Diazo-oxo-L-norleucine

[09-October-2023] NEW YORK, Oct. 9, 2023 /PRNewswire/ -- A new combination of treatments safely decreased growth of pancreatic cancer in mice by preventing cancer cells from scavenging for fuel, a new study finds. Led by researchers at NYU Grossman School of Medicine, its Department of Radiation Oncology, and the Perlmutter Cancer Center, the work builds on prior discoveries at NYU Langone that revealed how pancreatic cancer cells, to avert starvation and keep growing, find alternate fuel sources. Normally supplied by the bloodstream, oxygen, blood sugar, and other resources become scarce as the increasing density of fast-growing pancreatic tumors cuts off their own blood supply. In this environment, the ability to switch fuels contributes to the deadliness of pancreatic cancers. Published online October 9 in Nature Cancer, the new study involves a drug designed to prevent pancreatic ductal adenocarcinoma (PDAC) cells from one such switch. PDAC cells use the enzyme glutaminase to convert the amino acid glutamate into glutamine, a form that can be burned for fuel to sustain rapid tumor growth. Drugs designed to block glutaminase, however, have been shown to cause cancer cells to switch to still other scavenging pathways. For this reason, the field next looked at experimental treatments like DRP-104, designed by Dracen Pharmaceuticals, a new "prodrug" form of the compound 6-Diazo-5-oxo-L-norleucine (DON) that is preferentially activated within tumors to overcome toxicity issues seen with DON. DON was designed to starve cancer cells by mimicking glutamine, which unlike glutaminase blockers, broadly inhibits all metabolic pathways that use glutamine. Currently in clinical trials against non-small cell lung cancer, DRP-104 cannot be burned as fuel, but clings to the same enzymes as glutamine. In the current study, DRP-104 treatment alone decreased PDAC growth in mouse models of pancreatic cancer. Importantly, the current team also found that PDAC cells pushed into metabolic crisis by DRP-104 increase signaling through a protein called extracellular signal-regulated kinase or ERK, to make up for their loss of glutamine metabolism. When the team combined DRP-104 with an existing drug that blocks the ERK signaling pathway, trametinib, it further improved survival in pancreatic cancer mouse models compared to DRP-104 treatment alone. "Despite a decade of advances in understanding how cancer cells switch fuel sources, we have not yet effectively translated this into clinically relevant therapies," says corresponding study author Alec Kimmelman, MD, PhD, the Anita Steckler and Joseph Steckler Chair of Radiation Oncology at NYU Langone Health. "Broad antagonism of metabolic pathways with glutamine analogs may provide another mode of attack against these highly resistant tumor cells. The fact that such drugs are already being tested in the clinic makes us hopeful that we may finally see patient outcomes improve, if this approach proves to be effective in clinical trials." Moving forward, the research team will seek to understand how glutamine antagonism impacts other adaptive nutrient scavenging mechanisms in pancreatic cancers and whether these could be targeted as well. The success of such approaches will depend on careful balancing of improved therapeutic efficacy and toxicity from the potential effects on normal tissues, Kimmelman adds. Along with Kimmelman, authors from Perlmutter Cancer Center and the Department of Radiation Oncology at NYU Langone were Joel Encarnación-Rosado, Albert Sohn, Douglas Biancur, Elaine Lin, Victoria Osorio-Vasquez, and Diana González-Baerga. Also Perlmutter authors were Ende Zhao and Diane Simeone. Also authors of the study were Tori Rodrick and Drew Jones from the Division of Advanced Research Technologies at NYU Grossman School of Medicine; Seth Parker from the Department of Biochemistry & Molecular Biology at University of British Columbia in Vancouver, and Yumi Yokoyama and Robert Wild from Dracen Pharmaceuticals, Inc., of San Diego. Funding for the study came from Perlmutter Cancer Center support grant P30CA016087 and National Cancer Institute grants P01A1080192, P01CA117969, R35CA232124, P30CA016087-38, 1R01CA251726-01A1; as well as from the Lustgarten Foundation, Stand Up to Cancer, and the Howard Hughes Medical Gilliam Fellowships. Kimmelman has financial interests in Vescor Therapeutics, is on the scientific advisory board of Rafael/Cornerstone Pharmaceuticals and OncoRev, and has been a consultant for Deciphera and Abbvie. These relationships are being managed according with the policies of NYU Langone Health. Yokoyama and Wild are employees of, and have ownership in, Dracen Pharmaceuticals, maker of DRP-104. Contact: Gregory Williams gregory.williams@nyulangone.org

Wheat -- the most widely cultivated crop in the world -- is under growing attack from harmful toxins. Across Europe, almost half of wheat crops are impacted by the fungal infection that gives rise to these toxins, according to a new study. Wheat -- the most widely cultivated crop in the world -- is under growing attack from harmful toxins. Across Europe, almost half of wheat crops are impacted by the fungal infection that gives rise to these toxins, according to a study led by fungal biologist Dr Neil Brown from the UK's University of Bath, in collaboration with colleagues at the University of Exeter. These troublesome 'mycotoxins' are produced by the fungus that causes Fusarium Head Blight, a disease that affects wheat and other cereals growing in the field. Eating products contaminated with mycotoxins causes sickness in humans and livestock, such as vomiting and other gastrointestinal problems. Mycotoxins are also bad news for farmers and the economy because they reduce the grain's