Tag: Drug Resistance

High levels of ammonia in colon tumors inhibits T cell growth and response to immunotherapy

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Newswise — High levels of ammonia in tumors leads to fewer T cells and immunotherapy resistance in mouse models of colorectal cancer, new findings from the University of Michigan Rogel Cancer Center revealed. Researchers found that ammonia inhibits the growth and function of T cells, which are vital for anti-tumor immunity. The findings appear in Cell Metabolism.

“We identified the mechanism of how ammonia dysregulates T cell function and showed that reducing ammonia levels using FDA-approved drugs for hyperammonemia can reduce tumor size in several different models including metastatic colorectal cancer,” says Hannah Bell, Ph.D., a postdoctoral fellow in cancer biology and author on this paper. “Use of this drug also synergizes with immunotherapy. If you treat the mice with immunotherapy when you also treat them with this ammonia reducing agent, you’re able to sensitize the tumors to treatment.”

“Most colorectal cancers are insensitive to immune therapies,” adds Yatrik Shah, Ph.D., Horace W. Davenport Collegiate Professor of Physiology and first author of the study. “We’ve found that one of the mechanisms that leads to this resistance is likely the high level of ammonia that accumulates in the microenvironment.”

Bell explains that while there are many factors that contribute to immunotherapy resistance, there are few therapeutic interventions that can reactivate therapy sensitivity. “Our study shows that this is a relatively safe and FDA-approved method that could work alongside immunotherapy to make treatment more effective for patients. This new method provides a potentially direct avenue to treat tumors and reactivate the immune system.”

How does ammonia accumulate in colorectal tumors in the first place? Ammonia levels are regulated by a balance of production and cellular detoxification. Most ammonia is generated by the microbiota, but Bell and Shah’s work suggests that increased production of ammonia is not what results in accumulation. “Our work demonstrates that tumors have lost the ability to detoxify ammonia leading to build up,” said Shah.

Further, the accumulation of ammonia is likely not isolated to just colorectal tumors. Shah says this discovery may open doors in explaining resistance to other cancer types as well. “Only about 20-30% of all cancer patients are sensitive to immunotherapy. 70% of patients don’t derive any benefit from it,” Shah said. “Now, we have a mechanism that could explain this resistance in tumors beyond colon cancer.”

More work needs to be done before researchers can bring these findings into the clinic.

Additional Authors: Amanda K. Huber; Rashi Singhal; Navyateja Korimerla; Ryan J. Rebernick; Roshan Kumar; Marwa O. El-derany; Peter Sajjakulnukit; Nupur K. Das; Samuel A. Kerk; Sumeet Solanki; Jadyn G. James; Donghwan Kim; Li Zhang; Brandon Chen; Rohit Mehra; Timothy L. Frankel; Balázs Győrffy; Eric R. Fearon; Marina Pasca di Magliano; Frank J. Gonzalez; Ruma Banerjee; Daniel R. Wahl; Costas A. Lyssiotis; Michael Green

COI: N/A

Funding: NIH grants: R01CA148828, R01CA245546, R01DK095201, R37CA237421, R01CA248160, R01CA244931 (C.A.L); UMCCC Core Grant P30CA046592 and R35GM130183; T32 training grant GM008322 and F30CA257292. American Heart Association (826245) and NIH grant F30CA257292. NIH F31 fellowship (F31CA247457) and NIH fellowship (F99CA264414).CMB Graduate Program T32GM007315. American Physiological Society postdoctoral fellowship (032650). Crohn’s and Colitis Foundation Research fellowship award (623914) and the American Heart Association postdoctoral fellowship (19POST34380588). National Research, Development and Innovation Office (PharmaLab, RRF-2.3.1-21-2022-00015 and 2020-1.1.6-JÖVŐ-2021-00013).

DOI: “Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer,” Cell Metabolism. DOI: 10.1172/JCI143691

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Michigan Medicine – University of Michigan

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December 23, 2022
Study Reveals How Naturally-Occurring Compound Kills Major Drug-Resistant Bacteria

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Newswise — Scientists analysing the effects of an organic compound on drug resistance bacteria have discovered how it can inhibit and kill a germ that causes serious illness or in some cases death.

Pseudomonas aeruginosa is a type of bacteria, often found in hospital patients, which can lead to infections in the blood, lungs (pneumonia), or other parts of the body after surgery.

Hydroquinine, an organic compound found in the bark of some trees, was recently found to have bacterial killing activity against the germ and several other clinically important bacteria, including Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae.

The team behind the discovery, from the University of Portsmouth and Naresuan and Pibulsongkram Rajabhat Universities in Thailand, have now explored the molecular responses of Pseudomonas aeruginosa strains to hydroquinine. They did this by looking at which genes were switched on and which were switched off in response to the drug.

