IDH1 R132H

The clinical value of IDH and ATRX mutations in prognostic assessment was confirmed (p ≤0.05). The overexpression of p53 had no significant impact on OS (p = 0.726). Therefore, p53 alone cannot predict survival in glioblastoma patients. Based on the results, these biomarkers may be a potential therapeutic target to prolong patient survival, hence the need for further investigations.

Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy.

Ivosidenib, used to treat acute myeloid leukemia, acts on a common cancer-linked variant of isocitrate dehydrogenase 1 (IDH1 R132H) inhibiting its "gain-of-function" activity-the undesired reduction of 2-oxoglutarate (2OG) to the oncometabolite 2-hydroxyglutarate (2HG)...Such details, essential for understanding inhibition mechanisms, are not readily resolved in conventional steady-state kinetics or by techniques that rely only on measuring binding. Extending the new method and analytical framework presented here to other enzyme systems will be straightforward and should rapidly reveal insight that is difficult or often impossible to obtain using other methods.

P2/3, N=147, Active, not recruiting, National Cancer Institute (NCI) | N=485 --> 147 | Trial completion date: Aug 2024 --> Mar 2025 | Trial primary completion date: Aug 2024 --> Apr 2023

P1, N=49, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: May 2024 --> May 2025

In Taiwanese GBM patients, bevacizumab usage is linked to improved survival rates, affirming its safety and effectiveness...TP53 mutations are associated with enhanced survival, but their functional implications necessitate detailed exploration. This study pioneers genetic analysis in Taiwanese GBM patients using NGS, advancing our understanding of their genetic landscape.

P1, N=75, Recruiting, Hutchmed | Trial completion date: Sep 2023 --> Jun 2025 | Trial primary completion date: Sep 2023 --> Sep 2024

We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

GBs with detectable ALK-protein expression could potentially experience substantial clinical advantages through the utilization of newly introduced ALK inhibitors allowing personalized treatment to a subset of patients. Hence, future studies targeting ALK in IDH wildtype Glioblastomas including clinical trials on larger scales are recommended.

P2, N=145, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

Additionally, IDH1 R132H mutation predicted higher seizure-free ratios in LGG patients with intact ATRX expression (OR = 6.793, 95%CI = 1.217 - 37.923, P = 0.029) one year after diagnosis. Therefore, our findings suggest that IDH1 mutation can predict seizure occurrence and control in LGG patients, providing further insights into the relationship between glioma and epilepsy.

No IDH2 mutations were found. The use of independent diagnostic methods may improve the detection of IDH-mutant specimens in chondroid tumors.

Cell-free DNA obtained from cyst fluid in cystic brain tumors is a reliable alternative to tumor DNA when diagnosing brain tumors.

P1/2, N=70, Recruiting, Washington University School of Medicine | Trial completion date: Jan 2030 --> Jan 2032 | Trial primary completion date: Jan 2030 --> Jan 2032

The present study demonstrates that liquid biopsy may be used in brain tumors to detect IDH1 mutation which represents an important prognostic biomarker in patients with different types of gliomas, being associated to OS.

P3, N=560, Recruiting, CarThera | Not yet recruiting --> Recruiting

P1/2, N=57, Recruiting, Northwestern University

Taken together, we provide proof for the potential of our sCSC technology as a potent addition to biomarker-driven drug development projects or studies on tumor therapy resistance. Moreover, follow-up projects such as comparing in vitro drug sensitivity profiles of hiPSC-derived tissue progenitors of different lineages, might help to understand a variety of tissue-related functions of IDH1 mutations.

P3, N=220, Recruiting, Servier Affaires Médicales | Phase classification: P3b --> P3

P2, N=94, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P3, N=331, Active, not recruiting, Institut de Recherches Internationales Servier

Baseline bone blast count was strongly predictive of response to treatment. Further evaluation of these observations is needed.

In conclusion, our preclinical evaluation demonstrated a target-specific internalization of [F]AG-120 in vitro, a high metabolic stability in vivo in mice, and a slightly higher accumulation of activity in IDH1R132H-glioma compared to IDH1-glioma. Overall, our findings contribute to advancing the field of molecular imaging and encourage the evaluation of [F]AG-120 to improve diagnosis and management of glioma and other IDH1R132H-related tumors.

DKI demonstrated a potential to detect changes in the white matter of the brain non-visible on conventional MRI in patients with gliomas. *Clinical Relevance/Application: Understanding the changes occurring in brain areas distant from the tumor is crucial for treatment and patient care.

In the first randomized Phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, vorasidenib prolonged median PFS by BIRC, relative to placebo, irrespective of IDH1/2 VAF.

