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By Dr. Chinta Sidharthan Reviewed by Danielle Ellis, B.Sc. Nov 21 2024

Researchers identify gliocidin, a blood-brain barrier-penetrating prodrug, that targets glioblastoma's unique metabolic vulnerability, offering a promising therapeutic strategy and extended survival in preclinical models. Study: Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma. Image Credit: April stock/Shutterstock.com

In a recent study published in Nature, a team led by researchers from Memorial Sloan Kettering Cancer Center investigated the effects of the compound gliocidin in targeting glioblastoma, an aggressive form of brain tumor.

The study found that gliadin acts on specific cellular pathways to selectively kill glioblastoma cells without harming normal cells. Moreover, the compound can penetrate the blood-brain barrier, which highlights its potential as a treatment option for glioblastoma. Background

Glioblastoma is one of the most lethal forms of brain cancer and is known for its resistance to standard therapies. Despite significant advances in cancer therapies, currently used immunotherapies and targeted therapies have had minimal success in improving survival rates in glioblastoma. This resistance is believed to stem from several challenges unique to glioblastoma, such as its complex cellular heterogeneity and immune-evasive characteristics.

Additionally, crossing the blood-brain barrier to reach tumor cells remains a significant obstacle. Researchers are exploring novel metabolic pathways as potential therapeutic targets. Unlike typical cancer drugs that inhibit cell division, some emerging therapies aim to disrupt cancer-specific vulnerabilities. The use of prodrugs, which are converted into active drugs within the body, is gaining special attention due to their ability to target malignant cells while sparing healthy tissue selectively. About the study

In the present study, the researchers aimed to identify a compound that could selectively target glioblastoma cells. A high-throughput chemical screen of over 200,000 compounds was conducted using low-passage glioblastoma cells derived from genetically engineered mouse models. Compounds toxic to normal replicative cells were excluded. The screening identified gliocidin as a promising candidate due to its selective toxicity against glioblastoma cells.

To investigate the mechanism of action, the team then employed multiple experimental approaches. Genetic analyses were performed using clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) screens to identify pathways and enzymes essential for the activity of gliocidin.

Pharmacokinetics and biodistribution studies in animal models were used to determine the ability of gliocidin to cross the blood-brain barrier and maintain effective concentrations in the brain. The researchers used glioblastoma-bearing mouse models to test the brain penetration abilities and bioavailability of gliocidin. Drug administration was optimized using intraperitoneal injection, and tissue analysis was used to confirm its presence in the brain.

Additionally, the researchers used liquid chromatography-mass spectrometry (LC-MS) to measure the levels of intermediate compounds and final metabolites in cells and tissues to understand gliocidin metabolism. Related StoriesStudy defines three subtypes of Chiari type-1 malformation to guide treatmentSpecific redox protein identified as a critical regulator of ferroptosisCannabis use linked to brain changes in young adults at risk of psychosis

Structural studies, including cryo-electron microscopy, were also conducted to characterize the interaction between the active form of gliocidin, gliocidin-adenine dinucleotide (GAD), and the enzyme inosine monophosphate dehydrogenase 2 (IMPDH2), to understand the binding mechanisms involved in gliocidin activation and metabolism. Gliocidin was also tested in combination with temozolomide, a standard chemotherapeutic for glioblastoma, to evaluate potential synergistic effects. Results

The study found that gliocidin effectively targeted glioblastoma cells by exploiting specific metabolic vulnerabilities of the cancer cells. Gliocidin was metabolized into GAD within the NAD+ salvage pathway, which then indirectly inhibited IMPDH2, a key enzyme in the purine synthesis pathway. This inhibition was found to lead to a severe reduction in guanine nucleotide levels, causing replication stress and cell death in glioblastoma cells.

Furthermore, the biochemical assays confirmed that gliocidin selectively disrupted guanine nucleotide synthesis in glioblastoma cells without affecting normal cells. The study demonstrated this specificity across multiple glioblastoma cell lines and patient-derived xenograft models. Additionally, the pharmacokinetic studies revealed that gliocidin successfully crossed the blood-brain barrier and accumulated in the brain, ensuring sustained exposure of the cancer cells to the compound.

Moreover, the in vivo studies in glioblastoma-bearing mice also showed that gliocidin monotherapy significantly suppressed tumor progression. When combined with temozolomide, a standard glioblastoma treatment, gliocidin produced synergistic effects, leading to greater tumor reduction and improved survival outcomes. An analysis of tumor samples from treated mice revealed that the combination therapy enhanced glioblastoma cell death by targeting both proliferative and non-proliferative tumor cells.

