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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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Politics

Britain must ‘lead from the front’ in Ukraine and ‘tough choices to come’, says Sir Keir Starmer

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Britain must 'lead from the front' in Ukraine and 'tough choices to come', says Sir Keir Starmer

There are more tough choices to come on Ukraine and Britain must “lead from the front”, Sir Keir Starmer has said.

The prime minister gave a statement in parliament after he unveiled proposals for a “coalition of the willing” to enforce any peace deal in the war-torn country, and announced a plan for Kyiv to use £1.6bn of UK export finance to buy 5,000 more air defence missiles.

Politics latest: Farage says Zelenskyy ‘rude’ to Trump

He said the “tough choices that we made last week are not done” and a “lasting peace” in Ukraine “has to be our goal”.

“Britain will lead from the front for the security of our continent, the security of our country, and the security of the British people,” he said.

It follows a hectic week of diplomacy for Sir Keir, during which he held talks with Donald Trump in the White House on Thursday, hosted Ukraine’s president in Downing Street on Saturday and then a wider summit of world leaders on Sunday.

Sandwiched in between his Washington DC trip and busy weekend back home was Volodymyr Zelenskyy’s extraordinary row with the US president in the Oval Office, which cast more doubt on America’s support for Kyiv.

More on Keir Starmer

Sir Keir said the showdown is something “nobody wants to see” but he would not pick a side.

He called America an “indispensable” ally, adding: “We will never choose between either side of the Atlantic

Ukraine's President Volodymyr Zelensky and Prime Minister Sir Keir Starmer head to a private room to hold a meeting during a Leaders' Summit on the situation in Ukraine at Lancaster House, London. Picture date: Sunday March 2, 2025.
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Zelenskyy and Starmer. Pic: PA

“In fact, if anything, the past week has shown that that idea is totally unserious because while some people may enjoy the simplicity of taking a side, this week has shown with total clarity that the US is vital in securing the peace we all want to see in Ukraine.”

In front of the world’s cameras on Friday, Mr Trump accused the Ukrainian president of “disrespecting” the United States and “gambling with World War Three” after he expressed scepticism that Vladimir Putin could be trusted to honour ceasefire agreements.

It has intensified fears among some Western leaders that the US cannot be relied upon to continue supporting Ukraine, or provide a security guarantee to deter the Russian leader if a peace deal is struck.

After the PM’s statement, Liberal Democrat leader Sir Ed Davey said the UK needs to “reduce our dependency on the United States” as he fears President Trump is “not a reliable ally with respect to Russia”.

However, many other opposition politicians have praised Sir Keir’s diplomacy this week, with Tory leader Kemi Badenoch backing the prime minister for “working with allies in Europe and with the United States to bring peace to Ukraine and not a surrender to Russia”.

Read More:
The ‘coalition of the willing’ that could secure peace in Ukraine

Sir Keir has been positioning himself as a peace broker between the US and Europe following Mr Trump’s ascension to the White House and his clear indication he no longer wants to bankroll NATO’s defence.

He has suggested a coalition of European allies could step up and defend a potential deal for Ukraine to “guarantee the peace” and indicated some EU nations could follow in the UK’s footsteps and increase defence spending.

However, he argues that while a security guarantee should be led by Europe, it needs US backing.

Mr Trump has not committed to such a guarantee and previously suggested a minerals deal between the US and Ukraine could act as one.

In response to a question from Reform UK leader Nigel Farage, Sir Keir told the Commons this would “not be enough on its own”.

In any case, the deal has been put on hold following Mr Trump’s row with the Ukrainian president.

Shortly after the PM finished speaking, Mr Trump hit out at Mr Zelenskyy once again, saying the US would “not put up with him” for much longer after he said the end of the war with Russia is “very far away”.

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World

Long-range drone strikes weakening Russia’s combat ability, senior Ukrainian commander says

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Long-range drone strikes weakening Russia's combat ability, senior Ukrainian commander says

Russia is finding it “significantly” harder to conduct combat operations against Ukraine because of a rise in Ukrainian long-range drone strikes on Russian weapons supplies, ammunition depots and fuel refineries, a senior commander has said.

