Isocitrate Dehydrogenase Mutation Research Articles

Hexosaminidase B-driven cancer cell-macrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma

Glycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and non-cancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn’t induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.

Ultra-early stage lower-grade gliomas: How can we define and differentiate these easily misdiagnosed gliomas through intraoperative molecular diagnosis.

Some lower-grade gliomas (LGG) are difficult to distinguish morphologically from glial cell proliferation or inflammatory changes during surgery, leading to a high risk of incorrect diagnosis. It is crucial to differentiate between the two for making surgical decisions. We define these critical cases as "ultra early stage lower-grade gliomas (UES-LGG)". We analyzed 11 out of 13 cases diagnosed with "gliosis" or "inflammatory changes" during surgery who tested positive for isocitrate dehydrogenase (IDH). Additionally, we conducted qRT-PCR detection on 35 samples diagnosed with LGG during surgery and analyzed their DNA content within an effective circulating threshold range to infer the critical value between UES-LGG and LGG. We conducted experiments using five standardized samples to infer the limited range of accurate detection of UES-LGG during surgery. In the comparative analysis of 11 samples and 35 samples, it was found that while there was no significant difference in the average DNA detection concentration between the two groups (159.36 ± 83.3 ng/μL and 146.83 ± 122.43 ng/μL), there was a notable statistical variance in the detection threshold for positive mutations (31.78 ± 1.14 and 26.14 ± 2.69, respectively). This suggests that the IDH mutation rate may serve as an indicator for differentiation between the two groups. Subsequently, DNA was extracted from standardized IDH mutant samples and subjected to gradient dilution for detection purposes. The results indicated a consistent increase in detection threshold as detection concentration decreased. When the detection concentration fell below <0.1 ng/μL, it became impossible to carry out effective threshold range detections. To further identify the precise detection interval, we conducted gradient division once again and sought to simulate the functional relationship between DNA copy number and cycle threshold within this interval. The research revealed that when the minimum detection concentration exceeded 250 copies/μL, a 100% detection rate could be achieved. This article defines UES-LGG as a tumor type easily misdiagnosed in clinical practice due to its extremely low positivity rate during surgery. The popularization of qRT-PCR based intraoperative molecular diagnosis greatly reduces errors caused by manual detection and improves disease detection rates during surgery. It provides a theoretical basis for more accurate surgical plans for surgeons.

Gaining Insight into the Catalytic Mechanism of the R132H IDH1 Mutant: A Synergistic DFT Cluster and Experimental Investigation.

Human isocitrate dehydrogenase 1 (IDH1) is an enzyme that is found in humans that plays a critical role in aerobic metabolism. As a part of the citric acid cycle, IDH1 becomes responsible for catalyzing the oxidative decarboxylation of isocitrate to form α-ketoglutarate (αKG), with nicotinamide adenine dinucleotide phosphate (NADP+) as a cofactor. Strikingly, mutations of the IDH1 enzyme have been discovered in several cancers including glioblastoma multiforme (GBM), a highly aggressive form of brain cancer. It has been experimentally determined that single-residue IDH1 mutations occur at a very high frequency in GBM. Specifically, the IDH1 R132H mutation is known to produce (D)2-hydroxyglutarate (2HG), a recognized oncometabolite. Using the previously determined catalytic mechanism of IDH1, a DFT QM model was developed to study the mechanistic properties of IDH1 R132H compared to wild type enzyme. Validating these insights, biochemical in vitro assays of metabolites produced by mutant vs wild type enzymes were measured and compared. From the results discussed herein, we discuss the mechanistic impact of mutations in IDH1 on its ability to catalyze the formation of αKG and 2HG.

Vorasidenib- A Paradigm Shift in IDH1- or IDH2-Mutant Low-Grade Glioma Treatment.

