bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-47. A PHASE 1, RANDOMIZED, PERIOPERATIVE TRIAL OF VORASIDENIB AND IVOSIDENIB IN IDH1-MUTANT DIFFUSE GLIOMA: UPDATED RESULTS
Authors: Mellinghoff Ingo , Wen Patrick , Taylor Jennie , Taylor Elizabeth , Arrillaga-Romany Isabel , Ellingson Benjamin , Mahboub-Johnson Paria , Baron Eric , Hassan Islam , Steelman Lori , Clarke Jennifer , Cloughesy Timothy 
Published: November 2024

Abstract

BACKGROUND
Vorasidenib (VOR) and ivosidenib (IVO) showed clinical activity in subjects with isocitrate dehydrogenase mutant (mIDH) gliomas. We evaluated both agents in a phase 1, randomized, open-label perioperative trial (NCT03343197). Pharmacodynamics, pharmacokinetics, and preliminary objective response rate (ORR) data as of 29-April-2020 were previously reported (Mellinghoff et al. Nat Med. 2023). Progression-free survival (PFS) data were not mature at publication time. We report here longer-term follow-up results, including mature PFS.

METHODS
Participants with grade 2/3 non-enhancing mIDH1 R132H mutant gliomas were randomized to VOR (50 or 10 mg QD), IVO (500 or 250 mg BID), or no treatment (control) for 4 weeks prior to planned surgery, with the option to continue treatment with VOR or IVO post-surgery. Secondary objectives included PFS, ORR assessed by Investigator in the post-surgery period, and safety profile of VOR and IVO.

RESULTS
Enrollment completed in April-2019. 49 participants were randomized, of which 46 participants (24 oligodendroglioma, 20 astrocytoma, 1 anaplastic oligodendroglioma, 1 anaplastic oligoastrocytoma) received treatment with either VOR (N=24) or IVO (N=22) after surgery. As of 23-September-2023 data cutoff, 11 (46%) and 5 (20%) participants remain on treatment for VOR and IVO, respectively. Median (range) post-operative treatment duration was 44.7 months (0.9–62.7) for VOR, 23.9 months (0–62.7) for IVO. Median (95% CI) PFS was 41.4 months (9.3, NE) for VOR and 38.6 months (18.3, NE) for IVO. ORR per Response Assessment in Neuro-Oncology in low-grade gliomas (RANO-LGG) was 46% for VOR and 27% for IVO. Longer safety follow up will also be presented.

CONCLUSION
These results provide further evidence of prolonged response using IVO and VOR immediately following surgery in predominantly non-enhancing gliomas. This longer-term follow-up is consistent with Phase 3 INDIGO study results where VOR demonstrated PFS benefit with manageable safety compared with placebo in participants with non-enhancing mIDH gliomas.
CTNI-60. SAFETY LEAD-IN RESULTS FOR QBS10072S IN THE INDIVIDUAL SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT) TRIAL, A RANDOMIZED ADAPTIVE PLATFORM TRIAL FOR NEWLY DIAGNOSED MGMT UNMETHYLATED GLIOBLASTOMA
Authors: Rahman Rifaquat , Trippa Lorenzo , Aquilanti Elisa , Lee Eudocia , Arrillaga-Romany Isabel , Wiley Jennifer , Chukwueke Ugonma , McFaline-Figueroa Jose , Partridge Kathryn , Beroukhim Rameen , Nayak Lakshmi , Batchelor Tracy , Lu-Emerson Christine , Drappatz Jan , Lassman Andy , Welch Mary , Ahluwalia Manmeet , Bi Wenya , Arnaout Omar , Haas-Kogan Daphne , Tanguturi Shyam , Aizer Ayal , Doherty Lisa , Fell Geoffrey , Lavallee Maria , Smokovich Anna , Peabody Shannon , Westergaard Catharina , Bhutani Vasvi , Russ Alyssa , Barlow Brooke , Chiocca Ennio , Ringold Gordon , Weitzman Ron , Holland Jaymes , Reardon David , Ligon Keith , Wen Patrick 
Published: November 2024

Abstract

BACKGROUND
QBS10072S, is a L-type amino acid transporter 1 (LAT-1) targeted alkylating agent that utilizes LAT1 as both a transport and targeting mechanism. QBS10072S can cross the blood-brain barrier, exhibits potential for cytotoxicity with a mechanism distinct from temozolomide and has low off-target effects. QBS10072S is being evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial (NCT02977780), a randomized phase 2 adaptive multi-arm platform trial.