The new study, published in Antibiotics, revealed hydroquinine significantly alters the expression levels of virulence factors Pseudomonas aeruginosa. It also suggests the compound interferes with the assembly and movement of the bacteria.

Dr Robert Baldock from the School of Pharmacy and Biomedical Sciences at the University of Portsmouth, said: “There’s quite a long list of antibiotics that don’t work on Pseudomonas. aeruginosa, but our experiments found some of the genes governing the motility of the bacterium were quite drastically switched off by hydroquinine. Biofilm formation and the swarming and swimming of the germ were significantly reduced.

“If we know that this drug is working in a really unique or different way then it firstly explains why it’s active on these drug-resistant cells, but it also means that you can potentially look at combining it with other existing antibiotics to make them more effective.”

Drug-resistant bacteria occur in more than 2.8 million infections and are responsible for 35,000 deaths per year. Antimicrobial resistance happens when germs change over time and no longer respond to medicines, making it difficult to treat infections.

Amoxicillin and Trimethoprim are commonly prescribed antibiotics that certain strains of Pseudomonas. aeruginosa have become resistant to. Hydroquinine is already known to be an effective agent against malaria in humans, and it is also being used in the Netherlands to treat nocturnal muscle cramps. Until now there has been little investigation into its drug-resistant properties.

Dr Jirapas Jongjitwimol from the Department of Medical Technology at Naresuan University added: “Antimicrobial resistance has become one of the greatest threats to public health globally, so to discover an organic compound has the potential to be used as an effective weapon in the fight is very exciting.

“We now need to look at how the compound works against a wider variety of bacterial strains so that we better understand why some germs are affected or not affected by it.”

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University of Portsmouth

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October 28, 2022
Controlling Gut Flora Can Reduce Mortality in Critically Ill Patients on Life Support

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Newswise — Preventing severe lung infections in mechanically ventilated intensive care patients by applying topical antibiotics to the upper digestive tract results in a clinically meaningful improvement in survival, new research shows.

The results are being presented during the ‘Hot Topics’ session of the European Society of Intensive Care Medicine annual congress in Paris and simultaneously published in the Journal of the American Medical Association (JAMA).

Professor John Myburgh AO, lead author and Director of the Critical Care Division at The George Institute for Global Health, said that ventilator-associated pneumonia is a major cause of death and disability in critically ill patients being mechanically ventilated in intensive care units.

“While the concept of ‘selective decontamination’ of the digestive tract, or ‘SDD’, has been around for decades, this is the first large-scale randomised clinical trial that used a high-quality commercially prepared product specifically designed to prevent ventilator-associated pneumonia in these patients,” he said.

“In nearly 3,000 patients treated with SDD, we saw a reduction in death of around two percent, equivalent to one death prevented for every 50 patients treated.”

SDD is an infection-control measure where non-absorbed antibiotics and antifungal agents are applied to the mouth and stomach, combined with a short course of intravenous antibiotics.

This inhibits the development of ventilator-associated pneumonia caused by harmful bacteria and overgrowth of fungi that normally live in the upper part of the gut but enter and infect the lungs once patients are placed on a ventilator.

While SDD may reduce infections and prevent deaths, it has not been widely adopted as the evidence was not considered strong enough and there are widely held concerns about the potential risk of causing antibiotic resistance.

To address this uncertainty, the Selective Decontamination of the Digestive tract in the Intensive Care Unit (SuDDICU) trial was designed to determine whether adding SDD to the usual care of ICU patients would reduce all-cause hospital mortality compared to usual care alone.

The SuDDICU trial recruited 5,982 mechanically ventilated adults from 19 ICUs in Australia between April 2018 and May 2021. Each ICU delivered either SDD with usual care or usual care alone for 12 months and then crossed over to the other option for a second 12-month period.

The study found that while SDD with standard care compared to standard care alone did not result in a statistically significant reduction in in-hospital mortality (27.0% vs 29.1% respectively), the range of values included a clinically important benefit.

“Moreover, we saw that SDD was also associated with a significant reduction in new hospital-acquired infections and there were no adverse events related to the administration of SDD itself,” said Professor Myburgh.

George Institute investigators combined the results with those of other major randomised clinical trials of SDD conducted over the last 20 years in a systematic review and meta-analysis, also being published in JAMA and presented at the conference by senior author, Associate Professor Anthony Delaney.

“This review provides a high degree of certainty for clinicians to administer SDD to critically ill, mechanically ventilated patients in their ICUs to reduce the incidence of ventilator-associated pneumonia and the potential increased risk of death,” A/Prof Delaney said.

