bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDDR-10. SIRTUIN 2 INHIBITION SELECTIVELY INDUCES SENESCENCE IN ATRX-DEFICIENT MALIGNANT GLIOMAS BY MODULATING CHROMATIN LANDSCAPES GENOME-WIDE
Authors: Malgulwar Prit Benny , Danussi Carla , Dharmaiah Sharvari , Johnson William E , Rao Arvind , Huse Jason 
Published: November 2023

Abstract
Inactivating mutations in ATRX characterize large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. We utilized integrated mulit-omics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanim(s). CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (Sirt2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. Sirt2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroprogenitor cells (mNPCs) and impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs). While effects on cellular proliferation in these contexts were more modest, markers of senescence significantly increased, suggesting that Sirt2 inhibition promotes terminal differentiation in ATRX-deficient glioma. These phenotypic effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to Sirt2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon Sirt2 inhibition. Finally, Sirt2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. Our findings indicate that Sirt2 inhibition selectively targets ATRX-deficient gliomas through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.
DDDR-12. ESTABLISHING A SAFE AND EFFICACIOUS ANTI-GLIOBLASTOMA THERAPY
Authors: del Genio Carmen , Nguyen Sidney , Shalit Zachary , Pizzi Elizabeth , Messay Bamlak , Fontaine Dominique , Shentu Yujia , Wishart Heather , Ford James , Micalizio Glenn , Gaur Arti 
Published: November 2023

Abstract
Glioblastomas (GBM) are primary brain tumors that are among the most treatment-resistant human cancers with a median survival of only 14 months and a 5-year survival rate of less than 5%. The standard-of-care for GBM has remained unchanged for two decades and more than half of newly diagnosed patients do not see any therapeutic benefit with existing regimens. Due to a 25:1 failure ratio in developing new brain tumor treatments, the FDA has approved only four drugs against GBM in the past three decades. This failure in clinical development can be attributed primarily to severe toxic side effects, the inability of most compounds to cross the blood brain barrier (BBB) and use of pre-clinical models that do not represent the molecular heterogeneity of GBM. To fulfill this unmet need for curative treatments we are developing an anti-GBM therapy in a clinically relevant patient-derived in vivo model and selectively targeting estrogen receptor-beta (ERβ) using ent-28, a novel, highly selective and potent agonist of ERβ. ent-28 has 9000-fold higher selectivity for ERβ compared to estrogen, or 17β- estradiol; precluding non-specific binding of ERα. ent-28 inhibits the proliferation of GBM patient-derived adherent and stem cells but not of human astrocytes and neural progenitor cells in vitro. More critically, ent-28 is not toxic and does not have off- target side effects in immune-competent mice even after one year long chronic treatment. These data have enabled us to further establish that using an oral route of delivery, ent-28 crosses the BBB and significantly reduces or ablates intra-cranial, orthotopically implanted GBM patient-derived xenografts, resulting in increased survival of ent-28 treated mice. Pre-clinical data will be presented on safety, pharmacokinetics, metabolic stability, in vivo efficacy, mechanism of action and species rationalization for this novel, ERβ agonist that is being developed as an anti-GBM therapy.
DDDR-16. CURCUMIN ANALOGS EXHIBIT ANTI-TUMOR ACTIVITY AGAINST GLIOBLASTOMA AT LOWER CONCENTRATIONS THAN CURCUMIN
Authors: Inai Kyoko , Hamabe-Horiike Toshihide , Ono Masaya , Iwashimizu Sonoka , Ito Ryo , Sunagawa Yoichi , Katanasaka Yasufumi , Hawke Philip , Arakawa Yoshiki , Morimoto Tatsuya 
Published: November 2023

Abstract

PURPOSE
Glioblastoma (GBM) has a high risk of recurrence and a poor prognosis due to the difficulty of surgical resection and resistance to the standard treatment, temozolomide. Therefore, the development of new therapeutic agents against GBM is required. This study investigated the anti-tumor activity of the curcumin (Cur) analogs Compound A (ComA) and B (ComB) against GBM.