The researchers also found that gliocidin’s efficacy depended on nicotinamide nucleotide adenylyltransferase 1 or NMNAT1, an enzyme in the NAD+ salvage pathway. Tumors with higher NMNAT1 expression showed greater sensitivity to gliocidin. Interestingly, combination therapy with temozolomide was found to increase NMNAT1 expression further, amplifying the anti-tumor effects of gliocidin. Conclusions

Overall, the results established that gliocidin could selectively kill glioblastoma cells by disrupting critical nucleotide synthesis pathways. Its ability to penetrate the brain highlights its potential as a promising treatment for glioblastoma.

Furthermore, the enhanced efficacy observed when gliocidin was administered in combination with temozolomide further supports the potential of gliocidin as a future therapeutic approach for glioblastoma patients. Journal reference: Chen, Y.J., Iyer, S. V., Hsieh, D.C.C., Li, B., Elias, H.K., Wang, T., Li, J.,… Parada, L.F. 2024. Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma. Nature. doi: 10.1038/s41586-024-08224-z https://www.nature.com/articles/s41586-024-08224-z

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Man and boy arrested on suspicion of arson after restaurant fire leaves two in critical condition

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Man and boy arrested on suspicion of arson after restaurant fire leaves two in critical condition

A 54-year-old man and a 15-year-old boy have been arrested on suspicion of arson with intent to endanger life after a restaurant fire in east London on Friday.

Three people were taken to hospital in a life-threatening condition after the fire at the Indian Aroma in Ilford.

Two remained in a critical condition on Sunday morning, according to the Metropolitan Police.

The restaurant suffered extensive damage in the blaze.

Two further victims are thought to have left the scene before officers arrived, Scotland Yard said.

Woodford Avenue from above. Pic: UK News and Pictures
Image:
Woodford Avenue from above. Pic: UK News and Pictures

Police are still trying to identify them.

CCTV footage seen by the PA news agency appears to show a group of people wearing face coverings walk into the restaurant and pour liquid on the floor.

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Seconds later, the inside of the restaurant is engulfed in flames.

“While we have made two arrests, our investigation continues at pace so we can piece together what happened on Friday evening,” said the Met Police’s DCI Mark Rogers.

“I know the community [is] concerned and shocked by this incident.

The moment the fire broke out.
Image:
The moment the fire broke out.

“I would urge anyone with any information or concerns to come forward and speak to police.”

Hospital porter Edward Thawe went to help after hearing screams from his nearby home.

He described the scene as “horrible” and “more than scary and the sort of thing that you don’t want to look at twice.”

He said: “I heard screaming and people saying they had called the police.”

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The 43-year-old said he saw a woman and a severely burned man who may have been customers.

Another witness, who did not want to be named, said he saw three “severely burned” people being doused by the emergency services and given oxygen.

“I can only imagine the pain they were going through,” he said.

On Saturday, the London Ambulance Service told Sky News: “We sent resources to the scene, including ambulance crews, an advanced paramedic, an incident response officer and paramedics from our hazardous area response team.

“We treated five people for burns and smoke inhalation. We took two patients to a major trauma centre and three others to local hospitals.”

The police investigation is continuing.

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Fast-track asylum appeals process to be introduced – as average time for decisions is more than one year

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Fast-track asylum appeals process to be introduced - as average time for decisions is more than one year

A new fast-track asylum appeals process will be introduced to speed up the process of deporting people without a right to remain in the UK, the home secretary has said.

As it currently takes, on average, more than a year to reach a decision on asylum appeals, the government plans to set up a new independent panel focused on asylum appeals to help reduce the backlog.

Home Secretary Yvette Cooper said “completely unacceptable” delays in the appeals process left failed asylum seekers in the system for years.

There are about 51,000 asylum appeals waiting to be heard.

The new independent body will use professionally-trained adjudicators, rather than relying on judges.

Ministers are introducing a new 24-week deadline for the first-tier tribunal to determine asylum appeals by those receiving accommodation support and appeals by foreign offenders.

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Police clash with protesters in Bristol

But they believe the current tribunal system, which covers a wide range of different cases, is still failing to ensure failed asylum seekers can be returned as swiftly as possible, nor can it accommodate a fast-track system for safe countries.