METHODS
Adult patients with newly diagnosed MGMT-unmethylated glioblastoma are eligible for INSIGhT. Since there is no safety data available for QBS10072S in combination with radiotherapy, a safety lead-in evaluation was conducted utilizing a 3 + 3 design. Starting dose for QBS10072S was 12mg/m2 in combination with radiation therapy and adjuvantly as monotherapy in 28 day cycles. Patients were monitored for dose-limiting toxicities (DLTs) to identify the maximum tolerated dose and recommended phase 2 dose (RP2D).

RESULTS
Nine patients were enrolled December 2022 to October 2023 for safety lead-in testing, and median age was 57 years (41-67) with 6 (66%) males, 6 (66%) patients with gross total resection, and median KPS 90 (range 80-100). Pharmacokinetic studies indicated that drug exposure was lower than prior studies, and three patients received 12mg/m2, 15mg/m2, and 18mg/m2, respectively, per dose escalation protocol. No DLTs nor adverse events leading to study drug discontinuation were reported during the evaluation period. Four patients had possible treatment-related CTCAE grade ≥ 3 toxicity including lymphopenia (n=3) and fatigue (n=1). The RP2D was determined to be 18mg/m2. Seven patients were discontinued from study treatment due to progressive disease and two patients remain on treatment.

CONCLUSION
QBS10072S, concurrent and adjuvant to radiation therapy, was well-tolerated in patients with newly diagnosed unmethylated MGMT glioblastoma. QBS10072S 18mg/m2 is being evaluated as a treatment arm in phase 2 testing in the ongoing INSIGhT trial.
CTNI-62. EVALUATION OF SAFER-SEQS CTDNA ASSAY OPTIMIZED FOR DETECTING LOW CTDNA COUNTS FROM CSF AND PLASMA: ASSESSING SENSITIVITY AND FEASIBILITY FOR CLINICAL IMPLEMENTATION
Authors: Tobin Grace , Bettegowda Chetan , Huang Peng , Iacoboni Michaella , Fisher Joy , Dailey Erin , Schreck Karisa 
Published: November 2024

Abstract

BACKGROUND
Gliomas with BRAF alterations are often difficult to treat in the recurrent setting due to emergent resistance to FDA-approved targeted therapies. Additionally, it is difficult to assess response to therapy given the limitations of radiographic techniques and the infeasibility of serial tissue sampling. This protocol will serve as a prototype for determining the feasibility of using CSF and plasma circulating tumor DNA (ctDNA) as biomarkers for response to a novel-BRAF inhibitor, plixorafenib. Plixorafenib is a small-molecule selective inhibitor of Class 1 and 2 BRAF mutations that does not induce paradoxical reactivation of MAPK signaling.

METHODS
This clinical trial is designed as a single institution, signal-finding study to demonstrate the feasibility and sensitivity of detecting ctDNA at baseline and after one month of treatment with plixorafenib (primary endpoint). In addition, we will evaluate the correlation of ctDNA with disease status over time and response rate to plixorafenib. Patients aged 18 years or older with measurable recurrent BRAF-V600 mutant glioma (by RANO 2.0), who have received prior BRAF and/or MEK inhibitor therapy will be screened and consented for the study prior to surgery. Leptomeningeal disease allowed. A total of 12 evaluable patients will be enrolled. Patients will undergo clinically-indicated resection or biopsy for confirmation of disease progression and characterization of putative resistance alterations. All patients will have a ventricular reservoir placed at time of surgery with CSF and plasma sampling. Patients will initiate the study drug (oral plixorafenib 900mg daily with cobicistat 150mg daily) when clinically recovered from surgery. Patients will take the drug continuously for 28-day cycles. MRI, CSF, and plasma assessments will occur approximately every two months to evaluate disease status. Enrollment is planned to begin November, 2024.
CTNI-73. ASSESSMENT OF MOLECULAR ALTERATIONS IN NEWLY DIAGNOSED GBM MGMT-UNMETHYLATED PATIENTS TREATED WITH VAL-083
Authors: Kamiya-Matsuoka Carlos , Weathers Shaio-Pei , Yung Alfred , Login Monica , Majd Nazanin , Brown Dennis , Langlands John , Schwartz Richard , Knight Stephanie , Puduvalli Vinay , de Groot John , O’Brien Barbara 
Published: November 2024