METHODS AND RESULTS
To evaluate anti-tumor activity against GBM, we performed a MTT assay. The human glioblastoma cell lines U87-MG and U251 were pre-treated with Cur, ComA, or ComB, then cell viability was examined using a cell counting kit, and IC50 values were calculated. The IC50 values for U87-MG were: Cur, 9.78 µM; ComA, 2.42 µM; and ComB, 1.28 µM. Those for U251 were: Cur, 9.50 µM; ComA, 2.27 µM; ComB, 0.64 µM. To examine the effects of ComA and ComB on normal cells, the same MTT assay was performed on primary cultured astrocytes from neonatal rats. Neither ComA nor ComB resulted in reduced cell viability in astrocytes at concentrations that had an anti-tumor effect on GBM cells (ComA, 3 µM; ComB, 1.5 µM). Next, a cell cycle analysis was performed with PI staining and an apoptosis assay with Annexin V/PI staining using flow cytometry. qPCR was performed to examine the mRNA expression levels of the cell cycle-related proteins CDK1 and CyclinB1. Both ComA and ComB, at lower concentrations than Cur, induced 1) G2/M phase arrest due to a decrease in the mRNA expression levels of CDK1 and CyclinB1 and 2) apoptosis.

DISCUSSION
These results suggest that both ComA and ComB, at lower concentrations than Cur, have an anti-tumor effect without affecting normal cells by inducing cell cycle arrest and apoptosis against GBM. Further detailed analysis and in vivo studies are expected to lead to the development of novel therapeutic agents for GBM.
DDDR-17. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS
Authors: Mayr Lisa , Trissal Maria , Schwark Kallen , Neyazi Sina , Beck Alexander , Labelle Jenna , Marques Joana Graca , Weiler-Wichtl Liesa , Madlener Sibylle , Kong Seongbae , Miclea Madeline , Supko Jeffrey , Guntner Armin Sebastian , Palova Hana , Neradil Jakub , Stepien Natalia , Loetsch-Gojo Daniela , Dorfer Christian , Dieckmann Karen , Peyrl Andreas , Azizi Amedeo A , Baumgartner Alicia-Christina , Slaby Ondrej , Pokorna Petra , Dubois Frank , Greenwald Noah , Bandopadhayay Pratiti , Beroukhim Rameen , Ligon Keith , Kramm Christof , Bronsema Annika , Bailey Simon , Stuecklin Ana Guerreiro , Mueller Sabine , Skrypek Mary , Martinez Nina , Bowers Daniel C , Jones David , Jones Chris , Jaeger Natalie , Sterba Jaroslav , Müllauer Leonhard , Haberler Christine , Kumar-Sinha Chandan , Chinnaiyan Arul , Mody Rajen , Furtner-Srajer Julia , Koschmann Carl , Gojo Johannes , Filbin Mariella 
Published: November 2023

Abstract
PDGFRA has been shown to be commonly altered in pediatric and young adult high-grade gliomas (pHGGs) including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a disease with almost no long-term survivors. Here, we performed comprehensive genomic and transcriptomic analyses of n=259 pediatric high-grade glioma cases which revealed PDGFRA genomic alterations (mutations and/or amplifications) in ~14.9% of patients. We tested a panel of patient-derived HGG and H3K27M DMG models against a range of PDGFRA inhibitors, and found that avapritinib outperformed other inhibitors in terms of (1) in vitro efficacy, (2) selectivity for PDGFRA inhibition and (3) blood brain barrier penetration, and demonstrated significant survival impact and PDGFRA pathway inhibition in two orthotopic H3K27M DMG mouse models. We furthermore report the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib was generally well tolerated with a manageable safety profile and no significant safety concerns. Preliminary data reveal radiographic response evaluated by RAPNO criteria in 3/7 (42%) patients with evaluable lesions. Complete or partial response was observed in 2 of 8 patients (25%); one patient showed stable disease; 5 of 8 patients progressed on therapy (62%). Molecular profiling of treated patients revealed PDGFRA amplification in 4 of 8 patients, PDGFRA receptor mutations in 4 of 8 patients. One patient with PDGFRA/KIT amplification developed a spontaneous EGFR gain and a secondary PDGFRA mutation in a cerebellar metastatic lesion that progressed on avapritinib therapy. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in HGG patients.
DDDR-19. FIRST-IN-CLASS CANCER THERAPEUTICS TARGETING THE DNA DAMAGE RESPONSE
Authors: Robertson Adam , Prikrylova Terezia , Lancero Hope , Wilson Christy , Petritsch Claudia 
Published: November 2023

