MTAP as an emerging biomarker in thoracic malignancies

Lung Cancer, Год журнала: 2024, Номер 197, С. 107963 - 107963

Опубликована: Сен. 30, 2024

Язык: Английский

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Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 21, 2024

ABSTRACT Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism a key mediator of GBM Uptake the essential sulfur-containing amino acid methionine drastically elevated in GBMs compared normal cells, however, it not known how this utilized or whether relates Here, we find that radiation acutely increases levels methionine-related metabolites variety treatment-resistant models. Stable isotope tracing studies further revealed activates S-adenosyl (SAM) conversion through an active signaling event mediated by kinases DNA damage response. In vivo tumor SAM synthesis after radiation, while brain production remains unchanged, indicating tumor- specific metabolic alteration radiation. Pharmacological and dietary strategies block slowed response increased cell death following vitro. Mechanistically, these effects are depletion repair proteins reversed supplementation. These selective lacking salvage enzyme methylthioadenosine phosphorylase. inhibition hindered growth flank orthotopic models when combined with By contrast, does reduce fails radiosensitize intracranial models, depleting SAM, as opposed simply lowering methionine, critical for hindering GBM. results highlight new link between define fates . Inhibiting radiation-induced slows augments efficacy Using MAT2A inhibitors deplete may selectively overcome resistance defective sparing brain.

Язык: Английский

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Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancer

The Journal of Pathology Clinical Research, Год журнала: 2024, Номер 11(1)

Опубликована: Дек. 12, 2024

Abstract Homozygous 9p21 deletions usually result in a complete loss of S‐methyl‐5′‐thioadenosine phosphorylase (MTAP) expression visualizable by immunohistochemistry (IHC). MTAP deficiency has been proposed as marker for predicting targeted treatment response. A tissue microarray including 2,710 urothelial bladder carcinomas were analyzed deletion fluorescence situ hybridization and IHC. Data compared with data on tumor phenotype, patient survival, intratumoral lymphocyte subsets, PD‐L1 expression. The rate increased from pTaG2 low (9.2% homozygous, 25.8% heterozygous) to high (32.6%, 20.9%; p < 0.0001) but was slightly lower pTaG3 (16.7%, 16.7%) tumors. In pT2–4 carcinomas, 23.3% homozygous 17.9% heterozygous found, tied advanced pT ( = 0.0014) poor overall survival 0.0461). Complete seen 98.4% deleted while only 1.6% negative tumors had retained copies 0.0001). linked stage 0.05 each). relationship between deletions/MTAP prognosis independent pN associated noninflamed microenvironment 0.05). is strongly deletion, aggressive disease, microenvironment. Drugs targeting MTAP‐deficiency may be useful carcinoma. IHC near perfect surrogate this type.

Язык: Английский

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Inhibitory Effect of PRMT5/MTA Inhibitor on MTAP‐Deficient Glioma May Be Influenced by Surrounding Normal Cells

Cancer Medicine, Год журнала: 2024, Номер 13(24)

Опубликована: Дек. 1, 2024

ABSTRACT Background Methylthioadenosine phosphorylase (MTAP) and protein arginine methyltransferase 5 (PRMT5) are considered to be a synthetic lethal pair of targets, due the fact that deletion MTAP leads massive production methylthioadenosine (MTA) decreasing activity PRMT5. In vitro in vivo experiments have demonstrated MRTX1719, small molecule selectively binds PRMT5/MTA complex, significantly inhibits proliferation MTAP‐deficient tumors has weak toxic effect on normal cells. However, it been reported MTAP‐deleted did not accumulate MTA metabolism by MTAP‐expressing stroma, which might lead diminished anti‐cancer MRTX1719. Methods We first analyzed whether there were intracerebral cells around glioma tissues paraffin‐embedded tissue microarray human specimens. Then, models gliomas coexisting with neurons or glial constructed for evaluating effectiveness anti‐tumor effects MRTX1719 this setting. Results surrounded large number cells, presence these reduced inhibitory vivo. Conclusions Due complexity tumor environment vivo, PRMT5/MTA‐specific inhibitors may somewhat attenuated, their ability achieve suitable therapeutic clinic require more in‐depth studies.

Язык: Английский

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Computer-aided design of a fluorescent MAT2A inhibitor for visualized cancer synthetic lethality

Bioorganic Chemistry, Год журнала: 2024, Номер 150, С. 107582 - 107582

Опубликована: Июнь 20, 2024

Язык: Английский

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MTAP protein status is highly concordant with CDKN2A fluorescent in situ hybridization and allows stratification of the luminal subtype in muscle‐invasive bladder cancer

Histopathology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 26, 2024

Aims Loss of heterozygosity in chromosome 9p21, common urothelial carcinoma (UC), typically involves deletion CDKN2A and MTAP genes. loss is emerging as a promising therapeutic target predictive biomarker UC. This single‐centrre retrospective study examined the incidence deletions muscle‐invasive bladder cancer (MIBC) metastatic (mUC), investigating their correlations with clinical, pathological, genomic features, well patient outcomes. Methods Fluorescence situ hybridization (FISH) immunohistochemistry (IHC) were performed on 302 MIBC specimens 63 biopsy‐proven metachronous metastases to assess protein expression. Results homozygous (HD), identified 30.3% MIBCs, loss, found 28.8% both significantly associated luminal‐URO subtype, FGFR3 mutations, normal/wildtype p53 IHC ( P < 0.05). expression was correlated HD, 84.0% sensitivity, 92.3% negative value (NPV), 96.3% specificity, 91.9% positive (PPV). 100% concordant between primary tumours nodal metastases. Patients had higher visceral (50%) compared bone/soft tissue (35.7%) nodes (14.3%). Mean progression‐free survival overall shorter for patients although not statistically significant. Conclusion Our findings highlight HD prevalent genetic alterations mUC, particularly within subtype ‐mutated, p53‐normal/wildtype tumours. can serve surrogate marker 9p21.3 highlighting its clinical relevance potential MIBC.

Язык: Английский

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Small-Molecule Modulators Targeting Coactivator-Associated Arginine Methyltransferase 1 (CARM1) as Therapeutic Agents for Cancer Treatment: Current Medicinal Chemistry Insights and Emerging Opportunities

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 7, 2024

Overexpression of coactivator associated arginine methyltransferase 1 (CARM1) is with various diseases including cancer. Therefore, CARM1 has emerged as an attractive therapeutic target and a drug response biomarker for anticancer discovery. However, the development conventional inhibitors been hampered by their limited clinical efficacy, acquired resistance, inability to inhibit nonenzymatic functions CARM1. To overcome these challenges, new strategies such isoform-selective inhibitors, dual-acting targeted protein degradation technology (e.g., PROTACs), even activators, are essential enhance activity modulators. In this perspective, we first summarize structure biofunctions its association Next, focus on recent advances in modulators, dual-target PROTAC degraders, from perspectives rational design, pharmacodynamics, pharmacokinetics, status. Finally, discuss challenges future directions CARM1-based

Язык: Английский

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Time for arginine methylation: PRMT5 inhibition to advance cholangiocarcinoma treatment

Gut, Год журнала: 2024, Номер unknown, С. gutjnl - 333632

Опубликована: Дек. 6, 2024

Язык: Английский

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