Abstract
Glioblastoma (GBM) commonly features molecular alterations in the TERT, EGFR, PTEN, and TP53 genes, which contributes to uncontrolled cell growth, evasion of apoptosis, and enhanced tumor cell survival. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7 and O6-guanine inducing double-strand breaks causing cell death independently of MGMT DNA repair and DNA mismatch repair deficiency. VAL-083 was evaluated in an open-label, biomarker-driven, phase 2 trial in MGMT-unmethylated, bevacizumab-naïve GBM patients. The molecular profile of tumors from a newly diagnosed GBM patient subgroup who received VAL-083 alone after chemo-radiation with concurrent TMZ, was determined in order to correlate with clinical outcomes. Thirty-four (34/36, 94.4%) patients who received 30 mg/m2 VAL-083 (days 1-3 of 21-day cycle) had available next-generation sequencing data on their primary tissue. Patient median age was 54.8 years (5-95pth: 29.8-66.0), median KPS was 90 (5-95pth: 80-100) and 58.8% were males. The median number of cycles of VAL-083 was 7.5 (5-95pth: 1-12). There were 5 dose reductions due to toxicity. The median time to progression (PFS) and overall survival (OS) were 9.2 mo (95%CI: 7.6-10.2) and 16.5 mo (95%CI: 13.3-19.0), respectively. The mean number of molecular alterations was 3.9 (5-95pth 1-8). Six (17.6%) patients had gene fusions. The most common molecular alterations were TERT promoter (91.2%), EGFR amplification (amp) (52.9%), PTEN (50.0%), EGFR (20.6%), and TP53 (20.6%). Additional alterations (in ≥2 patients; 6%) included EGFR-EGFR (EGFRvIII), BRCA2, CDKN2A/B, CDK4/6 amp, MDM2/4 amp, NF1, NOTCH1, PIK3R1 and RB1. While TP53 mutations showed a trend as predictors for time to progression (P 0.027), this was not observed with OS. None of the molecular alterations were predictors of number of treatment cycles or dose reductions. No specific molecular alterations were identified that predicted either improved or poorer patient outcome, during treatment with VAL-083. Clinicaltrials.gov identifier: NCT02717962.
CTNI-76. A PHASE 1/2 DOSE ESCALATION AND EXPANSION STUDY OF SONODYNAMIC THERAPY WITH SONALA-001 IN COMBINATION WITH NON-ABLATIVE MR-GUIDED FOCUSED ULTRASOUND IN SUBJECTS WITH PROGRESSIVE OR RECURRENT GLIOBLASTOMA
Authors: Placantonakis Dimitris , Grabowski Mathew , Burns Terry , Butowski Nicholas , Clanton Ryan , Henry Lenora , Potter Wyatt , Marcus Stuart , Benaim Ely 
Published: November 2024

