IDH1 mutation

Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.

Large-scale validation studies are imperative to integrate molecular profiles into clinical practice. Until then, management decisions should be individualized, balancing the thrombotic risks with oncologic considerations.

DWI and ADC measurements demonstrate strong potential as non-invasive tools for predicting glioma genetics. These imaging biomarkers can aid in tumour characterisation and provide valuable insights for guiding personalised treatment strategies.

After adjuvant therapy with radiotherapy and temozolomide, the patient presented with a growing mass in the right medial frontal lobe in March 2021...Mr. Daily-Lyles has nothing to disclose.

Transcriptome analysis shows increased expression of many pro-tumor pathways upon expression of IDH1 R132Q versus R132H, including transcripts of EGFR and PI3K signaling pathways. Thus, IDH1 mutants appear to modulate D2HG levels via altered catalysis and are associated with distinct epigenetic and transcriptomic consequences, with higher D2HG levels appearing to be associated with more aggressive tumors.

Currently, the FDA has granted approval for the use of the small molecule inhibitor Ivosidenib (AG-120) in the treatment of IDH1-mutated AML and cholangiocarcinoma...Representative mIDH1 inhibitors and their binding modes were also discussed. In particular, we summarized seven strategies to overcome drug resistance, which provide a basis for understanding the mechanism of drug resistance for IDH1 mutations and exploring guidance to overcome drug resistance.

Next-Generation Sequencing results highlighting mutations in those genes, and other cancer genes were further subjected to in silico study of protein-protein interactions, gene ontology, and pathway enrichment. We also include a state-of-the-art literature review about IDH1 and IDH2 molecular biology, biochemical properties, and the role of their mutations in cancer development and progression, along with insights into regional variations in cancer biology and treatment response.

Although the addition of modified FOLFOX (fluorouracil, leucovorin, and oxaliplatin) to active symptom control improved the overall survival of patients with progressing advanced BTC despite gemcitabine plus cisplatin treatment, its efficacy was modest. This review delineates the evolution of systemic therapies in patients with pretreated advanced BTC. By examining past developments and recent advances through prospective trials, it highlights novel approaches that may improve outcomes in this challenging disease.

Furthermore, integration with a microarray fluorescence chip enabled rapid and accurate quantification of IDH1 mutant allele frequency (MAF), highlighting its potential for glioma classification, disease monitoring, and therapeutic evaluation. These findings underscore the transformative potential of TDF-based interface engineering as a platform for high-performance biosensing and diagnostic applications.

This review also emphasizes the importance of collaborative efforts between clinicians, pathologists, and oncologists to optimize outcomes. By synthesizing the latest molecular insights and treatment trends, this review provides a valuable resource to guide the personalized management of HCC and CCA.

Delta habitat radiomics derived from preoperative contrast-enhanced MRI may enhance the accuracy of postoperative recurrence and survival predictions in BG patients. The validated nomograms provide actionable tools for optimizing postoperative surveillance and personalized clinical decision-making.

The Multivariable Combined Model performed better than Clinical Model 1 and Radiomic Feature Model 1 (DeLong all p < 0.05), and Radiomic Feature Model 3 performed better than Radiomic Feature Model 1 (DeLong p < 0.05). Compared with the conventional MRI Radiomics and Clinical Models, the Multivariable Combined Model, mainly based on DCE quantitative parameters and multi-modality Radiomics features, is the most promising and deserves attention in the current study.

Combining SHP2 inhibition with RT is a promising therapeutic avenue for IDH-mut glioma by suppressing the activated SHP2-ERK axis.

We assessed the performance of our method for grading glioma, glioma isocitrate dehydrogenase1 (IDH1) mutation status classification and pituitary tumor texture classification on two datasets, glioma or pituitary tumors collected in a local affiliated hospital and glioma imaging data from TCIA. Compared with commonly models and new models, our model achieves higher accuracy, with an accuracy of 90.72%, classified glioma IDH1 mutation status with an accuracy of 94.35%, and classified pituitary tumor texture with an accuracy of 94.64%.