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It comes amid protests about the use of hotel accommodation for migrants.

The home secretary said the overhaul would result in a system which is “swift, fair and independent, with high standards in place”.

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She said: “We inherited an asylum system in complete chaos with a soaring backlog of asylum cases and a broken appeals system with thousands of people in the system for years on end.

“That is why we are taking practical steps to fix the foundations and restore control and order to the system.

“We are determined to substantially reduce the number of people in the asylum system as part of our plan to end asylum hotels.

“Already since the election, we have reduced the backlog of people waiting for initial decisions by 24% and increased failed asylum returns by 30%.

“But we cannot carry on with these completely unacceptable delays in appeals as a result of the system we have inherited which mean that failed asylum seekers stay in the system for years on end at huge cost to the taxpayer.”

Official figures released earlier this month showed a total of 111,084 people applied for asylum in the UK in the year to June 2025, the highest number for any 12-month period since current records began in 2001.

‘Waving immigrants through even faster will not fix the problem’

Chris Philp, the shadow home secretary, said: “I think this goes nowhere near far enough.

“The underlying rights, which allows most illegal immigrants to stay here, are not changing. Simply waving illegal immigrants through even faster to full housing and welfare rights will not fix the problem.”

Chris Philp
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Chris Philp

He added: “Immigration judges will still apply ever expanding common-sense defying definitions of ECHR rights to allow foreign criminals and illegal immigrants to stay here.”

But the Liberal Democrats have been more positive in their response, with shadow attorney general, Ben Maguire, saying: “A faster application process would mean that those with no right to be here are sent back swiftly and those who do have a valid claim can get a job, integrate and contribute to the community.”

Asked for his thoughts on the policy, immigration lawyer Harjap Singh Bhangal told Sky News that it “definitely sounds like some sort of solution”.

He pointed that the backlog of asylum seekers waiting for a decision is “huge”, around 51,000 people – and that during this time, they are not allowed to work.

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A new fast-track asylum appeals process will be introduced to speed up the process of deporting people without a right to remain in the UK.

He said: “The equivalent would be saying that imagine if A-level students this year sat the exams and were told ‘well, hold on, you’re not going to get your results for two years’ time. But in the meantime, you can’t go to university.’

“You’d have mayhem, and it’d be pandemonium in the street. You’d have broken people idle with nothing to do. Essentially, this is what’s happening to asylum seekers.”

He added that one of the reasons it takes so long for cases to be heard is because asylum seekers have to represent themselves in court, which can mean upwards of half a day is spent translating and explaining everything to them.

Mr Bhangal also said the immigration system is “broken”, because “they take ages to make a decision which could be made in one week”.

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Family pay tribute to ‘beloved’ man who died in ‘accident while working on fairground ride’

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Family pay tribute to 'beloved' man who died in 'accident while working on fairground ride'

A man who died after suffering “serious head injuries” while “working on a fairground ride” has been named as Corrie Lee Stavers.

Emergency services were called to the Spanish City Summer Funfair in Whitley Bay in North Tyneside after reports that a man, in his 20s, had been injured around 2.15pm on Saturday, police said.

Mr Stavers, 28, was treated at the scene but was declared dead a short time later.

In a statement issued by the police, his family said: “It’s with broken hearts that we share the devastating news that our beloved Corrie has passed away.

“He was tragically taken from us in an accident while working on a fairground ride. None of us were prepared for this, and the pain of losing him so suddenly is impossible to put into words.

“Our lives will never be the same without him, but his memory will live on in our hearts forever.

“We love you endlessly Corrie, and we miss you more than words can ever say.

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“You’re with our mam now – rest in peace Corrie.”

The funfair, which is in Whitley Bay’s Spanish City Plaza area, has been shut “until further notice” and the Health and Safety Executive has been informed.

The annual funfair had opened on Thursday and had been due to run until Bank Holiday Monday.

Read more from Sky News:
Man and boy arrested after restaurant fire
Fast-track asylum appeals process to be introduced

A Northumbria Police spokesman said: “Emergency services attended and a man in his 20s was found to have suffered serious head injuries.

“Despite the best efforts of medical staff, a short time later the man was sadly declared dead.

“His next of kin have been contacted and are being supported by specialist officers.”

The spokesman added: “Our thoughts are with the man’s family at this extremely difficult time.

“We have contacted the Health and Safety Executive and are working with them to establish exactly what happened.

“The fair has been closed to the public and will remain closed until further notice.”

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