Abstract
Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective standard of care option and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination therapy that utilizes a drug, aminolevulinic acid HCL (SONALA-001, ALA), and a device, the Exablate 4000 Type 2.0 to deliver MR-guided focused ultrasound (MRgFUS). Preclinical studies have shown that SDT activates protoporphyrin IX (PpIX) to generate reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that ALA SDT was well-tolerated and not associated with off-target cellular or radiographic effects and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of iv SONALA-001 (ALA) in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Dose escalation will include an initial drug and energy dose escalation of ALA SDT utilizing an accelerated titration design with single subject cohorts for dose level cohorts 1 and 2, followed by cohort 3 with 3 + 3 design for additional dose escalation. SONALA-001 is administered 6 to 9 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of ALA SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Preliminary PK and safety results will be presented.
DDEL-10. MICROBUBBLE-ENHANCED FOCUSED ULTRASOUND REGULATES THE ENRICHMENT OF INFLAMMATORY PATHWAYS IN THE BLOOD-BRAIN BARRIER AND IMPROVES CAR T CELL ACCUMULATION IN GLIOMAS
Authors: Arvanitis Costas , Guo Yutong , Lee Hohyun , Kim Chulyong , Park Christian , Yamamichi Akane , Chuntova Pavlina , Gallus Marco , Bernabeu Miguel O , Jo Hanjoong , Okada Hideho , Kim Chulyong 
Published: November 2024

Abstract
A major challenge to brain cancer immunotherapy is posed by the rate-limiting obstacles to the systemic delivery of cytotoxic T cells, such as chimeric antigen receptor (CAR) T cells, in brain tumors posed by the blood brain barrier (BBB). Although the BBB can be bypassed by direct infusion of CAR-T cells in brain tumors, these approaches offer only short-term benefits, since they cannot affect distant tumor cell infiltrations, as evidenced by tumor relapse. Circulating microbubbles (MB) upon ultrasound (US) exposure (sonication) can exert mechanical stress in brain vessels to trigger a range of responses, including local increase in the BBB permeability and activation of inflammatory signaling and phenotypes. We hypothesize that ultrasound frequency tuned at MB resonance inside brain capillaries can transiently modulate the BBB signaling and function to improve CAR-T cell trafficking in glioma tumors. RNAseq and immunostaining of protein expression reveal that at frequencies just above microbubble resonance inside vessels (1.5MHz for 2µm MB), where maximum vessel wall shear stress is observed, there is a marked enrichment of inflammatory markers in the endothelial cells of brain vessels, including P-selectin and ICAM-1. Consistent with these findings, we observed that under high frequency excitation (1.5MHz), there is a 5-fold increase in the accumulation of EGFRvIII CAR-T cells in orthotopic EGFRvIII murine glioma tumors as compared not sonicated controls. We also found that over 85% of the tumor-infiltrating CAR-T cells express PSGL-1 and LFA-1 receptors, which interact with P-selectin and ICAM-1 to facilitate T cell extravasation. Together, these findings demonstrate that tuning the US frequency can improve CAR-T cell trafficking, potentially through upregulation of cell adhesion molecules in the glioma tumor microenvironment, and further support the functional relevance and potential clinical significance of the observed immuno-mechano-biological changes.
DDEL-11. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING OF SPATIAL HETEROGENEITY OF DRUG PENETRATION AND EXPOSURE IN THE HUMAN BRAIN AND BRAIN TUMORS
Authors: Li Jing , Wickramasinghe Charuka , Wu Andrew , Jiang Yuanyuan , Jiang Jun , Tovmasyan Artak , Kim Seongho , Sanai Nader 
Published: November 2024

Abstract

BACKGROUD
The difficulty in early, reliable prediction of drug penetration and exposure in the human brain and brain tumors makes development of new drugs and use of existing drugs for treating brain cancer a challenging and often unsuccessful task. We developed a physiologically based pharmacokinetic (PBPK) model platform for prediction of spatial pharmacokinetics in the central nervous system (CNS) following systemic drug administration.

METHODS
A 9-compartment CNS (9-CNS) PBPK model was developed to predict drug concentrations in brain blood, 2 brain parenchyma compartments (brain tissue adjacent to the CSF tract and deep brain parenchyma), 3 CSF compartments (ventricular CSF, cranial and spinal subarachnoid CSF), and 3 tumor compartments (tumor rim, bulk tumor, and tumor core). The pharmacokinetics in the CNS compartments were driven by plasma concentrations and governed by drug properties and CNS pathophysiology. The 9-CNS model was developed and validated with 4 drugs (abemaciclib, ribociclib, ceritinib, and temuterkib).

