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Novel Therapeutic Agent Could Be Effective for Treating Cancers With Certain Gene Mutations

AHA Publisher — Fri, 30 Jul 2021 07:00:55 +0000

Mount Sinai Health System via News-Medical – Mount Sinai researchers have developed a therapeutic agent that shows high effectiveness in vitro at disrupting a biological pathway that helps cancer survive, according to a paper published in Cancer Discovery, a journal of the American Association for Cancer Research, in July. The therapy is an engineered molecule, named MS21, that causes the degradation of AKT, an enzyme that is overly active in many cancers. This study laid out evidence that pharmacological degradation of AKT is a viable treatment for cancers with mutations in certain genes. AKT is a cancer gene that encodes an enzyme that is frequently abnormally activated in cancer cells to stimulate tumor growth. Degradation of AKT reverses these processes and inhibits tumor growth. “Our study lays a solid foundation for the clinical development of an AKT degrader for the treatment of human cancers with certain gene mutations,” said Ramon Parsons, MD, PhD, Director of The Tisch Cancer Institute and Ward-Coleman Chair in Cancer Research and Chair of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. “Examination of 44,000 human cancers identified that 19 percent of tumors have at least one of these mutations, suggesting that a large population of cancer patients could benefit from therapy with an AKT degrader such as MS21.” MS21 was tested in human cancer-derived cell lines, which are models used in laboratories to study the efficacy of cancer therapies. Mount Sinai is looking to develop MS21 with an industry partner to open clinical trials for patients. Translating these findings into effective cancer therapies for patients is a high priority because the mutations and the resulting cancer-driving pathways that we lay out in this study are arguably the most commonly activated pathways in human cancer, but this effort has proven to be particularly challenging. We look forward to an opportunity to develop this molecule into a therapy that is ready to be studied in clinical trials.” Jian Jin, PhD, Mount Sinai Professor in Therapeutics Discovery and Director of the Mount Sinai Center for Therapeutics Discovery at Icahn Mount Sinai To read the original article click here.

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Innovative Genome Editing Treatment Destroys Cancer Cells

AHA Publisher — Tue, 08 Dec 2020 08:00:17 +0000

Abigail Klein Leichman via Israel21c – There’s been a lot of press about upcoming Covid-19 vaccines built with mRNA – genetic messengers that carry instructions to cells to make proteins to treat or prevent disease. This same technology was used to treat cancer in mice in the laboratory of Prof. Dan Peer, VP for R&D and head of the Laboratory of Precision Nanomedicine at the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University. The novel lipid nanoparticle-based delivery system, called CRISPR-LNPs, carries mRNA that encodes for the enzyme Cas9. This enzyme acts as a molecular pair of scissors that snips the cancer cells’ DNA, effectively destroying them. The results of the study, funded by Israel Cancer Research Fund, were published November 18 in the Science Advances journal. “This is the first study in the world to prove that the CRISPR genome editing system can be used to treat cancer in a living animal effectively,” said Peer. “It must be emphasized that this is not chemotherapy. There are no side effects, and a cancer cell treated in this way will never become active again. The molecular scissors of Cas9 cut the cancer cell’s DNA, thereby neutralizing it and permanently preventing replication.” Peer and his team chose to test the technology on two of the deadliest cancers: glioblastoma and metastatic ovarian cancer. Glioblastoma is the most aggressive type of brain cancer, with a five-year survival rate of only 3%. A single treatment with CRISPR-LNPs doubled the average life expectancy of mice with glioblastoma tumors, improving their overall survival rate by about 30%. Ovarian cancer is the most lethal cancer of the female reproductive system; only a third of the patients survive this disease. Treatment with CRISPR-LNPs in a metastatic ovarian cancer mice model increased their overall survival rate by 80%. “The CRISPR genome editing technology, capable of identifying and altering any genetic segment, has revolutionized our ability to disrupt, repair or even replace genes in a personalized manner,” said Peer. “Despite its extensive use in research, clinical implementation is still in its infancy because an effective delivery system is needed to safely and accurately deliver the CRISPR to its target cells. The delivery system we developed targets the DNA responsible for the cancer cells’ survival. This is an innovative treatment for aggressive cancers that have no effective treatments today.” He said the research team now intends “to go on to experiments with blood cancers that are very interesting genetically, as well as genetic diseases such as Duchenne muscular dystrophy. It will probably take some time before the new treatment can be used in humans, but we are optimistic.” The researchers include, among others, Daniel Rosenblum, Anna Gutkin and Dinorah Friedmann-Morvinski from TAU; Dr. Zvi Cohen, head of neurosurgical oncology at Sheba Medical Center, Dr. Mark Behlke, CSO at Integrated DNA Technologies; and Prof. Judy Lieberman of Boston Children’s Hospital and Harvard Medical School. “Through Ramot, the technology transfer company of Tel Aviv University, we are already negotiating with international corporations and foundations, aiming to bring the benefits of genetic editing to human patients,” said Peer. To read the original article click here. For more articles from Israel21c click here.

