Integrating Molecular Insights into Biliary Tract Cancer Management: A Review of Personalized Therapeutic Strategies.

Biliary tract cancers (BTCs) are rare and aggressive malignancies with an increasing incidence and poor prognosis. The standard systemic treatment for BTCs has evolved to include immune checkpoint inhibitors associated with gemcitabine-cisplatin as first-line therapies. However, survival rates remain low, highlighting the critical need for personalized treatment strategies based on molecular profiling. Currently, significant advancements have been made in the molecular characterization of BTCs, where genetic alterations, such as IDH1 mutations and FGFR2 fusions, provide targets for therapy. Molecular profiling is crucial early in the management process to identify potential candidates for clinical trials and guide treatment strategy. The integration of these molecular insights into clinical practice has allowed for the development of targeted therapies, although many of them are still in the phase 2 trial stage without definitive survival benefits demonstrated in phase 3 trials. This integration of comprehensive molecular profile insights with traditional treatment approaches offers a new horizon in the personalized medicine landscape for BTCs, with the aim of significantly improving patient outcomes through precision oncology.

Sustained Clinical Response to Ivosidenib in Previously Treated Patients with Advanced Intrahepatic Cholangiocarcinoma Harboring an IDH1 R132 Mutation: Two Case Reports.

Introduction: Patients with progressing intrahepatic cholangiocarcinoma (iCCA) harboring an isocitrate dehydrogenase 1 (IDH1) mutation who received ivosidenib showed a median progression-free survival (PFS) benefit of 1.3 months compared to placebo in the phase 3 ClarIDHy trial. Case Presentations: We describe 2 consecutive patients with previously treated unresectable and metastatic iCCA harboring an IDH1 R132 mutation who achieved durable clinical responses with ivosidenib 500 mg once daily for >12 months until disease progression. In one case with a mixed response, a single progressive liver metastasis was additionally treated locally with interstitial brachytherapy, while ivosidenib was continued until further progression. Ivosidenib therapy resulted in long-term disease control with PFS of 20 and 13 months and duration of treatment of 26 and 13 months, respectively, with no relevant side effects. Conclusion: Patients with unresectable or metastatic IDH1-mutated iCCA can achieve sustained clinical responses for >12 months with ivosidenib. No new safety signals were observed during long-term treatment with ivosidenib.

3D-QSAR, Scaffold Hopping, Virtual Screening, and Molecular Dynamics Simulations of Pyridin-2-one as mIDH1 Inhibitors.

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure-activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.

PARP inhibitor therapy in patients with IDH1 mutated cholangiocarcinoma.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a "BRCAness" phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition. METHODS: We conducted a retrospective cohort review to identify patients with advanced, IDH1 mutated iCCA treated with a PARP inhibitor (PARPi) at the University of Michigan between 2018 and 2023. Patients are described with respect to prior lines of therapy, response to platinum-based chemotherapy, and progression-free survival (PFS) and overall survival (OS) from the time of PARPi initiation. RESULTS: Between 2018 and 2023 we identified 40 patients with IDH1 mutated iCCA of which 6 patients were treated with a PARPi as monotherapy or in combination with an ATR inhibitor or anti-PD-1 immune checkpoint inhibitor. Majority of patients (n = 5) carried an IDH1 R132C mutation per tissue-based next generation sequencing. All patients had previously received at least one line of cisplatin-based systemic therapy for advanced disease prior to treatment with PARPi. PFS and OS from time of PARPi initiation ranged from 1.4 to 18.5 months and 2.8 to 42.4 months, respectively. Best response on PARPi therapy included 2 partial responses. CONCLUSION: This is the first case series to describe PARPi treatment in IDH1 mutated iCCA. Results underscore the limitation of PARPi monotherapy, potentially support combined PARPi therapies, and highlight a need for effective treatment options for patients with IDH1 mutated iCCA.

FOXM1 requires IDH1 for late genes expression in mitotic cells.

Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that converts isocitrate to α-ketoglutarate in cells. However, research on IDH1 is more focused on the metabolite D-2-hydroxyglutarate than the cellular roles of the IDH1 protein. Metabolic enzymes can moonlight by participating in diverse cellular processes in cancer cells. This moonlighting function of the metabolic enzymes can contribute to changes in gene expression. It is unknown whether IDH1 associates with any transcription factor. We asked whether IDH1 coordinates with forkhead box protein M1 (FOXM1) in mitotic cells to regulate late genes expression. We found that depletion of IDH1 reduces canonical FOXM1-target expression in mitotic cells. Also, IDH1 binds to FOXM1 and a subset of MuvB proteins, Lin-9 and Lin-54, in mitotic cells. Based on these observations, we suggest that IDH1 coordinates with FOXM1 in mitotic cells to regulate late genes expression.