Brigadier General Yuriy Shchygol signalled these attacks would grow, revealing that his country plans to more than quadruple the production rate of deep strike drones – with a range of hundreds of miles – to more than 2,000 aircraft a month.

Brigadier General Yuriy Shchygol
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Brigadier General Yuriy Shchygol

Ukraine has been intensifying the tempo of its long-range drone strikes against targets inside Russia and Russian-occupied territory since late December – demonstrating what defence sources say is a world-leading capability that the Kremlin is struggling to counter.

The mission is an example of how Kyiv remains focused on combatting Moscow’s invasion even as world attention fixates on the fallout from a row between Donald Trump and Volodymyr Zelenskyy, as well as efforts by Europe to prepare a plan for peace.

Live updates: Ukraine war latest

The comments by Brigadier Shchygol, who coordinates long-range drone strikes for Ukraine’s Defence Intelligence, offer a rare insight into the impact of the covert mission, which is also carried out by other branches of the Ukrainian military and security services.

“Russia is finding it increasingly difficult to conceal the extent of the damage,” the commander told Sky News in an interview at an undisclosed location in Kyiv.

“Headquarters have been hit, command structures weakened, and panic is spreading among their officers. Compared to a year ago, conducting full-scale combat operations has become significantly more challenging for [the Russians].”

Ukrainian drones being launched from a secret location
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Ukraine’s drone technology is considered to be world-leading


Sky News analysis of long-range drone strikes last month found that since December, there had been a ramping up of attacks against oil refineries in Russia that are used to fuel Russian tanks, jets and warships.

The analysis took in strikes officially confirmed by the Ukrainian armed forces. Brigadier Shchygol said “far more” drone attacks by Ukraine are not publicly confirmed.

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Ukraine ramps up attacks on oil depots

In a sign of the importance placed on long-range drones, he said Kyiv’s ability to manufacture this weapon has already jumped 100-fold since late 2022 to more than 500 per month.

While the officer would not say how many of these drones are then deployed on operations, he noted: “Nothing is just sitting in storage unused.”

He said recent operations had targeted several storage sites for Russia’s Iranian-designed Shahed one-way attack drones – used by the Russian armed forces against Ukrainian military and civilian targets.

More than 3,000 Shahed unmanned aerial vehicles were destroyed, according to the officer, who said: “As a result, their deployment of these drones has significantly decreased.”

Top secret drone mission

Sky News was given rare access to view a drone mission last week at a top-secret area.

As night fell, soldiers dressed in black – all members of the Defence Intelligence of Ukraine, an elite branch of the armed forces – prepared a line of about 10 drones.

Ukrainian drones being launched from a secret location
Image:
Ukrainian drones being launched from a secret location

Each aircraft looked like a giant, grey metal mosquito.

The model is called “Lutti”, which is Ukrainian for “Fury”.

One by one, the drones burst into life, a propeller on the back whirring, pushing the aircraft forward at ever greater speed until it took off into the darkness.

We were told their target was an ammunition depot inside Russia.

Ukrainian drones being launched from a secret location
Image:
Ukraine’s drone technology is considered to be world-leading


"Vector", the commander on the ground, spoke with a balaclava pulled up to his eyes to protect his identity
Image:
“Vector” spoke with a balaclava pulled up to his eyes to protect his identity

“Vector”, the commander on the ground, said his drones have a success rate of 70 to 80%.

He said Ukraine’s deep strike operations are “very important”.

“We change the war with these drones,” Vector said, speaking with a balaclava pulled up to his eyes to protect his identity.

“We can show [Russia] that the war can come in their houses, in their towns, cities.”

Russia’s sheer size makes it vulnerable

Using drones to strike targets hundreds of miles inside Russia is a complex challenge.

As night falls, members of an elite branch of Ukraine's armed forces prepare a line of drones
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As night falls, members of an elite branch of Ukraine’s armed forces prepare a line of drones

But the sheer size of their enemy’s country works in Ukraine’s favour. The Russian military has weapons sites, ammunition storage areas, oil refineries and military headquarters dotted across its territory and lacks the air defences to be able to protect them all.