Low-grade gliomas (LGGs) pose significant challenges in cancer research and treatment due to their infiltrative nature and tendency for recurrence, making them the most common brain tumour in adults. Most of the LGGs have the propensity to cause notable alterations in the microenvironment of the tumour thus making them difficult to treat. These alterations can be attributed to the prevalent mutations in the genes that produce isocitrate dehydrogenase (IDH) enzymes, especially in grade 2 diffuse gliomas. [1] Despite its inability to provide a complete cure, chemoradiation has been adopted as the standard therapy in grade 3 gliomas since it can lead to long-lasting remission. Chemoradiotherapy, when administered promptly, can help prevent tumour progression, and recurrence after surgery and improve long-term outcomes. Nevertheless, immediate adjuvant chemoradiotherapy is not administered in patients afflicted with tumours containing IDH mutant grade 2 gliomas. This decision is often made to circumvent potential harm such as radiation-induced cognitive problems, chemotherapy-related DNA mutations, and other negative effects on their health. [2] Due to the intricacies associated with the treatment decisions and the inclination to delay aggressive therapies to avoid adverse events, creates a necessity for a novel therapeutic strategy that is both effective and well tolerated. Vorasidenib, an oral medication specifically designed to deal with IDH mutations has displayed promise despite existing challenges. By aiming to specifically target aberrant metabolic pathways triggered by mutant IDH enzymes, Vorasidenib offers a potential treatment capable of interrupting tumour growth and could subsequently result in better patient outcomes. Among the many reasons that make Vorasadenib an appealing option are its capability to penetrate the blood-brain barrier and its promising safety profile, resulting in effective treatment while alleviating potential side effects. [3] Vorasidenib’s efficacy is derived from its ability to halt the metabolic cascades driven by mutant IDH enzymes thus leading to decreased progression of the gliomas. Clinical studies elicit the substantial value Vorasadenib has to offer by enhancing progression-free survival and postponing the advancement of the illness in patients with grade 2 IDH-mutant gliomas. This offers an optimistic prospect for delaying the need for more aggressive treatments in these patients. [2,4] Hence, to conclude Vorasadenib can transform treatment norms and enhance outcomes for those suffering from IDH-mutant LGG. Furthermore, it is crucial to investigate different treatment combinations, finding markers that would help assess clinical response to treatment, which in turn would be an important milestone in the treatment journey.

The application value of support vector machine model based on multimodal MRI in predicting IDH-1mutation and Ki-67 expression in glioma

PurposeTo investigate the application value of support vector machine (SVM) model based on diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) and amide proton transfer- weighted (APTW) imaging in predicting isocitrate dehydrogenase 1(IDH-1) mutation and Ki-67 expression in glioma.MethodsThe DWI, DCE and APTW images of 309 patients with glioma confirmed by pathology were retrospectively analyzed and divided into the IDH-1 group (IDH-1(+) group and IDH-1(-) group) and Ki-67 group (low expression group (Ki-67 ≤ 10%) and high expression group (Ki-67 > 10%)). All cases were divided into the training set, and validation set according to the ratio of 7:3. The training set was used to select features and establish machine learning models. The SVM model was established with the data after feature selection. Four single sequence models and one combined model were established in IDH-1 group and Ki-67 group. The receiver operator characteristic (ROC) curve was used to evaluate the diagnostic performance of the model. Validation set data was used for further validation.ResultsBoth in the IDH-1 group and Ki-67 group, the combined model had better predictive efficiency than single sequence model, although the single sequence model had a better predictive efficiency. In the Ki-67 group, the combined model was built from six selected radiomics features, and the AUC were 0.965 and 0.931 in the training and validation sets, respectively. In the IDH-1 group, the combined model was built from four selected radiomics features, and the AUC were 0.997 and 0.967 in the training and validation sets, respectively.ConclusionThe radiomics model established by DWI, DCE and APTW images could be used to detect IDH-1 mutation and Ki-67 expression in glioma patients before surgery. The prediction performance of the radiomics model based on the combination sequence was better than that of the single sequence model.

Catalytically distinct IDH1 mutants tune phenotype severity in tumor models.

