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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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Israeli military announces ‘tactical pause’ in fighting in parts of Gaza amid hunger crisis

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Israeli military announces 'tactical pause' in fighting in parts of Gaza amid hunger crisis

Israel has begun a pause in fighting in three areas of Gaza to address the worsening humanitarian situation.

The IDF said it would halt fighting in three areas, Muwasi, Deir al-Balah and Gaza City, from 10am to 8pm local time until further notice, beginning today.

In a statement, the IDF said it would also establish secure routes to help the UN and aid agencies deliver food and other supplies.

Palestinians carry aid supplies that entered Gaza through Israel, in Beit Lahia in the northern Gaza Strip, July 27, 2025. REUTERS/Dawoud Ab
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Palestinians carry aid supplies. Pic: Reuters

Israel’s announcement of what it calls a “tactical pause” in fighting comes after it resumed airdrops of aid into Gaza.

While the IDF reiterated claims there is “no starvation” in Gaza, it said the airdrops would include “seven pallets of aid containing flour, sugar and canned food to be provided by international organisations”.

Reports suggest aid has already been dropped into Gaza, with some injured after fighting broke out.

Pic: IDF
Image:
Pic: IDF

In other developments, Bob Geldof has accused Israeli authorities of “lying” about starvation in the territory – telling Sunday Morning With Trevor Phillips the IDF is “dangling food in front of starving, panicked, exhausted mothers”.

He told Sky News: “This month, up to now, 1,000 children or 1,000 people have died of starvation. I’m really not interested in what either of these sides are saying.”

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Bob Geldof: ‘Israeli authorities are lying’

Israel cut off all supplies to Gaza from the start of March. It then reopened aid centres with new restrictions in May, but said the supply had to be controlled to prevent it from being stolen by Hamas militants.

On Saturday, reports referencing US government data said there was no evidence Hamas had stolen aid from UN agencies.

The IDF’s international spokesperson, Lieutenant Colonel Nadav Shoshani, described such reports as “fake news” and said Hamas thefts have been “well documented”.

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Malnourished girl: ‘The war changed me’

Airdrops ‘expensive and inefficient’

It comes as the Hamas-run health ministry in Gaza said as of Saturday, 127 people have died from malnutrition-related causes, including 85 children.

They include a five-month-old girl who weighed less than when she was born, with a doctor at Nasser Hospital describing it as a case of “severe, severe starvation”.

Health workers have also been weakened by hunger, with some putting themselves on IV drips so they can keep treating badly malnourished patients.

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Aid waiting to be distributed in Gaza

On Friday, Israel said it would allow foreign countries to airdrop aid into Gaza – but the UN Relief and Works Agency (UNRWA) has warned this will not reverse “deepening starvation”.

UNRWA head Philippe Lazzarini described the method as “expensive” and “inefficient”, adding: “It is a distraction and screensmoke. A manmade hunger can only be addressed by political will.

“Lift the siege, open the gates and guarantee safe movements and dignified access to people in need.”

UNRWA has the equivalent of 6,000 trucks in Jordan and Egypt waiting for permission to enter Gaza, he added.

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PM says UK will help drop aid to Gaza

MSF, also known as Doctors Without Borders, warned on Friday that 25% of young children and pregnant women in Gaza are now malnourished, and said the lack of food and water on the ground was “unconscionable”.

The UN also estimates Israeli forces have killed more than 1,000 people seeking food, the majority near the militarised distribution sites of the US-backed aid distribution scheme run by the Gaza Humanitarian Foundation.

Read more:
What does recognising a Palestinian state mean?
British surgeon claims IDF ‘deliberately’ shooting boys

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In a statement on Friday, the IDF had said it “categorically rejects the claims of intentional harm to civilians”, and reports of incidents at aid distribution sites were “under examination”.

The Gaza Humanitarian Foundation (GHF) has also previously disputed these deaths were connected with its organisation’s operations, with director Johnnie Moore telling Sky News: “We just want to feed Gazans. That’s the only thing that we want to do.”