Deconstructing Intratumoral Heterogeneity through Multiomic and Multiscale Analysis of Serial Sections.

Tumors may contain billions of cells, including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial tumor sections (MOMA). By combining deep sampling of IDH-mutant astrocytomas with integrative analysis of single-nucleotide variants, copy-number variants, and gene expression, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones. By genotyping nuclei analyzed by single-nucleus RNA-seq for truncal mutations, we further show that commonly used algorithms for identifying cancer cells from single-cell transcriptomes may be inaccurate. We also demonstrate that correlating gene expression with tumor purity in bulk samples can reveal optimal markers of malignant cells and use this approach to identify a core set of genes that are consistently expressed by astrocytoma truncal clones, including AKR1C3, whose expression is associated with poor outcomes in several types of cancer. In summary, MOMA provides a robust and flexible strategy for precisely deconstructing intratumoral heterogeneity and clarifying the core molecular properties of distinct cellular populations in solid tumors.

TET3 downregulation and low 5-hydroxymethylcytosine are epigenetic signatures of head and neck carcinoma.

BACKGROUND: Ten-eleven translocases (TETs) are enzymes responsible for demethylation processes, playing a crucial role in maintaining the body's methylation balance. Dysregulation of TET expression can lead to abnormal methylation levels. Isocitrate dehydrogenases (IDH) are upstream genes involved in Kreb cycle responsible for production of α-ketoglutarate (α-KG). α-KG and vitamin C are cofactors of TET3 enzyme. There is limited data on the relationship between TET3 and its cofactor Vitamin C in head and neck carcinoma (H&NC). METHODS AND RESULTS: In this study, we have investigated the expression of the TET3 gene along with IDH1/2 genes involved in the Krebs cycle in the peripheral blood of 32 H&NC patients compared to 32 healthy controls. We estimated serum levels of TET3 protein and vitamin C and 5-hydroxymethylcytosine (5-hmC) percentage in DNA isolated from EDTA blood samples. Our findings revealed that TET3 and IDH1/2 were downregulated in H&NC patients compared to healthy controls. Serum levels of TET3 and Vitamin C were low in H&NC patients compared to healthy controls. Diminished levels of percentage 5-hmC were detected in EDTA blood samples of H&NC patients compared to controls. Spearman correlation analysis revealed a significant positive correlation between TET3 levels, vitamin C levels and 5-hmC percentage. CONCLUSION: The low levels of Vitamin C are believed to contribute to decreased activity of the TET3 gene and less conversion of 5-methylcytosine (5-mC) to 5-hmC. Dietary supplementation of Vitamin C may increase TET3 activity.

Synthetic lethality between toxic amino acids, RTG-target genes and chaperones in Saccharomyces cerevisiae.

The toxicity of non-proteinogenic amino acids has been known for decades. Numerous reports describe their antimicrobial/anticancer potential. However, these molecules are often toxic to the host as well; thus, a synthetic lethality approach that reduces the dose of these toxins while maintaining toxicity can be beneficial. Here we investigate synthetic lethality between toxic amino acids, the retrograde pathway, and molecular chaperones. In Saccharomyces cerevisiae, mitochondrial retrograde (RTG) pathway activation induces transcription of RTG-target genes to replenish alpha-ketoglutarate and its downstream product glutamate; both metabolites are required for arginine and lysine biosynthesis. We previously reported that tolerance of canavanine, a toxic arginine derivative, requires an intact RTG pathway, and low-dose canavanine exposure reduces the expression of RTG-target genes. Here we show that only a few of the examined chaperone mutants are sensitive to sublethal doses of canavanine. To predict synthetic lethality potential between RTG-target genes and chaperones, we measured the expression of RTG-target genes in canavanine-sensitive and canavanine-tolerant chaperone mutants. Most RTG-target genes were induced in all chaperone mutants starved for arginine; the same trend was not observed under lysine starvation. Canavanine exposure under arginine starvation attenuated and even reversed RTG-target-gene expression in the tested chaperone mutants. Importantly, under nearly all tested genetic and pharmacological conditions, the expression of IDH1 and/or IDH2 was induced. In agreement, idh1 and idh2 mutants are sensitive to canavanine and thialysine and show synthetic growth inhibition with chaperone mutants. Overall, we show that inhibiting molecular chaperones, RTG-target genes, or both can sensitize cells to low doses of toxic amino acids.