Abstract
Hemispherian is advancing first-in-class therapeutics for cancers that are historically difficult to treat. Glioblastoma multiforme (GBM) is the primary indication for our lead compound GLIX1, which is currently in late-stage preclinical development. GLIX1 is developed together with a biomarker-based companion diagnostic assay to pair diagnostics and optimal treatment. It is Hemispherian’s mission to provide superior treatment options for brain cancer patients. Hemispherian’s proprietary molecules selectively target the DNA damage response in cancer cells. These molecules take advantage of a pre-existing condition of all cancer cells – nearly all cancer cells have a reduction in levels of the DNA base modification, 5-hydroxymethylcytosine. Hemispherian scientists have found that restoration of this base modification to normal cells activates the DNA damage response resulting in cancer cell death. Targeting of the enzyme responsible for maintaining genomic 5-hydroxymethylcytosine, TET2, led to the discovery of the GLIX family of molecules. Hemispherian’s lead GLIX molecules, GLIX1 and GLIX5, show excellent efficacy in vivo in xenograft models, have a superior safety profile, are orally bioavailable and are blood brain barrier penetrant. GLIX efficacy against a panel of patient-derived cell lines representing a broad spectrum of pediatric and adult brain tumor diagnoses will be discussed. Taken together, these molecules have an exceptional profile for treating a broad range of cancers including cancers of the brain.
DDDR-22. PREDICTING AND TARGETING CLONALLY EXPANDING, TMZ-RESISTANT TUMOR CELLS IN GLIOBLASTOMA
Authors: Ullrich Vivien , Ertmer Sarah , Berger Pia , Langer Sarah , Baginska Anna , Gull Hanah , Dorsch Madeleine , Cima Igor , Dobersalske Celia , Kebir Sied , Glas Martin , Rauschenbach Laurèl , Sure Ulrich , Roesch Alexander , Gruener Barbara M , Scheffler Björn 
Published: November 2023

Abstract
Emerging evidence supports the notion that phenotypic plasticity contributes to disease progression and drug resistance in malignant glioma. We have recently described a rare population of ALDH1A1+ tumor cells in newly diagnosed, treatment-naive glioblastoma that can adapt to the exposure of the standard chemotherapeutic temozolomide (TMZ). Their subclonal growth leads to AKT-driven, TMZ-resistant cellular hierarchies. Accumulation of ALDH1A1+/pAKT+ cells can therefore be noted subsequent to TMZ in patient relapse tissue and in PDX models of disease. We have also shown that this series of events requires a sequential targeting approach where these subclones are allowed to enrich under TMZ and, only in a second step, are treated with AKT inhibitors. This “enrich and kill” strategy doubles the TMZ-based survival benefit in preclinical PDX models (Kebir et al., Clin Cancer Res 2023). Here, we took advantage of short-term expanded patient-derived cell cultures, which allow the study of early stages of this type of adaptive plasticity in controlled conditions. Specifically, we characterized the human lysine-specific demethylase 5B (KDM5B) as a prospective indicator for subclonal expansion in rare cells under first-time exposure to TMZ. We used genetic reporters, pharmacological interference, CHIP-seq analysis and cellular barcoding to investigate the dynamics of KDM5B expression and the related intracellular cross-signaling. We monitored patient cell samples over prolonged periods of time, and we found that KDM5Bhigh treatment-naive glioblastoma cells preferentially contribute to the dynamics of ALDH1A1 subclones and drug resistance under the influence of TMZ. These findings may lay ground for the development of biomarker-assisted clinical trials. This work is supported by DFG/GRC-CRU337/2 (proj#405344257).
DDDR-30. IDENTIFICATION OF DRIVERS OF RESISTANCE IN BRAFV600E PEDIATRIC HIGH-GRADE GLIOMA AND NOVEL THERAPEUTIC TARGETS
Authors: Lehmann Rebecca , Zhu Joshua , Mayoh Chelsea , Tsoli Maria , Rayner Benjamin , Ziegler David 
Published: November 2023

