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
LOUISVILLE, Ky. — Hall of Fame horse racing trainer D. Wayne Lukas has been hospitalized and will not return to training, Churchill Downs announced Sunday after speaking with members of his family.
Lukas’ family said the 89-year-old has battled a severe infection that has worsened and that he has declined an aggressive treatment plan to instead return home. His horses have been transferred to assistant trainer Sebastian “Bas” Nicholl.
“Wayne built a legacy that will never be matched,” Nicholl said. “Every decision I make, every horse I saddle, I’ll hear his voice in the back of my mind. This isn’t about filling his shoes – no one can. It’s about honoring everything that he’s built.”
Lukas is one of the most accomplished people in the history of the sport. His 15 Triple Crown victories are second only to good friend Bob Baffert, and Lukas has a record-tying 20 in the Breeders Cup.
He won the Kentucky Derby four times since 1988. His most recent victory in the Triple Crown came last year with Seize the Grey in the Preakness, his seventh — one short of Baffert’s record.
“Wayne is one of the greatest competitors and most important figures in Thoroughbred racing history,” Churchill Downs president Mike Anderson said. “He transcended the sport of horse racing and took the industry to new levels. The lasting impact of his character and wisdom, from his acute horsemanship to his unmatched attention to detail, will be truly missed. The enormity of this news is immense, and our prayers are with his family and friends around the world during this difficult time.”
Iranian nuclear sites sustained “extremely severe damage and destruction” in air strikes, the US has said – a stance mostly supported by the UN’s nuclear watchdog.
General Dan Caine, chairman of America’s joint chiefs of staff, told reporters that the destruction wrought by Operation Midnight Hammer will take “some time” to assess.
But he added that “initial battle damage assessments indicate that all three sites sustained extremely severe damage and destruction”.
The sites are Fordow, Natanz and Isfahan.
Image: Three nuclear sites in Iran were targeted by US strikes
Fordow is a secretive nuclear facility buried about 80m below a mountain and one of two key uranium enrichment plants in Iran, along with Natanz.
Isfahan features a large nuclear technology centre and enriched uranium is also stored there, diplomats say.
At Fordow, satellite images taken after the attack show holes in the mountain in which the nuclear site was situated.
Image: A satellite image showing two clusters of holes at the Fordow nuclear site in Iran following US strikes on the facility. Pic: Maxar
Images of Natanz, which is also suspected of having an underground facility, appear to show a new hole in a rocky area.
Pete Hegseth, the US defence secretary, said the initial assessment was that “all of our precision munitions struck where we wanted them to strike and had the desired effect”.
“Which means, especially in Fordow, which was the primary target here, we believe we achieved destruction of capabilities there,” he added.
America’s attack brings the US into direct involvement in the war between Israel and Iran, which started on 13 June. It prompted threats of reprisals from Tehran, raising fears of a wider regional conflict.
Rafael Grossi, head of the International Atomic Energy Agency (IAEA), said the facility at Natanz had been “completely destroyed”, while its underground halls “suffered a lot” because of cuts to electricity as the result of Israeli attacks.
He also told CNN that the Isfahan site had suffered “very significant damage”.
At Fordow, which is deep underground, he said it was difficult to know how much damage had been done.
Satellite images appear to show major damage at Isfahan.
Natanz was believed to have possibly already suffered extensive damage in Israel’s strikes earlier this week.
Fourteen bunker buster bombs were used in the attacks on Fordow and Natanz, and numerous Tomahawk cruise missiles were also used in the operation, which involved seven B-2 stealth bombers and was described by Donald Trump as “very successful”.
However, a senior Iranian source told the Reuters news agency that most of the highly enriched uranium at Fordow was moved to an undisclosed location ahead of the attacks.
Personnel numbers were said to have been cut, too.
The IAEA said there had been “no increase in off-site radiation levels” after the strikes.
Donald Trump said no further attacks were planned and he hoped diplomacy would take over.
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1:15
What is Operation ‘Midnight Hammer’?
Fears of a wider conflict
Iran’s foreign minister, Abbas Araghchi, warned that the US strikes “will have everlasting consequences”, adding that his country “reserves all options” to retaliate.