RESULTS
When considering tumor heterogeneity and inter-individual plasma pharmacokinetic variability following clinical standard dosing regimens, the model-predicted steady-state unbound drug tumor concentrations varied from 7.1 to 356 nM for abemaciclib, 74 to 4577 nM for ribociclib, 0.66 to 97 nM for ceritinib, and 0.8 to 288 nM for temuterkib, which were consistent with the heterogeneous drug tumor concentrations observed in glioblastoma patients. Drug penetration into the deep brain parenchyma was significantly less than that into tumors and CSF-adjacent brain tissue, particularly for strong ABCB1/ABCG2 substrate drugs. The ventricular and cranial subarachnoid CSF shared similar pharmacokinetics, while the spinal CSF pharmacokinetics was different.

CONCLUSION
A novel 9-CNS PBPK model was developed and validated for mechanistic prediction of spatial heterogeneity of drug penetration and exposure in the human brain, brain tumors, and CSF. It provides a valuable computational modeling tool to assist development and design of improved drugs or dosing regimens for brain cancer treatment.
DDEL-18. OPTIMIZED METHOD TO QUANTIFY TTFIELDS-INDUCED PERMEABILIZATION OF CELL MEMBRANES
Authors: Martinez-Paniagua Melisa , Khan Sabbir , Patel Chirag 
Published: November 2024

Abstract
Tumor Treating Fields (TTFields) therapy is FDA-approved for glioblastoma. Using plate-based readouts of FITC-dextran fluorescent probes in U87 human glioblastoma cells, we previously reported increased uptake of FITC-dextrans (4-20kDa) post-TTFields exposure. However, this approach is unable to distinguish FITC-dextran uptake in live-vs-dead cells post-TTFields exposure. We demonstrate flow cytometry (FC) as a more robust and economical method to quantify the amount of FITC-dextrans entering the cells. We first identified the optimal [FITC-dextran] for the FC-based approach (titration 0-6.5mg/mL). Cells were then seeded onto coverslips and exposed to 200kHz TTFields, 1-3V/cm peak-to-peak (inovitro systemTM, Novocure), or no-TTFields (control), for 24-72h. Cells were harvested and stained for 1h using 4kDa or 20kDa FITC-dextrans. Cells were washed and analyzed by FC for mean±SD fluorescence intensity, and compared by unpaired t-test. Dead cells were excluded using propidium iodide staining. In the control vs. TTFields group, 4kDa FITC-dextrans had significantly increased uptake at 24h (4.9±0.3 vs. 8.0±1.7, p=0.01), 48h (6.5±0.2 vs. 8.3±1.0, p=0.01), and 72h (5.7±0.3 vs. 8.8±1.0, p=0.001). Likewise, in the TTFields group, the 20kDa FITC-dextrans had significantly increased uptake at 24h (5.6±0.3 vs. 7.5±0.9, p=0.006), 48h (4.8±0.3 vs. 6.6±0.8, p=0.006), and 72h (5.3±0.2 vs. 11.3±2.6, p=0.004). In the TTFields group, the 20kDa FITC-dextrans had significantly increased uptake between the 24h and 72h timepoints (p=0.03). The FC-based method utilized 0.36mg of FITC-dextrans/sample, much less compared to the 1-3mg recommended for plate-based methods. Another advantage of the FC-based method was exclusion of the dead cell population after TTFields exposure. We validated a FC-based-method that is economical and can reproducibly quantify the membrane permeabilization induced by TTFields. Compared to control conditions, TTFields increase membrane permeabilization of cells that remain alive after TTFields exposure, in a time-dependent manner for the 20kDa probe.
DDDR-09. POTENTIAL OF GSPT1 AS A NOVEL TARGET FOR GLIOBLASTOMA THERAPY
Authors: Sasayama Takashi , Hamada Takeshi , Tanaka Kazuhiro , Nagashima Hiroaki , Yamanishi Shunsuke , Ueyama Takehiko 
Published: November 2024