Mutations in isocitrate dehydrogenase 1 (IDH1) impart a neomorphic reaction that produces D-2-hydroxyglutarate (D2HG), which can inhibit DNA demethylases to drive tumorigenesis. Mutations affect residue R132 and display distinct catalytic profiles for D2HG production. We show that catalytic efficiency of D2HG production is greater in IDH1 R132Q than R132H mutants, and expression of R132Q in cellular and xenograft models leads to higher D2HG concentrations in cells, tumors, and sera compared to R132H. Though expression of IDH1 R132Q leads to hypermethylation in DNA damage pathways, DNA hypomethylation is more notable when compared to R132H expression. 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, resulting in distinct epigenetic and transcriptomic consequences where higher D2HG levels appear to be associated with more aggressive tumors.

A - 141 The Relationship of Tumor Location and Treatment on Cognition in Long-Term IDH-Mutant Glioma Survivors

Abstract Objective Isocitrate dehydrogenase 1 mutation (IDH-M) denotes a distinct subtype of glioma which has a relatively favorable prognosis but nevertheless requires treatment including surgery, radiation and/or chemotherapy and the tumors inevitably recur. Factors influencing cognition in long-term survivors (LTS) of IDH-M have not been well characterized. We investigated factors affecting cognition in a cohort of well characterized of IDH-M LTS. Method Patients (N = 65; 98.5% Caucasian; 47.7% female; Mage = 47.51; Medu = 16.06) who were at least 3 years post-IDH-M diagnosis who completed neuropsychological assessment in the Neuro-oncology division at Massachusetts General Hospital were included. Tests of processing speed, working memory, episodic memory, and executive function were analyzed along with tumor, treatment, and individual difference factors relevant to cognition. Exploratory analyses were conducted to generate hypotheses regarding factors of interest. Results Tumor hemisphere affected delayed recall of word list learning Z-score (F = 4.00; p = 0.024; left = −1.41; right = −0.59). Tumor lobe affected visual learning (F = 3.11; p = 0.054; frontal = −0.594; temporal = −0.807; parietal = −1.983). There were no effects of treatment type (photon vs proton radiation; single vs multi-agent chemotherapy), presence of seizures, psychiatric diagnosis, tumor subtype (oligodendroglioma/astrocytoma), grade (2,3,4) or disease duration (Mean = 9.5y; min = 3y; max = 28.8y) on cognition. Conclusions In this heavily treated group of IDH-M glioma LTS referred for neuropsychological evaluation, typical lateralizing/localizing cognitive deficits were revealed. However, simple dichotomies may fail to capture relevant contributors to cognitive impairment. Integration with individual factors including premorbid cognition, radiation dosimetry and brain network connectivity may be necessary to predict cognitive trajectories and outcomes.

Advances in the treatment of IDH-mutant gliomas.

Isocitrate dehydrogenase (IDH) mutation is a defining molecular driver of WHO grade 2-4 astrocytomas and oligodendrogliomas. In this article, we review the recent therapeutic approaches specifically targeting IDH-mutant gliomas and summarize ongoing clinical trials in this population. The IDH inhibitor vorasidenib recently demonstrated its efficacy after surgical resection in grade 2 IDH-mutated gliomas. Several studies in patients with IDH-mutant gliomas are currently exploring various strategies to target IDH mutations, including the use of small-molecule inhibitors, immunotherapies, peptide vaccines and agents targeting metabolic and epigenomic vulnerabilities. Mutant-IDH targeting holds significant promise in treating progressive or recurrent IDH-mutant gliomas. Recent results with IDH inhibitors will change practice and influence the existing guidelines in a near future.

Multi-pool chemical exchange saturation transfer MRI in glioma grading, molecular subtyping and evaluating tumor proliferation.