High-throughput screening of 221 anticancer drugs using NCC-dCS2-C1 identified three candidates, ixazomib, pazopanib, and ponatinib, that demonstrated low IC50 values, indicating their potential efficacy in treating dCS. We conclude that NCC-dCS2-C1 is a valuable tool for preclinical and basic research on dCS.

It demonstrated favorable preclinical pharmacokinetics and safety profiles, reduced 2-HG in vivo robustly and sustainably in the mutant IDH1 and 2 tumor xenograft models, and displayed high brain penetration in mice. In the clinical studies, the drug showed good safety and encouraging efficacy in patients with relapsed/refractory myeloid malignancies carrying IDH1 and/or IDH2 mutations.

We did not find a statistically significant difference in EFS and OS among the NPM1 subtypes. However, our results showed that the prognoses of NPM1 AML can be influenced by other co-occurring mutations. A larger study is needed to confirm our findings.

Ivosidenib demonstrated long-term disease control and manageable toxicity for some patients with mIDH1 conventional CS and is under further investigation (NCT06127407).

The authors present a case in which IN cancer therapy with NEO100 was well tolerated and was associated with striking tumor regression, providing further evidence that this novel conceptual approach to cancer therapy might become useful for the improved treatment of recurrent glioma. https://thejns.org/doi/10.3171/CASE24683.

This study identifies MGMT promoter methylation in a subset of glioblastomas IDH-wild-type. These findings highlight the molecular diversity of glioblastomas and suggest potential targets for tailored therapeutic strategies.

To assess D-2-HG production in living immortalized glioma cells, we engineered D2HGlo sensors that localize to subcellular compartments, which yielded findings of elevated D-2-HG in the cytosol, mitochondria, and nucleus of IDH1 mutant cells. D2HGlo was used to perform a side-by-side comparison of cytosolic and secreted D-2-HG to reveal that glycolysis, but not glutamine catabolism, drives D-2-HG production in IDH1 mutant cells.

IdyllaTM offers a rapid, user-friendly, and specific method for detecting IDH1/2 mutations, ideal for immediate clinical needs. NGS, while more time-consuming and costly, provides comprehensive genetic profiles valuable for personalized medicine and research. The choice between these methods should be guided by the clinical context, resource availability, and individual patient needs. For routine diagnostics, we recommend an algorithmic approach starting with the FastTrack method followed by NGS for wildtype cases.

This post-approval study offers real-world evidence in support of the use of AEF therapy as first-line treatment.

The activity of the IDH1 H170A mutant, which is unable to bind oxaloacetate in the clasp domain, was unaffected by oxaloacetate. This allosteric regulatory site may serve as a potential target for novel IDH1 inhibitors.

The strongest risk factor for adverse outcomes, however, was AML not in CR. This analysis provides benchmarks for interpretation of results emerging from post-transplant maintenance trials in IDHmut AML and suggest that maintenance strategies may further optimize the promising outcome in this molecularly defined subgroup by reducing relapse risk, especially for patients whose AML is not in remission at time of alloHCT.

P1, N=36, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: Feb 2025 --> Feb 2026

Recognizing the clinical significance of these alterations, ivosidenib and pemigatinib have been approved in Korea for BTC patients with IDH1 mutations and FGFR2 fusions, respectively. This review explores the epidemiology, risk factors, and molecular features of BTC, along with corresponding targeted therapies. Furthermore, we compare the unique characteristics of BTC in Korea with global data to inform future research and clinical practice.

P2, N=60, Recruiting, Rigel Pharmaceuticals | Not yet recruiting --> Recruiting

Here we discovered a novel O -2- hydroxyglutarylation by D2HG using chemical proteomics and further revealed distinct chiral preferences for D/L2HG modifications. Notably, we identified two kinases, MRCKA and SLK, modified by D2HG and L2HG respectively, and detected reduced phosphorylation of their substrates, suggesting an inhibitory effect of D/L 2HG modifications on the kinases' activity.

iCCAs with pathogenic FGFR2 fusions/rearrangements and IDH1 mutations have distinct immunophenotypes. Tailoring immunotherapeutic approaches to specific molecular subsets could improve treatment outcomes across the divergent molecularly defined iCCA subtypes.

