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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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M’s star Raleigh caps torrid series with 31st HR

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M's star Raleigh caps torrid series with 31st HR

CHICAGO — There is no stopping Cal Raleigh at the moment.

Raleigh has a major-league-leading 31 homers after he helped the Seattle Mariners take two of three against the Chicago Cubs over the weekend. The switch-hitter went deep four times and drove in six runs in the series.

“Just trying to have good at-bats, really,” Raleigh said. “Trying to stay consistent. Really just trying to home in on my approach and not worry too much about what the pitcher is trying to do to me.”

Raleigh had two hits, walked twice and scored three runs in Seattle’s 14-6 victory Sunday. He is batting .327 (37-for-113) with 16 homers and 34 RBIs in his past 29 games.

Raleigh was the designated hitter for the series finale after being behind the plate Saturday. He hammered the first pitch of his at-bat against Colin Rea — a 93.8 mph fastball — for a two-run shot in the top of the first on a hot afternoon at Wrigley Field. The massive drive to center had an exit velocity of 105 mph.

The DH walked in the third and singled and scored in the fifth. After popping out softly for the final out of the sixth, he walked again in the eighth and scored on Randy Arozarena‘s two-run double.

“Thirty-one home runs, he just continues to march through history here,” Mariners manager Dan Wilson said. “It’s fun to watch. … He’s a smart player, so later in the game, not getting too anxious, not trying to out of the zone, not trying to get away from his identity as a hitter and who he is. Just staying right where he needs to stay.”

The 28-year-old Raleigh, who agreed to a $105 million, six-year contract with Seattle in March, is the first switch-hitter to mash at least 30 homers before the All-Star break. He needs four more homers to match Ken Griffey Jr. for the most before the break in Mariners history.

“I think a lot of people don’t watch to pitch to him, and then if you do and fall behind, he hits a lot of homers, obviously,” Seattle pitcher Logan Gilbert said. “He can beat you in a lot of different ways, and it seems like he’s doing it every game, too.”

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Shoeless Jazz: Yanks star loses both cleats, scores

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Shoeless Jazz: Yanks star loses both cleats, scores

NEW YORK — Shoeless Jazz crossed the plate, a century after Shoeless Joe.

Both of Jazz Chisholm Jr.‘s cleats flew off his feet as he scored from second base in the New York Yankees‘ 4-2 win over the Baltimore Orioles in an unusual morning start Sunday.

“I was so sweaty. My socks were wet. Everything had just slipped straight out,” he said.

Chisholm doubled twice, including a go-ahead, two-run drive off the right-center-field wall in the eighth inning, then slid into catcher Gary Sánchez for the final run as New York put the shoe on the other foot, so to speak. The AL East-leading Yankees won their second straight after losing seven of eight in a game that will be remembered for Chisholm’s size 10½ Jordan 1 spikes.

Shoeless Joe supposedly was given his nickname on June 6, 1908, playing semipro ball for the independent Greenville Spinners against the Anderson Electricians. New cleats had caused blisters, and he took them off and hit a long home run in the seventh inning.

Jackson won a World Series title with the Chicago White Sox in 1917, then was among eight players on the so-called “Black Sox” who were banned for life after they were accused of intentionally losing the 1919 Series to Cincinnati in exchange for money from gamblers. He finished with a .356 average in 13 major league seasons.

Asked whether he should be called Shoeless Jazz, Chisholm responded: “Wow. Is that how Shoeless Joe got his name? He ran out of his shoe?” When told Jackson earned the nickname in the 1910s, Chisholm quipped: “Oh, so he wasn’t wearing shoes.”

“I saw a lot of firsts,” Yankees captain Aaron Judge said. “11:30 game to a guy losing both his shoes. I’ve seen one cleat kind of running but not both like that. That was awesome.”

Chisholm is hitting .350 (21-for-60) with 11 RBIs since returning from a strained right oblique that caused him to miss 28 games. He raised his average to .242.