To evaluate the performance of multi-pool Chemical exchange saturation transfer (CEST) MRI in prediction of glioma grade, isocitrate dehydrogenase (IDH) mutation, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss and Ki-67 labeling index (LI), based on the fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5). 95 patients with adult-type diffuse gliomas were analyzed. The amide, direct water saturation (DS), nuclear Overhauser enhancement (NOE), semi-solid magnetization transfer (MT) and amine signals were derived using Lorentzian fitting, and asymmetry-based amide proton transfer-weighted (APTwasym) signal was calculated. The mean value of tumor region was measured and intergroup differences were estimated using student-t test. The receiver operating curve (ROC) and area under the curve (AUC) analysis were used to evaluate the diagnostic performance of signals and their combinations. Spearman correlation analysis was performed to evaluate tumor proliferation. The amide and DS signals were significantly higher in high-grade gliomas compared to low-grade gliomas, as well as in IDH-wildtype gliomas compared to IDH-mutant gliomas (all p < 0.001). The DS, MT and amine signals showed significantly differences between ATRX loss and retention in grade 2/3 IDH-mutant gliomas (all p < 0.05). The combination of signals showed the highest AUC in prediction of grade (0.857), IDH mutation (0.814) and ATRX loss (0.769). Additionally, the amide and DS signals were positively correlated with Ki-67 LI (both p < 0.001). Multi-pool CEST MRI demonstrated good potential to predict glioma grade, IDH mutation, ATRX loss and Ki-67 LI.

Neomorphic IDH Heterodimer Mutants: An Underestimated Point in Cancer Pathogenesis.

Mutations in an essential metabolic enzyme, isocitrate dehydrogenase (IDH), were found in many cancers. The impact of IDH1 and IDH2 proteoforms mutations can vary and de-pend on the cancer type and other genetic alterations. The wild-type IDH1/2 consists of two identical subunits, but the mutant enzyme is a heterodimer of mutant and wild-type subunits, while the mutant homodimer loses its catalytic activity. Thus, the balance of expression of wild-type and mutant proteoforms directly affects enzyme neomorphic activity, cell metabolic por-trait, and, therefore, cell survival and proliferation rates. Here, we generalize the influence of the presence of IDH mutations and the expression of mutant and wild-type proteoforms for various nosologies to demonstrate the deficiency in knowledge about the mutual distribution of the pro-teoforms in cancer cells. The review is supplemented with a brief description of IDH mutations' role in cell metabolic reprogramming and a summary of methods for IDH mutation detection. Eventually, we highlight the necessity of assessing the expression of wild-type and mutated IDH quantitatively, which can help create and deliver personalized approaches for tumor therapy.

Discovery of Aloperine as a Potential Antineoplastic Agent for Cholangiocarcinoma Harboring Mutant IDH1.

Intrahepatic cholangiocarcinoma (ICC) is a universally lethal malignancy with increasing incidence. However, ICC patients receive limited benefits from current drugs; therefore, we must urgently explore new drugs for treating ICC. Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn, can suppress cancer cell growth via numerous mechanisms and have therapeutic effects on liver-related diseases. However, the impact of quinolizidine alkaloids on intrahepatic cholangiocarcinoma has not been fully studied. In this article, the in vitro anti-ICC activities of six natural quinolizidine alkaloids were explored. Aloperine was the most potent antitumor compound among the tested quinolizidine alkaloids, and it preferentially inhibited RBE cells rather than HCCC-9810 cells. Mechanistically, aloperine can potentially decrease glutamate content by inhibiting the hydrolysis of glutamine, reducing D-2-hydroxyglutarate levels and, consequently, leading to preferential growth inhibition in isocitrate dehydrogenase (IDH)-mutant ICC cells. In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH.

Preparation and Preclinical Evaluation of 18F-Labeled Olutasidenib Derivatives for Non-Invasive Detection of Mutated Isocitrate Dehydrogenase 1 (mIDH1).

Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling and cannot be used for longitudinal studies. Positron emission tomography (PET) imaging with mIDH1-selective radioligands is a promising alternative approach that could enable non-invasive assessment of the IDH status. In the present work, we developed efficient protocols for the preparation of four 18F-labeled derivatives of the mIDH1-selective inhibitor olutasidenib. All four probes were characterized by cellular uptake studies with U87 glioma cells harboring a heterozygous IDH1 mutation (U87-mIDH) and the corresponding wildtype cells (U87-WT). In addition, the most promising probe was evaluated by PET imaging in healthy mice and mice bearing subcutaneous U87-mIDH and U87-WT tumors. Although all four probes inhibited mIDH1 with variable potencies, only one of them ([18F]mIDH-138) showed significantly higher in vitro uptake into U87-mIDH compared to U87-WT cells. In addition, PET imaging with [18F]mIDH-138 in mice demonstrated good in vivo stability and low non-specific uptake of the probe, but also revealed significantly higher uptake into U87-WT compared to U87-mIDH tumors. Finally, application of a two-tissue compartment model (2TCM) to the PET data indicated that preferential tracer uptake into U87-WT tumors results from higher specific binding rather than from differences in tracer perfusion. In conclusion, these results corroborate recent findings that mIDH1-selective inhibition may not directly correlate with mIDH1-selective target engagement and indicate that in vivo engagement of wildtype and mutated IDH1 may be governed by factors that are not faithfully reproduced by in vitro assays, both of which could complicate development of PET probes.

Assessment the Impact of IDH Mutation Status on MRI Assessments of White Matter Integrity in Glioma Patients: Insights From Peak Width of Skeletonized Mean Diffusivity and Free Water Metrics.

Gliomas are highly invasive brain tumors that evade accurate geographic assessment by conventional MRI due to microscopic invasion along white matter (WM) tracts. Advanced diffusion MRI techniques are needed to assess occult WM involvement. To evaluate peak width of skeletonized mean diffusivity (PSMD) and peak width of skeletonized free water (PSFW), and axonal water fraction (AWF) for assessing glioma-induced alterations in normal-appearing WM and their relationship with isocitrate dehydrogenase 1 (IDH1) mutation. Retrospective. One hundred five glioma patients (46 ± 13 years), 53 healthy controls (HCs) (46 ± 9 years). 3.0 T, T1WI, T1-CE, T2WI, T2FLAIR, and DKI. PSMD and PSFW were compared between lesion and contralateral sides in glioma patients and between patients and HCs. The associations between these metrics and clinical variables, including IDH1 mutation, was assessed. Corpus callosum (CC) injury, quantified by the AWF, was evaluated for its mediated effect of IDH1 mutation on contralesional PSMD and PSFW. Paired-t tests, ANCOVA, univariate and multivariate linear regression, and mediation analysis with significance set at P < 0.05. Contralateral PSMD and PSFW were significantly higher in left-sided gliomas (PSMD: 0.206 ± 0.027 vs. 0.193 ± 0.023; PSFW: 0.119 ± 0.019 vs. 0.106 ± 0.020) than in HCs, with similar increases in right-sided gliomas (PSMD: 0.219 ± 0.036 vs. 0.195 ± 0.023; PSFW: 0.129 ± 0.031 vs. 0.109 ± 0.020). IDH1 wild-type gliomas were associated with higher contralateral PSMD and PSFW (β = -0.302 and -0.412). AWF of CC mediated the impact of IDH1 mutations on contralesional PSMD and PSFW (mediated proportion: 42.7% and 53.7%). PSMD and PSFW are effective biomarkers for assessing WM integrity in gliomas, significantly associated with IDH1 mutation status. AWF of CC mediates the relationship between IDH1 mutation and contralesional PSMD and PSFW. 4 TECHNICAL EFFICACY: Stage 2.

Mutant IDH Modulates Suppressive Myeloid Populations in Malignant Glioma.

Mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 have critical diagnostic and prognostic significance in diffuse gliomas. Neomorphic mutant IDH activity has been previously implicated in T-cell suppression; however, the effects of IDH mutations on intratumoral myeloid populations remain underexplored. In this study, we investigate the influence of IDH status on the myeloid compartment using human glioma specimens and preclinical models. We performed RNA sequencing and quantitative immunofluorescence on newly diagnosed, treatment-naive IDH-mutant grade 4 astrocytoma and IDH-wild-type (IDH-WT) glioblastoma (GBM) specimens. We also generated a syngeneic murine model, comparing transcriptomic and cell-level changes in paired isogenic glioma lines that differ only in IDH mutational status. Among patient samples, IDH-mutant tumors displayed an underrepresentation of suppressive myeloid transcriptional signatures, which was confirmed at the cellular level with decreased numbers of intratumoral M2-like macrophages and myeloid-derived suppressor cells. Introduction of the mutant IDH enzyme into murine glioma was sufficient to recapitulate the transcriptomic and cellular shifts observed in patient samples. We provide transcriptomic and cellular evidence that mutant IDH is associated with a quantitative reduction of suppressive myeloid cells in gliomas and that introduction of the mutant enzyme is sufficient to result in corresponding cellular changes using an in vivo preclinical model. These data advance our understanding of high-grade gliomas by identifying key myeloid cell populations that are reprogrammed by mutant IDH and may be targetable through therapeutic approaches.

Low-Grade Gliomas: A New Mutation, New Targeted Therapy, and Many Questions.

The discovery in 2008 that many adult gliomas harbor a hitherto unknown mutation in the metabolic gene isocitrate dehydrogenase (IDH) initiated revolutionary advances in our understanding of the biology, and correspondingly our classification, of gliomas. IDH mutations are found in most nonglioblastoma adult gliomas and portend a better prognosis. Massive efforts have unraveled many of the pleiotropic cellular effects of these mutations and spawned several lines of investigation to target the effect to therapeutic benefit. In this article are reviewed the implications of the IDH mutation in gliomas, in particular focusing on recent studies that have culminated in a rare positive phase 3 trial in these generally refractory tumors.

The effects of BMP2 and the mechanisms involved in the invasion and angiogenesis of IDH1 mutant glioma cells

PurposeThis study investigated the effect of an isocitrate dehydrogenase 1 (IDH1) mutation (mutIDH1) on the invasion and angiogenesis of human glioma cells.MethodsDoxycycline was used to induce the expression of mutIDH1 in glioma cells. Transwell and wound healing assays were conducted to assess glioma cell migration and invasion. Western blotting and cell immunofluorescence were used to measure the expression levels of various proteins. The influence of bone morphogenetic protein 2 (BMP2) on invasion, angiogenesis-related factors, BMP2-related receptor expression, and changes in Smad signaling pathway-related proteins were evaluated after treatment with BMP2. Differential gene expression and reference transcription analysis were performed.ResultsSuccessful infection with recombinant lentivirus expressing mutIDH1 was demonstrated. The IDH1 mutation promoted glioma cell migration and invasion while positively regulating the expression of vascularization-related factors and BMP2-related receptors. BMP2 exhibited a positive regulatory effect on the migration, invasion, and angiogenesis of mutIDH1-glioma cells, possibly mediated by BMP2-induced alterations in Smad signaling pathway-related factors.After BMP2 treatment, the differential genes of MutIDH1-glioma cells are closely related to the regulation of cell migration and cell adhesion, especially the regulation of Smad-related proteins. KEGG analysis confirmed that it was related to BMP signaling pathway and TGF-β signaling pathway and cell adhesion. Enrichment analysis of gene ontology and genome encyclopedia further confirmed the correlation of these pathways.ConclusionMutation of isocitrate dehydrogenase 1 promotes the migration, invasion, and angiogenesis of glioma cells, through its effects on the BMP2-driven Smad signaling pathway. In addition, BMP2 altered the transcriptional patterns of mutIDH1 glioma cells, enriching different gene loci in pathways associated with invasion, migration, and angiogenesis.

Glioma resource outreach with support: A program to identify and initiate supportive care interventions for unmet needs among adult lower-grade glioma patients