Abstract
The BRAFV600E mutation has recently been discovered as a driver mutation in a subset of pediatric high-grade gliomas (pHGG), with tumors driven by this mutation responding to targeted BRAF and MEK inhibitors. Unfortunately, resistance inevitability develops, resulting in disease progression. There is currently limited understanding of the mechanisms underlying drug resistance in BRAFV600E pHGG, and no effective counter-therapies exist. This study aimed to identify driver pathways of resistance in BRAFV600E pHGG and subsequently novel therapeutic targets. BRAF inhibitor-resistant, MEK inhibitor-resistant and BRAF+MEK inhibitor-resistant BRAFV600E pHGG cultures were derived through chronic exposure of a BRAFV600E patient-derived culture to vemurafenib (BRAF inhibitor), trametinib (MEK inhibitor) or a combination of both drugs, respectively. Cytotoxicity assays confirmed resistance. All resistant cell lines spontaneously changed from a spheroid phenotype to adherent growth, indicating changes in tumor characteristics. RNAseq identified &gt; 1500 genes of interest, with subsequent Gene Set Enrichment Analysis identifying key pathways as novel drivers of resistance, the top-ranked gene sets being neural development and plasma membrane/cell adhesion. Approximately 45% of gene sets were enriched across all drug-resistant lines, indicating overlapping resistance mechanisms. Interrogation of the receptor tyrosine kinase (RTK) gene sets identified potent upregulation of several RTKs. Notably, overexpression of the RTK, EGFR, was confirmed through RNAseq and western blot as a potential key mediator of the acquired resistance. Combined treatment with vemurafenib and the EGFR inhibitor, dacomitinib, resulted in synergistic activity against both vemurafenib-resistant BRAFV600E pHGG cells and matched parental cells, providing a viable therapeutic option for drug-resistant BRAFV600E pHGG. Overall, novel drivers of resistance have been identified in BRAFV600E pHGG. EGFR overexpression was pinpointed as a key mediator and dual BRAF/EGFR inhibition displayed promising efficacy as a therapeutic option. Future studies will continue to elucidate the mechanisms of resistance using multi-omic approaches and the in vivo efficacy of dual BRAF/EGFR inhibition.
EOLP-01. TREATMENT OF HEADACHES IN GLIOMA: A SYSTEMATIC REVIEW OF CURRENT PRACTICES AND FUTURE DIRECTIONS
Authors: Coulibaly Nangorgo , Grossen Audrey , Battiste James 
Published: November 2023

Abstract

INTRODUCTION
Headaches are one of the most common morbidities in glioma reported in 36 to 62% of patients along the course of their disease. Gliomas represent 27% of primary CNS neoplasms and accounted for an average annual age-adjusted incidence rate of 6.0 per 100 000 population according to data collected between 2010 and 2014. OBJECTIVES: The goal of this review was to evaluate current treatment options for glioma patients presenting with headaches and identify current headache treatment methods that could play a role in those patients.

METHODS
A systematic review of studies involving headaches in patients with gliomas was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search was conducted on PubMed, Ovid Medline, and Embase databases through January 3rd, 2023, with the following search terms: (analgesic OR anti-inflammatory OR prophylaxis OR steroids) AND (headache) AND (glioma or glioblastoma) AND (treatment). For each patient, we extracted: the therapy used, its outcome, and any side effects.

RESULTS
There were 11 out of 195 articles included in the review. For the articles that were fully reviewed (n =93), the majority of the exclusions 49% (n=40) were due to lack treatment method for patients’ headache. The most reported treatment options were Analgesics (n=211), steroids (dexamethasone, n=116), Surgical resection (n=2), and CGRP inhibitor (Fremanezumab, n=1). Most of the included studies 55% (n=6) only discussed headache treatment in 1 patient with 67% (n=4) of them being case report highlighting the lack of evidence covering this topic.