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‘I still have hope’: Parents of IDF soldier taken hostage by Hamas fear he’ll be one of last freed

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'I still have hope': Parents of IDF soldier taken hostage by Hamas fear he'll be one of last freed

Yehuda searches through a downstairs room looking for a plastic bag containing the most precious of objects.

It’s a small, blackened Rubik’s Cube that belongs to Yehuda’s son Nimrod – one of 20 living Israeli hostages still being held by the terrorist group Hamas in Gaza.

It was found in Nimrod’s burnt-out tank after the October 7th attacks.

“He likes PlayStation and Rubik’s Cube,” says Nimrod’s mother, Vicky.

“They found the Rubik’s Cube in the tank. It was complete but a little bit dark and they brought it back to us.”

Stills from Holland PKG of Vicky Cohen whose son Nimrod Cohen, an 19 y/o IDF soldier, who is being held hostage by Hamas
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Vicky Cohen

We spoke to Nimrod’s parents Yehuda and Vicky about the emotional rollercoaster hostage families in Israel are going through – as hope rises and fades of a ceasefire agreement with Hamas.

“I still have hope that maybe I will see Nimrod again,” says Vicky.

“It almost breaks my heart because I still had expectation,” she says – in spite of the latest failure to find resolution in talks between Israel and Hamas in Doha.

“But I still have hope that maybe something good will happen,” she says.

Rubik's cube owned by Nimrod Cohen, an 19 y/o IDF soldier, who is being held hostage by Hamas
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Nimrod’s charred Rubik’s Cube

Vicky says: “We heard [during] the last weeks, President Trump saying we will hear about a ceasefire soon – next week – in a few days.

“We heard our prime minister [Benjamin Netanyahu] say visiting Washington and meeting Trump was very successful – and heard members of the coalition talking about our prime minister eventually understanding he needs to end the war. But until now nothing.”

The delegation coming back to Israel doesn’t mean a total collapse of ceasefire talks, but US envoy Steve Witkoff said the response to the latest ceasefire proposals by Hamas showed “a lack of desire”.

And so the rollercoaster of emotion for the hostage families continues.

Middle East latest: Gaza aid airdrops a ‘smokescreen’

Nimrod Cohen, an 19 y/o IDF soldier, who is being held hostage by Hamas
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Nimrod

Nimrod’s father Yehuda Cohen said: “Of course it’s a disappointment but it’s not the first one. A long time ago I learned not to get my expectations up so the disappointment won’t be too deep.

“The solution is very simple – I’ve got it on my shirt – ceasefire and hostage deal. Meaning the only way to get all the hostages is ending the war.”

Stills from Holland PKG on Yehuda Cohen (pictured) whose son Nimrod Cohen is being held hostage by Hamas
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Nimrod’s father Yehuda

Yehuda shows us Nimrod’s bedroom at the family home. It’s exactly as it was when Nimrod left to return to his army duties a few days before the October 7 attacks.

Except in a corner, there’s a box of uniforms and personal possessions, including a wallet which Nimrod had left at his army outpost – all returned to the family by the IDF.

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Stills from Holland PKG on Yehuda and Vicky Cohen's son Nimrod Cohen, an 19 y/o IDF soldier, who is being held hostage by Hamas.
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The IDF handed Nimrod’s parents a box of his possessions left at his army outpost

It’s just like the bedroom of any other teenager – Nimrod was 19 when he was kidnapped. But two birthdays have passed since then. Nimrod is 21 now – a milestone spent in captivity a few weeks ago.

It’s believed there are 20 living Israeli hostages in Gaza – all male – and that Hamas is holding the bodies of 27 more hostages who have been killed.

Read more from Sky News:
Israel resumes airdrops into Gaza
Bob Geldof accuses Israel of ‘lying’
25% of children malnourished, charity says

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Starvation in Gaza continues

But even if a deal is agreed, the first phase is expected to secure the release of only half of the living hostages – and Nimrod’s parents say their son, as a soldier, is not likely to be one of the 10.