“We are reaching those targets. The slowing pace of their offensives – and in some places, even Ukrainian counter-offensives reclaiming territory – proves that our strikes are effective and growing more so,” Brigadier Shchygol said.

Read more:
Which countries could send peacekeeping troops to Ukraine?
In the room with Volodymyr Zelenskyy

A huge planning and reconnaissance effort underpins Ukraine’s long-range drone strikes.

It identifies targets and coordinates attacks between the different teams.

Varying volumes of drones are required for each mission – with some of the most complex strikes needing 100 unmanned aircraft.

From farm aircraft to fighter drone

The brigadier was speaking in a large room inside a disused building in Kyiv where five examples of different Ukrainian long-range drones were on display.

Brigadier General Yuriy Shchygol
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Brigadier Shchygol spoke to Sky News from a room where long-range drones were on display

They tell the story of the evolution of vital battlefield technology that began life on a farm.

The earliest form of the long-range drone looks like an ordinary light aircraft, with rectangular wings and two propellers. It is a lot smaller than a manned plane but much larger than a regular drone – probably about the length of a car, with a similar wingspan.

This model, fitted with a camera and a large fuel tank to fly for long periods, had been used for surveillance for agricultural purposes.

It was adapted after Russia’s full-scale invasion to conduct reconnaissance and even bombing missions.

The idea was then modified further to develop similar-sized drones that look more like fighter jets, with pointed noses and triangular wings. These were designed to hold explosives in the main body of the plane.

Some of the drones are remotely piloted, others work via autopilot.

Russia’s war has forced Ukraine to use technology and innovation to fight back against its far more powerful foe.

It has accelerated the use of autonomous machines in an irreversible transformation of the warzone that everyone is watching and learning from.

Brigadier Shchygol said: “Right now, Ukraine’s battlefield experience is essentially a manual for the world.”

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Environment

Tesla owners get creative to distance themselves from Elon with new car logos & projectors

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Tesla owners get creative to distance themselves from Elon with new car logos & projectors

Tesla owners are finding creative ways to distance themselves from Elon Musk. They are now removing Tesla logos from their vehicles, replacing them with badging from other automakers, and even using projections on a Cybertruck in one case.

We previously reported on the surge in sales of stickers reading variations of “I bought this car before I knew Elon was crazy.” One particular business selling such stickers claimed to be selling hundreds per day as Tesla owners are looking to distance themselves from the automaker’s CEO.

Things have escalated since then, and the hate against Tesla has ramped up quite a bit. Some Tesla owners are even worried about people vandalizing their vehicles.

Now, some Tesla owners have found some more creative, tongue-in-cheek ways to distance their Tesla ownership from Elon Musk than slapping a sticker on their bumper.

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For example, Tesla vehicles are being spotted de-badged with the Tesla logos replaced with badges from other automakers (pictures via Stonk King):

It’s not exactly a new phenomenon, but lately, more of these Tesla vehicles with other automaker logos have been spotted.

But here’s an even more creative and clearer example of a Tesla owner trying to distance themselves from Musk.

A Tesla Cybertruck projecting images on its tailgate has been spotted several times in the last week:

It displays pleas not to graffiti the vehicle and adds things like “this truck already makes me look stupid enough.”

The short video is signed “Mussk production,” with the “ss” referencing the Schutzstaffel, a Nazi paramilitary group.

Electrek’s Take

Obviously, these are somewhat tongue-in-cheek examples, but between these, Tesla protests worldwide, and declining sales, it is genuinely mindboggling to see the destruction of Tesla’s brand in such a short period of time.

I have been covering Tesla for roughly 15 years and I remember when it was completely unknown brand, loved only by a handful of EV nerds, like myself, and hated by fossil fuel propagandists.

It took a great deal of work from Tesla employees and the EV community to build Tesla into an incredibly beloved global EV brand. A deep social media addiction, purchasing of Twitter, a move into politics, a few salutes, and now most of that incredible work is gone.

It takes years to build a reputation and seconds to destroy it.

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