There is insufficient evidence at this time to suggest that intraoperative optical histologic methods offer increased diagnostic accuracy when compared to conventional techniques.

We next found enhanced CIN levels and the sensitivity of IDH1 R132H/WT and TP53 R248Q/R248Q genotypes, introduced into U87 MG glioma cells by CRISPR/Cas9, to different drugs, including conventional temozolomide. It was found that U87 MG cells carrying IDH1 R132H/WT exhibit dramatic sensitivity to paclitaxel, which was independently confirmed on cell cultures derived from patients with naturally occurring IDH1 R132H/WT. Overall, our results suggest that the development of CIN-enhancing therapy for glioma tumors with the IDH1 R132H/WT genotype could be advantageous for adjuvant treatment.

This study presents the first documented case of LLT, thereby expanding its anatomical site of tongue and confirming the presence of a significant IDH1 mutation, thus enhancing our understanding of the molecular alterations in LLT.

Integrating perfusion MRI with genetic analysis offers a promising approach to improving the diagnostic and therapeutic landscape for brain tumors, indicating a substantial step toward personalized neuro-oncology. These findings support further validation in larger, multi-institutional studies to solidify their role in clinical practice.

Based on the results of the study, the authors have also provided possible future risk stratification and diagnosis workflow for CML disease. The online version contains supplementary material available at 10.1007/s12288-024-01808-9.

In this large cohort of IDHm glioma patients, ivosidenib was well tolerated. Our results support the use of IDHi therapy in patients with grade 2 or 3 astrocytoma or oligodendroglioma and highlight limited effectiveness in patients with enhancing disease.

Conclusion The findings suggest that PD-L1 may be a promising therapeutic target, even in the absence of significant grade-specific trends by demonstrating PD-L1 presence in the majority of glioma cases, highlighting its potential as a therapeutic target in GBM immunotherapy. The results provide insight into the immune landscape of gliomas and pave the way for future research into effective combination therapies for GBM, despite the lack of a significant correlation between glioma grade and PD-L1 expression.

As first-line systemic therapy, the addition of an immune checkpoint inhibitor, such as durvalumab or pembrolizumab, to gemcitabine plus cisplatin has been shown to prolong overall survival compared with gemcitabine plus cisplatin...Regarding second-line treatment after a gemcitabine-based regimen, fluorouracil and folinic acid plus oxaliplatin have been the standard regimen. Additionally, FGFR2 fusion gene/rearrangement, mutations of IDH1/2, KRAS, and BRAF, and overexpression of HER2 are promising therapeutic targets for which the effectiveness of each targeted therapy has been reported, at this time, as a second-line or later treatment.

P4, N=120, Recruiting, Leiden University Medical Center | Trial completion date: Jan 2028 --> Jul 2028 | Trial primary completion date: Jan 2026 --> Jul 2026

Clinical (n = 31 patients) and survival data (n = 23 patients) indicate a clinical behaviour similar to other CNS WHO grade 4 IDH-mutant astrocytomas, however with an increased risk for leptomeningeal (n = 7) and extra-axial (n = 2) spread. Taken together, ASTRO PNC is defined by a distinct molecular and histological appearance that can mimic metastatic disease and typically follows an aggressive clinical course.

Finally, we found that l-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis.

Our findings indicate that PDCD1 and CD274 are highly expressed irrespective of IDH1 mutation statuses, suggesting that glioblastomas could benefit from immunotherapy. Moreover, IDH1Mu glioblastomas may require a combination of PI3K/AKT/mTOR inhibitors and immunotherapy due to PIK3R1 overexpression.