to interrupt this pathway and kill DIPG/DMG cells. We truly appreciate the tremendous fundraising efforts that go into supporting our, and the brain tumour research community’s work, and the confidence that the DIPG/DMG community has placed in us. We couldn’t do this work without their support.” The DIPG community—patients, caregivers, families, and friends, along with BCC donors have been instrumental in raising awareness and funds for this devastating disease and are the reason why this grant is possible. Brain Cancer Canada extends special thanks to the Kayge Fighters Against DIPG Foundation, whose generous contribution helped us achieve our $100,000 fundraising goal in BCC’s 2023 “No Child Should Have 1 Year to Live” holiday campaign. Paul and Mandy Fowler lost their son Kayge in 2019. They share, “We chose to partner with Brain Cancer Canada to maximize the impact these funds could have in the fight against DIPG.  We feel blessed to have found such caring charitable partners, who share our passion for progress in the war against the disease that stole our precious Little Bear. We are thrilled to be able to make this donation in honour of our boy, Kayge Gerald Scott Fowler.” “DIPG/DMG families are in urgent need for effective and precisely targeted treatment options for their children. Too many parents have already lost their children to this insidious cancer in part due to a lack of available scientific progress. Dr. Hawkins and her team are at the forefront of changing this by advancing our understanding of these lethal brain cancers,” said Angela Scalisi, Brain Cancer Canada Chair. “Investing in brain cancer research is not only essential, it serves as the cornerstone of hope, illuminating the path toward innovative treatments, and paving the way for a brighter future for patients and families impacted by this devastating disease.” For more details about this ground-breaking research initiative and other efforts by Brain Cancer Canada, please contact sac@braincancercanada.ca. Brain Cancer Canada is a national charity dedicated to supporting individuals diagnosed with malignant brain tumors. Through funding innovative research, neurosurgical technology, and advocating for increased options for treatments, Brain Cancer Canada aims to improve survival rates and the quality of life for patients, while providing essential support to their families.  This funding reflects our unwavering commitment to support research in pediatric brain cancer, addressing an inequity in funding and pursuing unmet need. Media Contact:  Media@braincancercanada.ca If you wish to make a donation to Brain Cancer Canada, please visit: https://braincancercanada.ca/donate/ 1-855-375-1381 #DIPG #DMG #BrainCancerCanada #TheHospitalForSickChilden #SickKids #DrHawkins #KaygeFighters #PediatricCancerResearch

Scientists have found that human ribosomes decode mRNA slower than bacteria, with implications for drug development. Scientists at St. Jude Children's Research Hospital revealed that human ribosomes decode messenger RNA (mRNA) 10 times slower than bacterial ribosomes, but do so more accurately. The study, published today in Nature, used a combination of field-leading structural biology approaches to better understand how ribosomes work. The scientists pinpointed where the process slows down in humans, which will be useful information for developing new therapeutics for cancer and infections. Ribosomes are molecular machines within cells, responsible for synthesizing proteins by decoding mRNA. By conducting mechanistic studies on bacterial and human ribosomes, researchers can understand their similarities and differences to develop drugs and understand disease. Many antibiotics, the drugs we use to treat bacterial infections, work by targeting bacterial ribosomes. In humans, changes in how accurately ribosomes decode mRNA have been linked to aging and disease, representing a potential point of therapeutic intervention. This gives the work implications for the treatment of infections and cancer. "Bacteria have been very well studied for many decades, but the kind of studies that we do, careful mechanistic studies, have been missing on human ribosomes," said corresponding author Scott Blanchard, Ph.D., St. Jude Department of Structural Biology. "We're very interested in human ribosomes because those are what need to be targeted to find new treatments for cancer and viral infections such as COVID." Resolution revolution Ribosomes decode mRNA using a molecule called aminoacyl-transfer RNA (tRNA) as substrate. The decoding process involves several different steps. The researchers deployed methods such as single-molecule fluorescence resonance energy transfer (smFRET) and cryo-electron microscopy (cryo-EM) to examine the human ribosome decoding mechanisms. The single-molecule imaging gives the researchers information on how quickly things occur. So, in this case, how quickly human ribosomes go through the different steps during the decoding process. Cryo-EM gives the researchers structural information. So, how the human ribosome looks or what conformations (shapes) it is in at each step. By combining these two methods, the scientists get information on how quickly these processes occur in humans compared to bacteria as well as about the underlying structural causes for any differences they observe. "We wanted to know how quickly a human ribosome can read the genetic code, how quickly it finds the tRNA that's complementary to the mRNA," said co-first author Mikael Holm, Ph.D., St. Jude Department of Structural Biology. "We found that the process is about 10 times slower for human ribosomes than it is in bacteria. But this slow down adds accuracy, because human ribosomes are known to be more accurate at translating the code than bacterial ribosomes." Specifically, the researchers found that while humans and bacteria both decode mRNA, the reaction pathway of aminoacyl-tRNA movement during the decoding process is different on human ribosomes and is significantly slower. These differences arise from structural elements in the human ribosome and in the human elongation factor, eEF1A, that