Professor Myburgh added that SDD alongside other important strategies reinforces the importance of effective and safe preventive medicine in this vulnerable patient population.

“We now plan to extend our trial to low and middle-income countries where mortality rates and the incidence of infections with antimicrobial resistant organisms are higher,” he said.

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George Institute for Global Health

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October 26, 2022
Both Types of THC Get You High–So Why Is Only One Illegal?

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Newswise — One is an illegal drug found in marijuana while the other is marketed as a safe herbal alternative. But the claimed differences between them aren’t backed by science, a group of UConn researchers report on Nov. 1 in Drug and Alcohol Dependence.

Tetrahydrocannabinol, or THC, is the psychoactive compound produced by cannabis plants. The federal government lists Δ9 -THC (pronounced delta-9-THC) on the Schedule 1 list of dangerous drugs with no accepted medical use. But other versions of THC that differ only by the location of a double bond, such as Δ8-THC, remain quietly quasi-legal on the federal level.

The legality differences between the various versions of THC are causing conflict between the hemp and cannabis industries. There is also potential for harm to consumers. Although Δ8-THC is viewed as an herbal extract of hemp, many manufacturers use solvents and chemical processes that can leave harmful residues in the product, and there are no standards for purity or safety. Because there are no limits, some products contain ridiculously high levels of ∆8 and other THC variants that could potentially cause harm due to the sheer dosage. And states do not agree on its safety or legality. Some states, such as Connecticut, have made Δ8-THC as controlled as Δ9-THC, while in others it remains legal. Cannabis producers allege the distinction is giving rise to unfair competition between the hemp and marijuana markets.

If regulating Δ9-THC as an illegal drug is based on the fact that it has physical and psychoactive effects, then the first step to rational regulation of Δ8-THC would look at whether it, too, has those effects. And people who have experience with both say it does; most agree the effects of Δ8 are similar to Δ9.

UConn School of Nursing professor and Center for Advancement in Managing Pain director Steve Kinsey, graduate student Olivia Vanegas, and their colleagues in UConn Chemistry and local startup 3BC Inc decided to test that in mice. Research done in Japan in the 1980s had shown that Δ8-THC produced the same effects in mice as Δ9-THC. Kinsey and Vanegas reproduced that work and found it to be true: the mice given Δ8 became lethargic, their body temperature dropped, and they became cataleptic, meaning the researchers could put the mice in unusual positions and they’d stay like that for several seconds, which is common in THC-treated mice, but not normal mice.

Then the researchers took it a step farther, blocking the mice’s THC receptors. Blocked mice had no reaction to Δ8-THC, making it clear that Δ8 interacts with the same receptors as Δ9-THC.

Then the researchers took a group of mice and gave them Δ8-THC twice a day for five days. Over time, the mice became desensitized to it. And when they were then given the THC blocker, the mice acted like they were in withdrawal.

Finally collaborators at RTI International ran an experiment “asking” the mice how the drug felt. First they trained the mice to go to a specific spot for a reward if they were dosed with Δ9-THC. After the training, the mice were dosed with Δ8-THC. Unsurprisingly, they went to the same reward spot as when they were dosed with Δ9.

“So they’re telling us the same thing people buying the stuff in gas stations tell us: Δ8 feels like THC,” Kinsey says.

Chemically, it’s unsurprising. Molecules as similar as Δ8- and Δ9-THC usually (though not always) act the same in the body. But legally it causes a lot of complications.

The distinction between Δ8- and Δ9- originally came about from the congressional Farm Bill covering hemp growing and sales. Hemp is defined as a cannabis plant that has less than 0.3% Δ9-THC by dry weight. Anything that has more concentrated Δ9-THC than that is considered marijuana. Additionally, the Farm Bill said anything else naturally present in the hemp plant is legal. That includes Δ8-THC.

“It’s creating a fight between marijuana and hemp” growers, says John Harloe, an attorney on Colorado’s THC taskforce. Products classified as marijuana “must be sold through dispensaries and pay high taxes, while hemp producers can sell essentially the same product but without the same regulations, due to the ambiguity in the Farm Bill,” Harloe says.

Harloe is bringing Kinsey and Vanegas’s paper to the Colorado taskforce to inform the discussion. The taskforce is trying to create appropriate regulation that will address the different chemical variations of THC and guard public safety without crippling the hemp industry. The paper is particularly valuable because there is so little research done on THC and its intoxicating effects, due to federal rules.

“Any bit of science is going to be influential,” Harloe says.

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University of Connecticut

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October 21, 2022
Phage Trial to Treat CF Patients With Multi-Drug Resistant Bacterial Infections

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Newswise — Cystic fibrosis (CF) is an inherited disorder that causes severe damage to the lungs and other organs in the body. Nearly 40,000 children and adults in the United States live with CF, an often difficult existence exacerbated by an opportunistic bacterium called Pseudomonas aeruginosa, which is a major cause of chronic, life-threatening lung infections.