Raman Spectroscopy of Blood Serum for Essential Thrombocythemia Diagnosis: Correlation with Genetic Mutations and Optimization of Laser Wavelengths.

Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm that increases the risk of thrombosis. To diagnose this disease, the analysis of mutations in the Janus Kinase 2 (JAK2), thrombopoietin receptor (MPL), or calreticulin (CALR) gene is recommended. Disease poses diagnostic challenges due to overlapping mutations with other neoplasms and the presence of triple-negative cases. This study explores the potential of Raman spectroscopy combined with machine learning for ET diagnosis. We assessed two laser wavelengths (785, 1064 nm) to differentiate between ET patients and healthy controls. The PCR results indicate that approximately 50% of patients in our group have a mutation in the JAK2 gene, while only 5% of patients harbor a mutation in the ASXL1 gene. Additionally, only one patient had a mutation in the IDH1 and one had a mutation in IDH2 gene. Consequently, patients having no mutations were also observed in our group, making diagnosis challenging. Raman spectra at 1064 nm showed lower amide, polysaccharide, and lipid vibrations in ET patients, while 785 nm spectra indicated significant decreases in amide II and C-H lipid vibrations. Principal Component Analysis (PCA) confirmed that both wavelengths could distinguish ET from healthy subjects. Support Vector Machine (SVM) analysis revealed that the 800-1800 cm-1 range provided the highest diagnostic accuracy, with 89% for 785 nm and 72% for 1064 nm. These findings suggest that FT-Raman spectroscopy, paired with multivariate and machine learning analyses, offers a promising method for diagnosing ET with high accuracy by detecting specific molecular changes in serum. Principal Component Analysis (PCA) confirmed that both wavelengths could distinguish ET from healthy subjects. Support Vector Machine (SVM) analysis revealed that the 800-1800 cm-1 range provided the highest diagnostic accuracy, with 89% for 785 nm and 72% for 1064 nm. These findings suggest that FT-Raman spectroscopy, paired with multivariate and machine learning analyses, offers a promising method for diagnosing ET with high accuracy by detecting specific molecular changes in serum.

Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia: a registry study.

Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with IDH1-mutated (mIDH1) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) mIDH1 AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration (T max) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.

Oncometabolite 2-hydroxyglutarate suppresses basal protein levels of DNA polymerase beta that enhances alkylating agent and PARG inhibition induced cytotoxicity.

Mutations in isocitrate dehydrogenase isoform 1 (IDH1) are primarily found in secondary glioblastoma (GBM) and low-grade glioma but are rare in primary GBM. The standard treatment for GBM includes radiation combined with temozolomide, an alkylating agent. Fortunately, IDH1 mutant gliomas are sensitive to this treatment, resulting in a more favorable prognosis. However, it's estimated that up to 75 % of IDH1 mutant gliomas will progress to WHO grade IV over time and develop resistance to alkylating agents. Therefore, understanding the mechanism(s) by which IDH1 mutant gliomas confer sensitivity to alkylating agents is crucial for developing targeted chemotherapeutic approaches. The base excision repair (BER) pathway is responsible for repairing most base damage induced by alkylating agents. Defects in this pathway can lead to hypersensitivity to these agents due to unresolved DNA damage. The coordinated assembly and disassembly of BER protein complexes are essential for cell survival and for maintaining genomic integrity following alkylating agent exposure. These complexes rely on poly-ADP-ribose formation, an NAD+-dependent post-translational modification synthesized by PARP1 and PARP2 during the BER process. At the lesion site, poly-ADP-ribose facilitates the recruitment of XRCC1. This scaffold protein helps assemble BER proteins like DNA polymerase beta (Polß), a bifunctional DNA polymerase containing both DNA synthesis and 5'-deoxyribose-phosphate lyase (5'dRP lyase) activity. Here, we confirm that IDH1 mutant glioma cells have defective NAD+ metabolism, but still produce sufficient nuclear NAD+ for robust PARP1 activation and BER complex formation in response to DNA damage. However, the overproduction of 2-hydroxyglutarate, an oncometabolite produced by the IDH1 R132H mutant protein, suppresses BER capacity by reducing Polß protein levels. This defines a novel mechanism by which the IDH1 mutation in gliomas confers cellular sensitivity to alkylating agents and to inhibitors of the poly-ADP-ribose glycohydrolase, PARG.