“That’s what I live for. That’s how I grew up playing baseball in high school, little league,” he said. “I don’t feel like it’s no need to change.”

New York trailed 2-0 when Chisholm hit a two-out double off Dean Kremer and headed for home on DJ LeMahieu‘s single to left.

“They say he’s the best shoe tier. I didn’t understand it until he actually did. It took me like a minute to take off my shoes just now.”

Jazz Chisholm Jr. on asking rookie Jasson Domínguez to tie his laces after putting on fresh socks and his spikes

Chisholm’s left shoe popped off between third and home. Seeing rookie catcher Maverick Handley move to his left for Colton Cowser‘s throw up the third-base line, Chisholm tried to veer to avoid contact. He caught the catcher with his right arm as Cowser was spun to the ground and the ball popped out of his mitt. Chisholm fell past the plate as the right shoe was jarred off and from his knees slapped a hand across the plate.

“He had dirt all over his face when I walked out there to get him. Looked like glitter on his face,” Yankees manager Aaron Boone said. “We were all kind of screaming.”

After he reached the dugout, Chisholm stretched out with his stockinged feet on the bench. He put on a fresh pair of socks and then his spikes, and Chisholm asked rookie Jasson Domínguez to tie the laces.

“They say he’s the best shoe tier,” Chisholm recalled in the postgame clubhouse. “I didn’t understand it until he actually did. It took me like a minute to take off my shoes just now.”

Baltimore led 2-1 in the eighth when Ben Rice singled leading off against Bryan Baker for his third hit. Giancarlo Stanton singled to put runners at the corners, and Paul Goldschmidt pinch ran for his fellow former MVP — the first pinch-running appearance of Goldschmidt’s big league career, according to the Elias Sports Bureau.

Baker fell behind 3-0 in the count and left a belt-high fastball over the plate. Chisholm drove it 384 feet off the middle of the wall.

“I wasn’t going to swing if it wasn’t a fastball,” he said.

Goldschmidt, 37, slid in just ahead of Sánchez’s tag. Chisholm was a minor leaguer in Arizona’s system when Goldschmidt starred for the Diamondbacks.

“He was the guy that everybody really watched doing baserunning,” Chisholm said. “Even when I got to Miami, he was still the blueprint of how to run the bases.”

Goldschmidt took pride in his baserunning.

“It’s something that wasn’t secondary behind hitting and defense,” he said.

Chisholm took third on the throw and LeMahieu followed with a chopper to shortstop Gunnar Henderson, who threw home. Chisholm slid headfirst and was at first called out by umpire Jansen Visconti, who didn’t realize Sánchez dropped the ball as he applied the tag.

His first run, however, was the one that will live on in replays for the flying footwear.

“Go out there. Keep playing like that,” Stanton had told him. “You don’t need them.”

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Mets demote struggling catcher Alvarez to minors

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Mets demote struggling catcher Alvarez to minors

The New York Mets have demoted struggling catcher Francisco Alvarez to Triple-A Syracuse, the team announced Sunday.

Catcher Hayden Senger was promoted to the majors in a corresponding move to become the backup to now-primary catcher Luis Torrens.

The moves come after Alvarez went 2-for-5 with a home run in the Mets’ 11-4 Saturday night victory over the Philadelphia Phillies, which snapped New York’s seven-game losing streak.

Alvarez, however, has struggled at the plate this season, hitting .236 with three home runs and 11 RBIs in 35 games. He has an OPS of .652 with 38 strikeouts.

Alvarez, 23, was baseball’s No. 1 prospect in 2022 and hit 25 home runs as a rookie in 2023. In parts of four seasons with the Mets since debuting in 2022, Alvarez is a .223 hitter with 40 homers and 122 RBIs in 263 games.

Senger, 28, made his major league debut this season with the Mets, appearing in 13 games and hitting .179 in 28 at-bats.

The Mets (46-31) enter Sunday night’s game against the Phillies (46-31) tied for first place in the National League East standings.

Field Level Media contributed to this report.

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