together are responsible for faithfully incorporating the right tRNA for each mRNA codon (piece of the sequence). The distinct nature and timing of conformational changes within the ribosome and eEF1A may explain how human ribosomes achieve greater decoding accuracy. "With our cryo-EM structural studies, we were able to resolve human ribosome structures to atomic resolution, which revealed unprecedented features such as rRNA and protein modifications, ions and solvent molecules present in the human ribosome," said co-first author Kundhavai Natchiar, Ph.D., St. Jude Department of Structural Biology. "These features finely characterize the molecular basis of interactions of the drug molecules with the human ribosome, which is indispensable for human ribosome-based drug design and discovery." Caught in the act The researchers also pinpointed exactly which step of the decoding process slowed down in human ribosomes. There are two steps in the process of the ribosome selecting the right tRNA: initial selection and proofreading selection. The second step, proofreading selection, is where the ribosome checks for a second time that it chose the right molecule. That is the step that is 10 times slower in humans than in bacteria. Think of a gymnast, contorting themselves into different shapes on the mat as they work through their routine. This is similar to how ribosomes transition into various conformations to achieve different results. The research showed that a lot of conformational gymnastics that human ribosomes undergo are not present in bacterial ribosomes and are thus likely tied to the slowdown of the proofreading selection process. The researchers also found that several drugs target the proofreading selection process, not initial selection. So, instead of hitting the step that is similar between humans and bacteria, these drugs focus on the most different, slowest step. "In structural biology, a single snapshot of a macromolecular machine is not always sufficient to explain how it functions," said co-first author Emily Rundlet, Ph.D., St. Jude Department of Structural Biology. "Often, the snapshot that's needed to answer your biological question is not the most stable form of the molecule, but instead it is short-lived and difficult to capture. Using smFRET and cryo-EM together brings the dimension of time to structural biology, which allows us to visualize important transient intermediate steps of human decoding and understand the different mechanisms on a new level."

Vaccines against COVID-19 were developed in record time, but the successful advancement of therapeutics, particularly those that could disrupt the CARS-CoV-2 virus cycle, have been slower to move through the clinic. Researchers at multiple companies and institutes are doggedly pursuing that goal so the virus can become little more than a hindrance in the future. A recent PBS report highlighted some of these efforts, focusing on clinical programs that have the potential to halt viral reproduction and keep those infected out of the hospitals. Experimental medications such as molnupiravir, in development by Merck and Florida-based Ridgeback Biotherapeutics, have the potential to fill the treatment gaps that vaccines cannot. Merck and Ridgeback are jointly developing molnupiravir, an orally available antiviral candidate for the treatment of COVID-19. Earlier this year, the two companies noted a slight setback in the development of that program. In April, Merck announced it was moving molnupiravir into the Phase III portion of the Phase II/III MOVE-OUT study in outpatient COVID-19 patients based on a planned interim analysis from the Phase II part of the study. However, at the time, the companies said the Phase III portion of another study, the Phase II/III MOVE-IN study in hospitalized patients, will not proceed due to data that suggests molnupiravir is unlikely to demonstrate a clinical benefit in that patient population. Daria Hazuda, vice president of infectious disease and vaccine discovery research at Merck, said they are hopeful the Phase III portion of the study, expected to be complete later this year, will demonstrate that molnupiravir is an effective treatment for mild to moderate cases of COVID-19. Beyond Merck, PBS noted research conducted by Adolfo Garcia-Sastre, the director of the Global Health and Emerging Pathogens Institute at Icahn School of Medicine at Mount Sinai and the University of California, San Francisco’s Quantitative Biosciences Institute. After extensive research on multiple antiviral options, the collaborators put their focus on plitidepsin, an injectable multiple myeloma drug medicine developed by Spain’s PharmaMar. Plitidepsin acts by blocking the protein eEF1A, present in human cells, which SARS-CoV-2 uses to reproduce and infect other cells. Through this inhibition, the expectation is that reproduction of the virus inside the cell is prevented, making this propagation to the rest of the cells unviable. Phase III research of plitidepsin was greenlit by Spanish health authorities last month. The scientific team hopes to see if the oncology drug effectively reduces days in the hospital for COVID-19 patients. In its report, the results of compare plitidepsin’s effectiveness in the Phase III study would be compared to Gilead Sciences’ remdesivir, which is currently the standard of care for COVID-19. Remdesivir, the only antiviral approved to treat COVID-19, can shorten the hospital stay of COVID-19 patients, it has fallen short in treating patients. Garcia-Sastre told PBS he hopes plitidepsin will demonstrate live-saving potential. Another potential antiviral highlighted by the news outlet is ivermectin, a decades-old drug approved to treat head lice infections as well as the treatment of some parasitic worms. Research has shown in a laboratory setting that the use of ivermectin inhibited the SARS-CoV-2 virus within 24 to 48 hours of treatment. The preclinical data showed that ivermectin prevented the virus’ RNA from replicating. While COVID-19 is not a parasitic disease, the laboratory tests showed that the drug targets the disease like one.