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Study Shows Oxidant Hydrogen Peroxide Can Actually Slow Down Cell Ageing

AHA Publisher — Mon, 16 Nov 2020 08:00:24 +0000

Chalmers University of Technology via News-Medical Net – At high concentrations, reactive oxygen species – known as oxidants – are harmful to cells in all organisms and have been linked to ageing. But a study from the Chalmers University of Technology, Sweden, has now shown that low levels of the oxidant hydrogen peroxide can stimulate an enzyme that helps slow down the ageing of yeast cells. One benefit of antioxidants, such as vitamins C and E, is that they neutralise reactive oxygen species – known as oxidants – which may otherwise react with important molecules in the body and destroy their biological functions. Larger amounts of oxidants can cause serious damage to DNA, cell membranes and proteins for example. Our cells have therefore developed powerful defence mechanisms to get rid of these oxidants, which are formed in our normal metabolism. It was previously believed that oxidants were only harmful, but recently we have begun to understand that they also have positive functions. Now, the new research from the Chalmers University of Technology shows that the well-known oxidant hydrogen peroxide can actually slow down the ageing of yeast cells. Hydrogen peroxide is a chemical used for hair and tooth whitening, among other things. It is also one of the oxidants formed in our metabolism that is harmful at higher concentrations. The Chalmers researchers studied the enzyme Tsa1, which is part of a group of antioxidants called peroxiredoxins. Previous studies of these enzymes have shown that they participate in yeast cells’ defences against harmful oxidants. But the peroxiredoxins also help extend the life span of cells when they are subjected to calorie restriction. The mechanisms behind these functions have not yet been fully understood.” Mikael Molin, Study Lead, Department of Biology and Biological Engineering, Chalmers University of Technology It is already known that reduced calorie intake can significantly extend the life span of a variety of organisms, from yeast to monkeys. Several research groups, including Mikael Molin’s, have also shown that stimulation of peroxiredoxin activity, in particular, is what slows down the ageing of cells, in organisms such as yeast, flies and worms, when they receive fewer calories than normal through their food. “Now we have found a new function of Tsa1,” says Cecilia Picazo, a postdoctoral researcher at the Division of Systems and Synthetic Biology at Chalmers. “Previously, we thought that this enzyme simply neutralises reactive oxygen species. But now we have shown that Tsa1 actually requires a certain amount of hydrogen peroxide to be triggered in order to participate in the process of slowing down the ageing of yeast cells.” Surprisingly, the study shows that Tsa1 does not affect the levels of hydrogen peroxide in aged yeast cells. On the contrary, Tsa1 uses small amounts of hydrogen peroxide to reduce the activity of a central signalling pathway when cells are getting fewer calories. The effects of this ultimately lead to a slowdown in cell division and processes linked to the formation of the cells’ building blocks. The cells’ defences against stress are also stimulated – which causes them to age more slowly. “Signal pathways which are affected by calorie intake may play a central role in ageing by sensing the status of many cellular processes and controlling them,” says Mikael Molin. “By studying this, we hope to understand the molecular causes behind why the occurrence of many common diseases such as cancer, Alzheimer’s disease, and diabetes shows a sharp increase with age.” The fact that researchers have now come to a step closer to understanding the mechanisms behind how oxidants can actually slow down the ageing process could lead to new studies, for example looking for peroxiredoxin-stimulating drugs, or testing whether age-related diseases can be slowed by other drugs that enhance the positive effects of oxidants in the body. More about: The mechanism of slowed ageing by the enzyme Tsa1: The Chalmers researchers have shown a mechanism for how the peroxiredoxin enzyme Tsa1 directly controls a central signalling pathway. It slows down ageing by oxidising an amino acid in another enzyme, protein kinase A, which is important for metabolic regulation. The oxidation reduces the activity of protein kinase A by destabilising a portion of the enzyme that binds to other molecules. Thus, nutrient signalling via protein kinase A is reduced, which in turn downregulates the division of cells and stimulates their defence against stress. More about: Related results from other research groups: Other studies have also shown that low levels of reactive oxygen species can be linked to several positive health effects. These oxidants are formed in the mitochondria, the ‘powerhouse’ of a cell, and the process, called mitohormesis, can be observed in many organisms, from yeast to mice. In mice, tumour growth is slowed by mitohormesis, while in roundworms it has been possible to link both peroxiredoxins and mitohormesis to the ability of the type 2 diabetes drug metformin to slow cellular ageing. Metformin is also relevant in the hunt for drugs that can reduce the risk of older people being severely affected by Covid-19. Studies in China and the United States have yielded some promising results, and one theory is that metformin may counteract the deterioration of the immune system caused by ageing. To read the original articles click here.

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Coronavirus Makes Changes That Cause Cells Not to Recognize It

AHA Publisher — Wed, 29 Jul 2020 07:00:04 +0000

North Carolina State University via EurekAlert – With an alarm code, we can enter a building without bells going off. It turns out that the SARS coronavirus 2 (SARS-CoV-2) has the same advantage entering cells. It possesses the code to waltz right in. On July 24 in Nature Communications, researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) reported how the coronavirus achieves this. The scientists resolved the structure of an enzyme called nsp16, which the virus produces and then uses to modify its messenger RNA cap, said Yogesh Gupta, PhD, the study lead author from the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio. “It’s a camouflage,” Dr. Gupta said. “Because of the modifications, which fool the cell, the resulting viral messenger RNA is now considered as part of the cell’s own code and not foreign.” Deciphering the 3D structure of nsp16 paves the way for rational design of antiviral drugs for COVID-19 and other emerging coronavirus infections, Dr. Gupta said. The drugs, new small molecules, would inhibit nsp16 from making the modifications. The immune system would then pounce on the invading virus, recognizing it as foreign. “Yogesh’s work discovered the 3D structure of a key enzyme of the COVID-19 virus required for its replication and found a pocket in it that can be targeted to inhibit that enzyme. This is a fundamental advance in our understanding of the virus,” said study coauthor Robert Hromas, MD, professor and dean of the Long School of Medicine. Dr. Gupta is an assistant professor in the Department of Biochemistry and Structural Biology at UT Health San Antonio and is a member of the university’s Greehey Children’s Cancer Research Institute. In lay terms, messenger RNA can be described as a deliverer of genetic code to worksites that produce proteins. To read the original article click here.

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