Mr Hegseth said the United States “does not seek war” but would “act swiftly and decisively when our people, our partners, or our interests are threatened”.
Iran has repeatedly denied it is seeking a nuclear weapon, and Mr Grossi said this month the IAEA had no proof of a “systematic effort to move into a nuclear weapon”.
Since the war broke out more than a week ago, Iranian authorities say more than 400 people have been killed since Israel’s bombardment began, mostly civilians.
Israel has taken out much of Iran’s military leadership with attacks targeting air defences and military bases.
Iran has been launching missiles back at Israel, and at least 24 people have been killed over the past nine days.
US Senator Chris Murphy, posting on X after the US strikes, said he and other senators received a classified briefing last week indicating that Iran did not pose an immediate threat through its nuclear programme.
“Iran was not close to building a deliverable nuclear weapon,” Senator Murphy said. “The negotiations Israel scuttled with their strikes held the potential for success.”
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2:36
What next after the US strikes on Iran?
‘Consultations’ with Vladimir Putin
The Iranian foreign minister told journalists on Sunday morning that he was flying to Moscow to have “serious consultations” with Vladimir Putin.
He described Moscow as a “friend of Iran”, adding: “We always consult with each other.”
Iran’s Revolutionary Guard Corps (IRGC) said that “invaders must now await responses that will bring regret” after the US strikes.
Gulf states like Bahrain, Saudi Arabia and Kuwait, all home to US military bases, are on high alert after the strikes, with Bahrain urging drivers to avoid main roads and Kuwait setting up shelters.
The UK has also further increased “force protection” measures for its military bases and personnel in the Middle East to their highest level.
Iran has requested an emergency meeting of the UN Security Council to “maintain international peace and condemn the US strikes”, according to state media.
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3:33
PM: ‘My focus is on de-escalation’
‘Bold decision’
Israeli Prime Minister Benjamin Netanyahu hailed the “bold decision” by Mr Trump, saying it would “change history”.
The IRGC said it had launched 40 missiles at Israel on Sunday morning, including its biggest ballistic missile, the Khorramshahr-4.
Iranian missiles hit sites in northern and central Israel, including in Haifa, Ness Ziona, Rishon LeZion and Tel Aviv.
The UK is preparing to fly British nationals out of Israel.
“Iran’s nuclear programme is a grave threat to international security. Iran can never be allowed to develop a nuclear weapon and the US has taken action to alleviate that threat,” said Sir Keir Starmer.
However, Mr Araghchi said the US and Israel had “blown up” negotiations and asked: “How can Iran return to something it never left, let alone blew up?”
Pakistan has said it would recommend Donald Trump for the Nobel Peace Prize for his work in helping to resolve the recent conflict between India and Pakistan.
Some analysts in Pakistan have suggested the move might persuade the US president to reconsider potentially joining Israel in striking Iran’s nuclear facilities.
Pakistan has condemned Israel’s attack on Iran as a violation of international law and said it threatens regional stability.
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1:57
Trump: US ‘helped a lot’ with India-Pakistan
Last month a surprise announcement by Mr Trump of a ceasefire brought an end to a four-day conflict between India and Pakistan, two nuclear-armed states.
The US president has repeatedly boasted of averting a nuclear war and saving millions of lives, and has complained about not getting enough credit.
Image: People in Pakistan light fireworks to celebrate the ceasefire deal. Pic: AP
While Pakistan agrees US diplomatic intervention brought the fighting to an end, India has disputed that, saying it was a bilateral agreement between the two militaries.
“President Trump demonstrated great strategic foresight and stellar statesmanship through robust diplomatic engagement with both Islamabad and New Delhi, which de-escalated a rapidly deteriorating situation,” Pakistan said.
“This intervention stands as a testament to his role as a genuine peacemaker.”
Mr Trump has long craved the Nobel Peace Prize, claiming he should have been awarded it for a variety of reasons.
In a post on his Truth Social platform on Friday, the president gave a long list of conflicts he claimed he had resolved, including Pakistan and India and the Abraham accords in his first term between Israel and some Muslim-majority countries.
“I won’t get a Nobel Peace Prize no matter what I do,” he added.