Evaluation of Microvascular Density in Glioblastomas in Relation to p53 and Ki67 Immunoexpression.

Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence frequently occurs after removal. Tumoral angiogenesis, the formation of neovessels, has a positive impact on tumor progression and invasion, although there are controversial results in the specialized literature regarding its impact on survival. This study aims to correlate the immunoexpression of angiogenesis markers (CD34, CD105) with the proliferation index Ki67 and p53 in primary and secondary glioblastomas. This retrospective study included 54 patients diagnosed with glioblastoma at the Pathology Department of County Emergency Clinical Hospital Târgu Mureș. Microvascular density was determined using CD34 and CD105 antibodies, and the results were correlated with the immunoexpression of p53, IDH1, ATRX and Ki67. The number of neoformed blood vessels varied among cases, characterized by different shapes and calibers, with endothelial cells showing modified morphology and moderate to marked pleomorphism. Neovessels with a glomeruloid aspect, associated with intense positivity for CD34 or CD105 in endothelial cells, were observed, characteristic of glioblastomas. Mean microvascular density values were higher for the CD34 marker in all cases, though there were no statistically significant differences compared to CD105. Mutant IDH1 and ATRX glioblastomas, wild-type p53 glioblastomas, and those with a Ki67 index above 20% showed a more abundant microvascular density, with statistical correlations not reaching significance. This study highlighted a variety of percentage intervals of microvascular density in primary and secondary glioblastomas using immunohistochemical markers CD34 and CD105, respectively, with no statistically significant correlation between evaluated microvascular density and p53 or Ki67.

Rationale design of novel substituted 1,3,5-triazine candidates as dual IDH1(R132H)/ IDH2(R140Q) inhibitors with high selectivity against acute myeloid leukemia: In vitro and in vivo preclinical investigations.

In this study, novel substituted 1,3,5-triazine candidates (4a-d, 5a-j, and 6a-d) were designed as second-generation small molecules to act as dual IDH1 and IDH2 inhibitors according to the pharmacophoric features of both vorasidenib and enasidenib. Compounds 6a and 6b for leukemia cell lines showed from low to sub-micromolar GI50. Moreover, compounds 4c, 5f, and 6b described the frontier antitumor activity against THP1 and Kasumi Leukemia cancer cells with IC50 values of (10 and 12), (10.5 and 7), and (6.2 and 5.9) µg/mL, which were superior to those of cisplatin (25 and 28) µg/mL, respectively. Interestingly, compounds 4c, 6b, and 6d represented the best dual IDH1(R132H)/IDH2(R140Q) inhibitory potentials with IC50 values of (0.72 and 1.22), (0.12 and 0.93), and (0.50 and 1.28) µg/mL, respectively, compared to vorasidenib (0.02 and 0.08) µg/mL and enasidenib (0.33 and 1.80) µg/mL. Furthermore, the most active candidate (6b) has very promising inhibitory potentials towards HIF-1α, VEGF, and SDH, besides, a marked increase of ROS was observed as well. Besides, compound 6b induced the upregulation of P53, BAX, Caspases 3, 6, 8, and 9 proteins by 3.70, 1.99, 2.06, 1.73, 1.75, and 1.85-fold changes, respectively, and the downregulation for the BCL-2 protein by 0.55-fold change compared to the control. Besides, the in vivo behavior of compound 6b as an antitumor agent was evaluated in female mice bearing solid Ehrlich carcinoma tumors. Notably, compound 6b administration resulted in a prominent decrease in the weight and volume of the tumors, accompanied by improvements in biochemical, hematological, and histological parameters.

Evaluation of the rapid Idylla IDH1-2 mutation assay in FFPE glioma samples.

IDH1 and IDH2 mutational status is a critical biomarker with diagnostic, prognostic, and treatment implications in glioma. Although IDH1 p.R132H-specific immunohistochemistry is available, it is unable to identify other mutations in IDH1/2. Next-generation sequencing can accurately determine IDH1/2 mutational status but suffers from long turnaround time when urgent treatment planning and initiation is medically necessary. The Idylla assay can detect IDH1/2 mutational status from unstained formalin-fixed paraffin-embedded (FFPE) slides in as little as a few hours. In a clinical validation, we demonstrate clinical accuracy of 97% compared to next-generation sequencing. Sensitivity studies demonstrated a limit of detection of 2.5-5% variant allele frequency, even at DNA inputs below the manufacturer's recommended threshold. Overall, the assay is an effective and accurate method for rapid determination of IDH1/2 mutational status.