Specifically, we found that ddPCR rescued hotspot mutations such as BRAF V600E (2/3, 66.7%), IDH1 R132G/H (3/8, 37.5%), TERT C228T (11/26, 42.3%), and TERT C250T (2/4, 50.0%). Collectively, our results suggest that a combined-modality approach involving MSK-IMPACTâ„¢ and ddPCR enables comprehensive assessment of limited CSF ctDNA samples with high sensitivity and provides a minimally invasive methodology to molecularly profiling glioma.

Introduction: Malignant brain tumors are almost universally fatal despite standard-of-care (SOC) therapy with radiation (XRT) and temozolomide (TMZ)...Extensive clinical trials have explored the clinical utility of IDH1 R132H mutation small molecule inhibitors such as ivosidenib and vorasidenib; however, the direct intracellular and intercellular effects of IDH1 R132H inhibition relative to SOC remain largely unknown...Patient-derived tumor slice cultures were able to grow and were observed to contain heterogeneous cell populations, including tumor cells, astrocytes, neurons, oligodendrocytes, and microglia. When slice cultures were treated with SOC and ivosidenib treatment, separate tumor subpopulations were shown to be sensitive to either treatment. Furthermore, scRNA analysis revealed unique subpopulations that were insensitive to either treatment.

Taken together, these data suggest a reduction of the AP mediated-immune suppression in mIDH1 gliomas. Uncovering these differences in the AP provides novel insights on the use of AP inhibitors for glioma treatment, revealing whether the AP is a preferred target in specific glioma types based on the IDH1 mutation status.

LFS patients may have glioma with higher incidence of non-canonical IDH1 mutations, lower likelihood of ATRX and IDH1 co-mutations, and less likely to be treated upfront after initial diagnosis despite having high risk profile for low grade glioma.

ACT001 restored sensitization of rGBM patients to TMZ treatment in sub-group of patients likely due to reduced DNA repair capacity by ACT001 treatment. Further study is warranted to evaluate the effect of ACT001 and TMZ combination in phase 2b study.

Cytopenia may serve as a prognostic biomarker for OS and PFS. Leukopenia may reflect adequate temozolomide dosing, anti-tumor activity, or changes in the tumor micro-environment. Peripheral biomarker monitoring may improve prognostic stratification and lead to personalized treatment with improved outcomes.

Most cases had usable DNA yield. Overall, hsitologic re-evaluation and molecular testing based on the 2021 WHO classification guidelines refined the diagnosis in 48% (27/56) of cases.

Purpose: A major barrier to improving outcomes in glioblastoma multiforme (GBM) is overcoming a heavily immunosuppressed tumor and systemic environment, as demonstrated by several negative phase III randomized studies of nivolumab in both newly diagnosed and recurrent GBM... Patients with newly diagnosed unifocal IDH-1 R132H WT WHO grade 4 GBM, ECOG 0-2, at least 70% tumor resected with plan to receive temozolomide-radiation (TMZ-RT) and adjuvant TMZ +/- Tumor Treating Fields are eligible...Age, sex, race, concurrent medication, corticosteroid use, and diet will be carefully accounted for. Patient reported outcomes using EORTC-QLQ-BN20 and QLQ-C30 will be collected at baseline, 3-, 6-, 9-, and 12-months.

Finally, we show that convection-enhanced delivery of RSL3 in combination with dietary Cysteine and Methionine restriction in vivo, significantly prolongs survival of the IDH1(R132H)-expressing mice. Our findings suggest that Ferroptosis provides promising therapeutic potential worth exploring further and our mouse model could be used to test the efficacy of different treatments for IDH1(R132H) gliomas.

These revealed interactions between the mutant IDH inhibitor vorasidenib and molecules related to astrocytic differentiation, Notch signaling, and cell growth and metabolism. The translational relevance of these findings was supported by molecular data from human tumors, patients treated with IDH inhibitors, and human-derived cell models. Overall, these studies nominate oligodendrocyte progenitors as candidate cells of origin for IDH mutated gliomas, and point to strategies that may enhance the efficacy of IDH inhibitors.

In this phase, ~60 patients will be randomized 1:1:1 to the RCD, VOR 40 mg QD alone, or no treatment prior to surgery. All patients can receive the RCD post-surgery.

P2, N=94, Recruiting, National Cancer Institute (NCI) | Active, not recruiting --> Recruiting

Additionally, several IDH1/IDH2 inhibitors such as ivosidenib and enasidenib have been approved by the FDA for treatment of AML patients with IDH1 and IDH2 mutations respectively. We have prototyped 18-plex assay designed to detect 7 IDH1 and 10 IDH2 mutations and call out its corresponding codon in EDTA whole blood samples using a single cartridge at an estimated LoD of 1%.