Abstract Background Lower-grade (WHO grades 2–3) gliomas typically affect young and middle-aged adults and exhibit isocitrate dehydrogenase (IDH) mutations. For such patients, symptoms related to the tumor and associated treatment contribute to morbidity and erode quality of life. With improved treatment, a better understanding of these effects over time is critically needed. Existing data characterizing unmet needs of lower-grade glioma patients is limited and little consensus exists on addressing these needs in clinical practice. Methods In order to better identify and address the unmet needs of lower-grade glioma patients, focus groups among patients and caregivers were initially conducted among patients treated at a single academic center. A semi-structured interview guide to comprehensively understand unmet needs was then developed. Each patient-defined unmet need was categorized into domains through qualitative content analysis. In parallel, a database of established local and regional community-based resources was established, and a dedicated resource specialist provided patient-specific referrals and follow-up. Results Eighty-five patients were interviewed. Median age was 41 years and the median time from tumor diagnosis was 63 months. Approximately 68% had a WHO grade 2 tumor and 60% were off therapy. Qualitative analysis of interview content identified 5 overarching domains of unmet need: Psychosocial; Neurologic/Cognitive; Lifestyle; Financial; and Other Medical. At least one unmet need was identified by 71% of participants and the most common domains were Psychosocial (40.7%) and Lifestyle (34.9%). Conclusions Our program begins to address frequently unmet survivorship needs of lower-grade glioma patients that spanned 5 major domains. Further research aimed to better define and address unmet needs among these patients is warranted.

Targeting Isocitrate Dehydrogenase (IDH) in Solid Tumors: Current Evidence and Future Perspectives.

The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included.

Clinical and radiological response of Maffucci related enchondromas to mutant IDH1 inhibitor Ivosidenib

Ollier Disease (OD) and Maffucci syndrome (MS) is a rare bone disorder that affects the growth and development of the bones, with an estimated prevalence of 1 in 100,000 people. It is associated with somatic mosaicism of isocitrate dehydrogenase-1 (IDH1) or 2 (IDH2) pathogenic variants. Ivosidenib is indicated for the treatment of acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma and is currently investigated in low-grade glioma with a susceptible isocitrate dehydrogenase-1 (IDH1) pathogenic variant, but its effects in patients with OD or MS are unknown. We here report the first case of a patient with MS who was treated with Ivosidenib for recurrent IDH-1 mutated glioma. Besides the stabilization of the tumor size, the patient observed significant improvement in his enchondromas that became stiffer, with reduced pain, and significant modification of the mineralization of the enchondromas observed on X-rays. This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.

AB066. From imaging to molecular diagnosis: VASARI magnetic resonance imaging features to predict isocitrate dehydrogenase mutation status in glioma.

Glioma, the most common brain tumor, poses significant challenges in patient care and economic burden. Clinicians often struggle with management strategies, especially under the 2021 World Health Organization (WHO) central nervous system (CNS) classification emphasizing molecular diagnosis. Isocitrate dehydrogenase (IDH) mutation status is crucial in glioma management. However, many facilities lack the capability for comprehensive molecular tests, and not all patients are candidates for invasive biopsies. MRI offers a non-invasive method to evaluate glioma characteristics. The Visually Accessible Rembrandt Images (VASARI) MRI feature set provides a systematic approach to analyzing brain glioma. This study examines the association of VASARI features with IDH mutation status and their predictive capability. This study included 105 glioma patients treated between 2017 and 2022 who had not undergone surgery, chemotherapy, or radiotherapy. Brain MRIs were assessed using VASARI MRI features by two blinded radiologists. Pathological and molecular examinations were conducted per the 2021 WHO CNS tumor classification. IDH mutations were assessed using polymerase chain reaction (PCR) followed by DNA sequencing. Chi-squared analysis identified VASARI features significantly associated with IDH mutation status. A random forest model predicted IDH mutation status using these features. Brain MRI assessments using VASARI terminology showed good inter-observer agreement (kappa =0.714-0.831) and excellent intra-observer agreement (kappa =0.910). Thirteen VASARI features were significantly associated with IDH mutation status. The prediction model based on VASARI MRI features achieved an area under the curve (AUC) of 0.97, with 93.75% sensitivity, 75% specificity, and 84.38% accuracy on test data. The VASARI MRI feature set is a reliable method for evaluating glioma patients and is feasible for routine radiological practice. Several VASARI features significantly associate with IDH mutation status, aiding glioma patient management. The IDH mutation prediction model based on VASARI features performs excellently and warrants further validation before routine implementation.