Abstract
Glioblastoma is the most common malignant brain tumor in adults, the survival rate of which has not significantly improved over the past three decades. Therefore, there is an urgent need to develop novel treatment modalities. We have reported G1 to S phase transition 1 (GSPT1) as a novel downstream target of RAC1, which is a tumor driving and promoting molecule, and that depletions of GSPT1 as well as RAC1 induced delayed cell cycle progression in primary astrocytes. Herein, we examined the potential of GSPT1 as a novel target for glioblastoma therapy. CC-885, a cereblon modulator that degrades GSPT1 by bridging GSPT1 to CRL4 E3 ubiquitin ligase complex, was administered to nude mice with transplanted brain tumors of U87 glioblastoma cells. The survival period was significantly longer in CC-885 treated mice than in control mice. Furthermore, we generated GSPT1-knockout (KO) U87 cells by genome editing and GSPT1-KO U87 cells with stable overexpression of FLAG-tagged GSPT1 (Rescued GSPT1-KO U87 cells). Mice with transplanted GSPT1-KO U87 cells and Rescued GSPT1-KO U87 cells showed significantly longer and similar survival periods, respectively, as those with WT U87 cells. GSPT1-KO U87 cells showed enhanced apoptosis, detected by cleaved PARP1, compared to WT U87 cells. Brain tumors due to transplantation of GSPT1-KO U87 cells also showed enhanced apoptosis compared to those due to transplantation of WT and Rescued GSPT1-KO U87 cells. GSPT1 expression was confirmed in patients with glioblastoma. However, the clinical study using 87 glioblastoma samples showed that GSPT1 mRNA levels were not associated with overall survival. Taken together, we propose that GSPT1 is an essential protein for glioblastoma growth, but not its malignant characteristics, and that GSPT1 is a potential target for developing glioblastoma therapeutics.
DDDR-26. IDENTIFICATION OF MODULATORS OF IDH INHIBITOR SENSITIVITY INIDH-MUTATED DIFFUSE GLIOMAS
Authors: Saleek Sumaiyah , Laugesen Eric , Subramani Poorani Ganesh , Tian Ruxiao , Wu Annette , Ghamrasni Samah El , Levine Adrian , Aamir Zoya , Petrecca Kevin , McBrayer Samuel , Suvà Mario , Hawkins Cynthia , Tabori Uri , Mak Tak , Fortin Jerome 
Published: November 2024

Abstract
Driver mutations in IDH1 and IDH2 characterize a substantial proportion of lower-grade diffuse gliomas in adults. Mutated IDH molecules cause the accumulation of D-2-hydroxyglutarate (D-2-HG), which perturbs many cellular functions, including metabolism, epigenetic regulation, and the ability to differentiate. This is notably associated with DNA and histone hyper-methylation. Recently, the newly developed IDH inhibitor, vorasidenib, was shown to delay tumor progression and the need for additional treatment in the groundbreaking INDIGO clinical trial. Nevertheless, the responses to vorasidenib were variable between patients, and so far have been established only for less aggressive disease. In addition, it is unclear to what extent vorasidenib can cause tumor regression. This highlights the need to identify molecules and pathways that control IDH inhibitor sensitivity. Towards this goal, we generated a new mouse model that combines Idh1R132H and Trp53 loss-of-function, targeted to oligodendrocyte progenitors. All the mutant mice develop diffuse gliomas that recapitulate the cardinal features of the corresponding human disease. We established multiple cell lines from these tumors, which retained expression of mutant IDH. The cells robustly produced D-2-HG, which was concentration-dependently suppressed by vorasidenib. Accordingly, vorasidenib could lower DNA methylation, and induce the expression of mature glial cell markers. To identify determinants of vorasidenib sensitivity, we performed genome-wide loss-of-function CRISPR/Cas9 functional genomics screens. In those experiments, targeting genes associated with astrocyte differentiation or Notch signaling enhanced cell fitness in the presence of vorasidenib, consistent with the anticipated effects of the drug on inducing cell differentiation. Conversely, vorasidenib-treated cells were more sensitive to the loss of regulators of cell growth and metabolism, and of some epigenetic regulators. These studies point to strategies that may enhance the efficacy of IDH inhibitors for the treatment of IDH mutated gliomas.