Yehuda says: “A partial deal means that the probability my son will be on that list is close to zero. So he’s going to be one of the last ones to be released, and that’s why we have to fight.”

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Bob Geldof accuses Israeli authorities of ‘lying’ about starvation in Gaza

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Bob Geldof accuses Israeli authorities of 'lying' about starvation in Gaza

Bob Geldof has accused the Israeli authorities of “lying” about starvation in Gaza – after Israel’s government spokesperson claimed there was “no famine caused by Israel”.

Earlier this week, David Mencer claimed that Hamas “starves its own people” while on The News Hour with Mark Austin, denying that Israel was responsible for mass hunger in Gaza.

Appearing on Sunday Morning with Trevor Phillips, Geldof said the claims are false.

Follow latest: Gaza aid airdrops a ‘smokescreen’ and ‘distraction’

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Israel challenged on starvation in Gaza

Sir Trevor asked the Live Aid organiser: “The Israeli view is that there is no famine caused by Israel, there’s a manmade shortage, but it’s been engineered by Hamas.

“I guess the Israelis would say we don’t see much criticism from your side of Hamas.”

In response, Geldof said “that’s a false equivalence” and “the Israeli authorities are lying”.

The singer then added: “They’re lying. [Benjamin] Netanyahu lies, is a liar. The IDF are lying. They’re dangling food in front of starving, panicked, exhausted mothers.

“And while they arrive to accept the tiny amount of food that this sort of set up pantomime outfit, the Gaza Humanitarian Front, I would call it, as they dangle it, then they’re shot wantonly.

“This month, up to now, 1,000 children or 1,000 people have died of starvation. I’m really not interested in what either of these sides are saying.”

He added: “If the newsfeeds and social feeds weren’t so censored in Israel, I imagine that the Israeli people would not permit what has been done in their name.”

Asked about the UK government’s reaction, Geldof said it was “not enough”.

“This is a distraction thing about ‘let’s recognise the state ‘ – absolutely, it should have been done ages ago, but it’s not going to make any material difference,” he said, referring to calls for Sir Keir Starmer to recognise Palestine as a state.

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Gaza: ‘This is man-made starvation’

In the Sky News interview earlier this week, Mr Mencer added: “This suffering exists because Hamas made it so. Here are the facts. Aid is flowing, through the Gaza Humanitarian Foundation. Millions of meals are being delivered directly to civilians.”

He also claimed that, since May, more than 4,400 aid trucks had entered Gaza carrying supplies.

It comes after MSF, also known as Doctors Without Borders, warned 25% of young children and pregnant women in Gaza are now malnourished.

The charity said Israel’s “deliberate use of starvation as a weapon” has reached unprecedented levels, and said that at one of its clinics in Gaza City, rates of severe malnutrition in children under five have trebled over the past two weeks.

MSF then described the lack of food and water on the ground “unconscionable”.

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Aid waiting to be distributed in Gaza

In a statement to Sky News, an Israeli security official said that “despite the false claims that are being spread, the State of Israel does not limit the number of humanitarian aid trucks entering the Gaza Strip”.

It then blamed other groups for issues delivering aid. They said: “Over the past month, we have witnessed a significant decline in the collection of aid from the crossings into the Gaza Strip by international aid organisations.

“The delays in collection by the UN and international organisations harm the situation and the food security of Gaza’s residents.”

Read more:
What does recognising a Palestinian state mean?
Surgeon claims IDF ‘deliberately’ shooting boys at Gaza aid points
Security shot at Palestinians at Gaza aid centre – ex-guard

The IDF also told Sky News: “The IDF allows the American civilian organisation (GHF) to distribute aid to Gaza residents independently, and operates in proximity to the new distribution zones to enable the distribution alongside the continuation of IDF operational activities in the Gaza Strip.

“Following incidents in which harm to civilians who arrived at distribution facilities was reported, thorough examinations were conducted in the Southern Command and instructions were issued to forces in the field following lessons learned.

“The aforementioned incidents are under review by the competent authorities in the IDF.”

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