CONCLUSION
Headache treatment in patients with gliomas is an area of neuro-oncology with much to be learned. There is a need to further study the etiology of headaches in order to provide effective treatment plans that could improve the quality of life in this patient population.
EOLP-03. BALANCING HOPE AND REALITY: A THEMATIC ANALYSIS OF PATIENT-CLINICIAN COMMUNICATIONS AT INITIAL NEURO-ONCOLOGY OUTPATIENT CLINIC VISITS FOR PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA
Authors: Hauswirth Anna , Strander Sumita , Temel Jennifer , Traeger Lara , Forst Deborah 
Published: November 2023

Abstract
BACKGROUND: Patients facing a new diagnosis of a high-grade glioma often report an inaccurate understanding of their poor prognosis. However, how oncologists communicate prognostic information at initial visits in the neuro-oncology clinic has not been fully studied. We sought to analyze how physicians share this devastating news with patients and their caregivers. METHODS: We audio-recorded and transcribed the initial neuro-oncology clinic appointments with patients with high-grade gliomas at a single academic medical center; during these visits, neuro-oncology clinicians (physicians and fellowship trainees) shared diagnostic and prognostic information with patients and caregivers. We analyzed visit content using thematic analysis. RESULTS: We enrolled 14 patients with newly diagnosed malignant gliomas (glioblastoma: 11 and anaplastic astrocytoma: 3); 9 neuro-oncology clinicians (6 attending physicians and 3 fellowship trainees) participated in the appointments. Emergent themes included: (1) Neuro-oncologists proactively offered diagnostic and prognostic information using clear and simple language to disclose incurability (e.g., that this is an “incurable,” “aggressive” cancer that “will come back”); (2) Neuro-oncologists shifted their language, content, and tone to balance this bad news with clinical information that offered hope and optimism (e.g., emphasizing a patient’s positive prognostic indicators, sharing examples of long-term survivors, and discussing ongoing research and clinical trials); (3) Neuro-oncologists further balanced diagnostic disclosure with offers of logistical support (e.g., support programs for the patient’s minor children and access to 24/7 telephone care) and emotional support (e.g., stating "I am always here”) to patients and family members. CONCLUSION: During initial clinic visits with patients with high-grade gliomas, neuro-oncologists disclosed frank information about the incurability of the illness while balancing this life-changing news with statements of hope, optimism, and support. Understanding how clinicians provide diagnostic and prognostic information may help inform efforts to improve patient-clinician communication and optimize support for patients and their families.
EOLP-07. A REAL-WORLD INTEGRATED OUTPATIENT PALLIATIVE AND SUPPORTIVE CARE CLINIC IN A REGIONAL COMMUNITY NEURO-ONCOLOGY PRACTICE
Authors: Celestino Dominique , Chand Deepna , Robert-Quinn Keith , Nguyen Minhdan , Truong Judy , Chow Jared , Mauritson Emmaline , Wagle Naveed , Carrillo Jose , Juarez Tiffany , Barkhoudarian Garni , Kesari Santosh , Sharma Akanksha 
Published: November 2023

Abstract

BACKGROUND
Palliative care (PC), a specialty focused on alleviating suffering, is appropriate at any stage of serious illness and can improve quality of life, survival and reduce care partner distress. Integration within the care of neuro-oncology (NOC) patients remains difficult. At our center, patients who might benefit from specialty palliative care have been seen by a dual fellowship trained NOC and PC specialist (A.S.) since February 2021. We present our experience here.

METHODS
This was a retrospective chart review including records from the electronic medical record system from February 2021 to May 2023. RESULTS/

CONCLUSION
A total of 58 patients received integrated PC from 651 seen in the general NOC practice. The most common diagnosis was glioma (59%), with the rest being a mixture of lymphoma or systemic cancer with brain involvement. Majority of patients were male (53%) and identified as White/Caucasian (86%). The average age of patients at referral was 58. The most common focus was symptom management (40%), followed by guidance around decision-making (14%), care partner support (11%), advance care planning (10%), and support with coping (9%). The most common symptoms discussed included fatigue (36%), seizures (22%), and pain (21%). By the submission of this abstract, 28 (48%) patients had passed away, 22 of whom (79%) had formally enrolled on hospice with an average of 24 days prior to death. The primary cause of death was respiratory failure towards end of life (71%). Three patients (11%) had chosen to employ the California End of Life Act. Advanced directives were discussed and completed in 82% and a proxy had been identified in 100%. This model of integrated PC for NOC clinics appears to be feasible, meaningful and is welcomed for it allows focused, dedicated attention to symptom management, distress alleviation, advance care planning and hospice transition.