P. aeruginosa infections are not easily treated. The pathogen can be resistant to most current antibiotics. However, an early-stage clinical trial led by scientists at University of California San Diego School of Medicine, with collaborators across the country, has launched to assess the safety and efficacy of treating P. aeruginosa lung infections in CF patients with a different biological weapon: bacteriophages.

Bacteriophages are viruses that have evolved to target and destroy specific bacterial species or strains. Phages are more abundant than all other life forms on Earth combined and are found wherever bacteria exist. Discovered in the early 20th century, they have long been investigated for their therapeutic potential, but increasingly so with the rise and spread of antibiotic-resistant bacteria.

In 2016, scientists and physicians at UC San Diego School of Medicine and UC San Diego Health used an experimental intravenous phage therapy to successfully treat and cure colleague Tom Patterson, PhD, who was near death from a multidrug-resistant bacterial infection. Patterson’s was the first documented case in the U.S. to employ intravenous phages to eradicate a systemic bacterial infection. Subsequent successful cases helped lead to creation of the Center for Innovative Phage Applications and Therapeutics (IPATH) at UC San Diego, the first such center in North America.

In 2020, IPATH researchers published data from 10 cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections, all at UC San Diego. In 7 of 10 cases, there was a successful outcome.

The new phase 1b/2 clinical trial advances this work. The trial is co-led by Robert Schooley, MD, professor of medicine and an infectious disease expert at UC San Diego School of Medicine who is co-director of IPATH and helped lead the clinical team that treated and cured Patterson in 2016.

It will consist of three elements, all intended to assess the safety and microbiological activity of a single dose of intravenous phage therapy in males and non-pregnant females 18 years and older, all residing in the United States.

The dose is a cocktail of four phages that target P. aeruginosa, a bacterial species commonly found in the environment (soil and water) that can cause infections in the blood, lungs and other parts of the body after surgery.

For persons with CF, P. aeruginosa is a familiar and sometimes fatal foe. The Cystic Fibrosis Foundation estimates that roughly half of all people with CF are infected by Pseudomonas. Previous studies have indicated that chronic P. aeruginosa lung infections negatively impact life expectancy of CF patients, who currently live, on average, to approximately 44 years.

In the first stage of the trial, two “sentinel subjects” will receive one of three dosing strengths of the IV bacteriophage therapy. If, after 96 hours and no adverse effects, the second stage (2a) will enroll 32 participants into one of four arms: the three doses and a placebo.

After multiple follow-up visits over 30 days and an analysis of which dosing strength exhibited the most favorable safety and microbiologic activity, i.e. most effective at reducing P. aeruginosa, stage 2b will recruit up to 72 participants to either receive that IV dose or a placebo.

Enrollment will occur at 16 cystic fibrosis clinical research sites in the United States, including UC San Diego. It is randomized, double-blind and placebo-controlled. The trial is being conducted through the Antibacterial Resistance Leadership Group and funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, with additional support for the UC San Diego trial site from the Mallory Smith Legacy Fund.

Mallory Smith was born with cystic fibrosis and died in 2017 at the age of 25 from a multidrug-resistant bacterial infection following a double lung transplant.

“Mallory’s death was a preventable tragedy,” said her mother, Diane Shader Smith. “We are supporting the IPATH trial through Mallory’s Legacy Fund because Mark and I deeply believe in the promise of phage therapy to save lives by combatting multidrug-resistant bacteria.”

In an article published in 2020 in Nature Microbiology, Schooley and Steffanie Strathdee, PhD, associate dean of global health sciences and Harold Simon Professor in the Department of Medicine and IPATH co-director, describe phages as “living antibiotics.”

As such, said Schooley, researchers need to learn how to best use them to benefit patients through the same systematic clinical trials employed to evaluate traditional antibiotics.

The primary objectives of the new trial are first to determine the safety of a single IV phage dose in clinically stable patients with CF who are also infected with P. aeruginosa, said Schooley.

“Second, it’s to describe the microbiological activity of a single IV dose and third, to assess the benefit-to-risk profile for CF patients with P. aeruginosa infections. This is one study, with a distinct patient cohort and carefully prescribed goals. It’s a step, but an important one that can, if ultimately proven successful, help address the growing, global problem of antimicrobial resistance and measurably improve patients’ lives.”

Estimated study completion date is early 2025.

For more information on the clinical trial and participant eligibility criteria, visit clinicaltrials.gov or visit IPATH and click on the Contact Us button.

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University of California San Diego

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October 11, 2022