Molecular Pathology of Gliomas.

Gliomas are the most common adult and pediatric primary brain tumors. Molecular studies have identified features that can enhance diagnosis and provide biomarkers. IDH1/2 mutation with ATRX and TP53 mutations defines diffuse astrocytomas, whereas IDH1/2 mutations with 1p19q loss defines oligodendroglioma. Focal amplifications of receptor tyrosine kinase genes, TERT promoter mutation, and loss of chromosomes 10 and 13 with trisomy of chromosome 7 are characteristic features of glioblastoma and can be used for diagnosis. BRAF gene fusions and mutations in low-grade gliomas and histone H3 mutations in high-grade gliomas also can be used for diagnostics.

Olutasidenib: a novel mutant IDH1 inhibitor for the treatment of relapsed or refractory acute myeloid leukemia.

INTRODUCTION: Recurrent mutations in isocitrate dehydrogenase 1 (mIDH1) occur in about 7% to 14% of all cases of acute myeloid leukemia (AML). The discovery of targetable mutations in AML, including IDH mutations, expanded the therapeutic landscape of AML and led to the development of targeted agents. Despite significant advances in current treatment options, remission and overall survival rates remain suboptimal. The IDH1 inhibitor, olutasidenib, demonstrated encouraging safety and clinical benefits as monotherapy in patients with relapsed or refractory (R/R) mIDH1 AML. AREAS COVERED: This review outlines the olutasidenib drug profile and summarizes key safety and efficacy data, focusing on the 150 mg twice daily dose from the pivotal registrational cohort of the phase 2 trial that formed the basis for the US Food and Drug Administration approval of olutasidenib in patients with R/R AML with a susceptible IDH1 mutation. EXPERT OPINION: Olutasidenib offers patients with R/R mIDH1 AML a new treatment option, with improved complete remission and a longer duration of response than other targeted mIDH1 treatment options. Olutasidenib provided clinical benefit with a manageable safety profile. Additional analyses to further characterize the safety and efficacy of olutasidenib in frontline and R/R settings as monotherapy and as combination therapy are ongoing.

Olutasidenib is an oral prescription medication for patients diagnosed with acute myeloid leukemia (AML) with a specific mutation in the isocitrate dehydrogenase 1 (IDH1) gene. The US FDA approved olutasidenib at a dose of 150 mg twice a day for use as stand-alone (monotherapy) treatment in patients with IDH1-mutated AML whose disease has come back or has not improved after previous treatment(s). Olutasidenib is not traditional chemotherapy; it is a targeted treatment called an IDH1 inhibitor, which blocks IDH1 when it has been altered (mutated). These alterations happen in some patients, and when they do, the products of these alterations can lead to leukemia. By blocking mutated IDH1, the body can resume normal blood cell production and functioning. In studies, response to olutasidenib was measured by the number of people who went into remission. Complete remission (CR) means there is no sign of cancer and laboratory values are normal. Complete remission with partial hematologic recovery (CRh) means there is no sign of cancer, but some lab values do not reach normal levels. Thirty-five percent of people taking olutasidenib achieved CR or CRh and stayed in remission for 25.9 months. About 14% of patients who did not achieve remission also experienced some improvement in symptoms. The most common side effects in studies were nausea, feeling tired, fever, constipation, diarrhea, abnormal liver function tests, and changes in certain blood tests. Serious side effects included liver problems and differentiation syndrome, which is a potentially life-threatening situation that can occur when blood cells mature too quickly. Olutasidenib is also being studied in patients with IDH1 mutated AML who have never been treated before and in combination with a chemotherapy medication called azacitidine.