value. Wheat plays a huge role in feeding humanity, providing 18% of the total calories in people's diets globally. Concerns both for our health and for global food supplies were the impetuses for the new study. Dr Brown, who works in the Milner Centre for Evolution in the Department of Life Sciences at Bath, said: "Contaminated crops and Fusarium toxins are always a worry, as they pose a significant threat to our health, especially as we only partially understand their effects on our wellbeing." "But on top of these health concerns, we must remember that wheat is a hugely important global crop, so it's essential for us to maintain high yields along with safe food production -- not least because climate change, and now the war in Ukraine (the world's fourth largest exporter of wheat), are already impacting on wheat yields and grain prices." Preventing toxin contaminations is therefore important both to help maintain the stable price of wheat and to protect our food security, ensuring global stability. Fungal toxins present in almost half of wheat The research team examined the largest datasets available from governments and agribusiness, both of which monitor Fusarium mycotoxins in wheat grain entering our food and animal feed supply chains. By using data from across Europe (including the UK) from the past 10 years, the team built the most complete picture yet of the mycotoxin threat and how it is changing. Fusarium mycotoxins were discovered in every European country. Half of the wheat intended for human food in Europe contains the Fusarium mycotoxin "DON" (commonly referred to as vomitoxin) while in the UK, 70% of wheat is contaminated. Governments set legal limits on DON contamination levels in wheat that is to be consumed by humans. These regulations provide effective protection, with 95% of wheat destined for the table meeting the safety limits for DON concentration. However, the finding that mycotoxins are ubiquitous is concerning, as the effect of constant, low-level exposure to mycotoxins in our diet over the course of a lifetime is not known. "There are real concerns that chronic dietary exposure to these mycotoxins impacts human health." said Dr Brown. The high cost of toxins When mycotoxins reach a certain level, the contaminated grain is diverted from human food to animal feed. "This comes at a cost to the cereal farmer, impacts cereal market prices, and shifts the health problem to our livestock." said Dr Brown. Consequently, the team found worryingly high levels of DON mycotoxin in wheat fed to livestock. Ms Louise Johns, a PhD student in Dr Brown's group, said: "It's far higher than in human food. This is a concern for animal health, but it also paints a picture of what mycotoxin levels in food wheat could look like without current regulations." For the first time, the Bath team has put a price on the impact of Fusarium Head Blight mycotoxins by estimating the value lost due to wheat being too contaminated with DON for human consumption. "Across Europe, we estimate that 75-million tonnes of wheat (5% of food wheat) exceeded the limit allowed for human consumption between 2010 and 2019. Downgrading this to animal feed equates to a loss of around 3,000 million euros over the last ten years," said Ms Johns. Interacting toxins Alarmingly, the researchers found that 25% of food wheat containing the mycotoxin DON also contained other Fusarium toxins. And this is likely an underestimate because not all wheat is routinely tested for other toxins. This means other potentially harmful toxins are likely to be slipping beneath the radar. It's possible that these toxins interact synergistically with DON to have adverse health effects that are greater than one toxin working alone. Dr Brown said: "We don't understand the health implications of being exposed to multiple toxins at the same time, especially when that exposure is chronic. We're worried about growing levels of co-contamination and possible synergies between toxins." Increasing threat Fusarium Head Blight is a disease that fluctuates year-to-year, but the authors of this study have found that in the Mediterranean, mycotoxin levels in high-disease years have become more severe since 2010. Here, mycotoxin levels recorded during the 2018 and 2019 outbreaks were higher than at any other time this decade. "We don't know what's causing the increase in Fusarium mycotoxins, which is why we need more research, but we suspect that changes in farming (such as soil preservation practices that provide a home for the Fusarium fungus) and climate change (such as warmer, more humid weather which favours the Fusarium fungus) are playing an important role." said Ms Johns. Study co-author Professor Dan Bebber from the University of Exeter Department of Biosciences added: "It's vital that we have better systems to monitor how Fusarium Head Blight disease is changing in the field and to predict which environments are most at risk in the future." Impact The team hopes that by exposing the scale of the Fusarium mycotoxin problem, their study will highlight the importance of controlling mycotoxins and stimulate further research. Professor Sarah Gurr, chair in Food Security at the University of Exeter, said: "We need to be vigilant in testing for mycotoxins in grain. We each eat around 66kg of wheat flour per year -- for example, in pasta and bread -- and it's important for wheat to be protected from Fusarium infection so as to mitigate this risk." Dr Brown believes the development of better ways to protect crops against fungal pathogens "is the only way for us to successfully mitigate the negative economic and health impacts of mycotoxins." He said: "As mycotoxin outbreaks become more severe in the future with climate change, this issue is only going to become more important."