IDH1 mutation produces R-2-hydroxyglutarate (R-2HG) and induces mir-182-5p expression to regulate cell cycle and tumor formation in glioma.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its regulatory mechanism in glioma remains incompletely understood. RESULTS: miR-182-5p expression was increased within IDH1-mutant glioma specimens according to TCGA, CGGA, and online dataset GSE119740, as well as collected clinical samples. (R)-2-hydroxyglutarate ((R)-2HG) treatment up-regulated the expression of miR-182-5p, enhanced glioma cell proliferation, and suppressed apoptosis; miR-182-5p inhibition partially eliminated the oncogenic effects of R-2HG upon glioma cells. By direct binding to Cyclin Dependent Kinase Inhibitor 2 C (CDKN2C) 3'UTR, miR-182-5p inhibited CDKN2C expression. Regarding cellular functions, CDKN2C knockdown promoted R-2HG-treated glioma cell viability, suppressed apoptosis, and relieved cell cycle arrest. Furthermore, CDKN2C knockdown partially attenuated the effects of miR-182-5p inhibition on cell phenotypes. Moreover, CDKN2C knockdown exerted opposite effects on cell cycle check point and apoptosis markers to those of miR-182-5p inhibition; also, CDKN2C knockdown partially attenuated the functions of miR-182-5p inhibition in cell cycle check point and apoptosis markers. The engineered CS-NPs (antagomir-182-5p) effectively encapsulated and delivered antagomir-182-5p, enhancing anti-tumor efficacy in vivo, indicating the therapeutic potential of CS-NPs(antagomir-182-5p) in targeting the miR-182-5p/CDKN2C axis against R-2HG-driven oncogenesis in mice models. CONCLUSIONS: These insights highlight the potential of CS-NPs(antagomir-182-5p) to target the miR-182-5p/CDKN2C axis, offering a promising therapeutic avenue against R-2HG's oncogenic influence to glioma.

IDH1, ATRX, p53, and Ki67 Expression in Glioblastoma patients: Their Clinical and Prognostic Significance-A Prospective Study.

Context Glioblastoma multiforme (GBM) is a malignant and aggressive primary brain tumor with a poor prognosis. This adverse prognosis is due to the tumor's tendency for advancement and recurrence caused by highly intrusive nature of the persisting GBM cells that actively escape from the main tumor mass into the surrounding normal brain tissue. On the basis of biomarker illustration, it can be classified into molecular subgroups. Aims (1) To determine the expression of IDH1, ATRX, p53, and Ki67 by immunohistochemistry, in a cohort of GBMs. (2) To determine whether altered protein expression of any of these growth-control genes in GBM will show association with patient survival. (3) To establish prognostically distinct molecular subgroups of GBM, irrespective of histopathological diagnosis. Results In this prospective observational study, 35 histologically diagnosed cases of glioblastoma were enrolled. The mean age at the time of presentation was 43.46 ± 17.25 years with a male:female ratio of 1.3:1. Of the 35 cases, microvascular proliferation was seen in 23 cases. Large foci of necrosis (>50%) were seen in 10 cases and 27 cases had mitotic count ≥ 5/high power field (HPF). Of 35 cases, 5 (14.3%) cases showed IDH1 immunopositivity and 30 (85.7%) cases were negative for IDH1. ATRX was retained in 24 (68.6%) cases, while it was lost in 11 (31.4%) cases. The p53 immunoexpression was seen in 31 (88.6%) cases, whereas p53 was negative in 4 (11.4%) cases. The overall median survival (OS) was 6 months. In two protein pairs, the three compositions were IDH1-/p53+ (74.3%), ATRX +/IDH1- (62.9%), and ATRX +/p53+ (57.1%). Combined three-protein immunohistochemical analysis revealed five different molecular variants. Also, 8.6% (3/35) of the samples had aberrant protein expression of all three proteins, i.e., ATRX-/p53 +/IDH1 + , while 11.4% (4/35) were wild-type protein expression group, i.e., ATRX +/p53-/IDH1-. Conclusion In patients with single protein expression, Kaplan-Meier survival analysis showed statistically better OS in IDH1 mutant glioblastomas. In cases with double protein pairs, IDH1/p53 revealed statistically significant association with better median OS. The survival analysis of patients with IDH1/ATRX/p53 protein combinations also denoted a better OS. Hence, GBM can be grouped into prognostically relevant subgroups using these protein expression signatures individually, as well as the combined protein expression signatures.

Cost-effectiveness of ivosidenib versus chemotherapy for previously treated IDH1-mutant advanced intrahepatic cholangiocarcinoma in Taiwan.

BACKGROUND: International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib's cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV. METHODS: A 3-state partitioned survival model was employed to assess ivosidenib's cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib's cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios. RESULTS: Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib's cost and utility values on estimate uncertainty. CONCLUSIONS: At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50-60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.