bluuebunny/crossref_metadata_2025 huggingface dataset:
DDDR-06. THE SMOKING CESSATION AGENT LOBELINE DELAYS HYPOXIC STRESS RECOVERY RESULTING IN GLIOBLASTOMA CELL DEATH
Authors: Attwood Kathleen , Robichaud Aaron , Han Jae Ho , Wajnberg Gabriel , Roy Jeremy , Weeks Adrienne
Published: November 2023

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour with a universally fatal prognosis. GBM is characterized by extensive regions of hypoxia which adversely impacts clinical outcomes, as hypoxia promotes chemoresistance. Tumour cells can adapt to and survive hypoxic stress by inducing rapid changes in the translational landscape, facilitated in part by the formation of stress granules (SGs). SGs are cytoplasmic aggregates of untranslated mRNAs and RNA binding proteins formed in response to a variety of cellular stressors, that allow cells to temporarily prioritize translation of stress-related proteins. Previous work in our laboratory has shown that GBM cells form SGs in vitro and in vivo, and that pharmacologically altering SG dynamics to prevent their dissolution (effectively locking cells in a stressed state) increases GBM cell death. Here we have identified another compound that delays the dissolution of hypoxia-induced SGs in GBM cells, the smoking cessation agent lobeline. SG dissolution typically occurs within 15 minutes post-hypoxia, however pre-treatment of immortalized GBM cells with lobeline delays SG dissolution for up to 2 hours. This delay in SG dissolution is dose dependent, as higher lobeline concentrations resulted in corresponding increases in the percentage of cells containing SGs and the average number of SGs per cell post-hypoxia. Lobeline also led to sustained phosphorylation of eIF2a (a key regulator of translation initiation) with an accompanying decrease in global protein translation levels post-hypoxia. Importantly, the combination of lobeline and hypoxia led to synergistic cell death in both immortalized and primary GBM cells, specifically through increased necrosis. Lobeline acts as a VMAT2 ligand and can stimulate dopamine release. Interestingly, we have found miRNA related to dopamine metabolism pathways overrepresented in extracellular vesicles isolated from GBM patient plasma. We postulate that disrupting the balance of stress pathways may have therapeutic potential in the future.
DDDR-07. TARGETING THE CIRCADIAN CLOCK WITH SMALL MOLECULE COMPOUNDS RESULTS IN ANTI-TUMOR EFFECTS SPECIFICALLY IN GLIOBLASTOMA STEM CELLS
Authors: Chan Priscilla , Wu Lian , Hovsepyan Anahit , Mkhitaryan Seda , Karapetyan Gevorg , Shah Khalid , Wakimoto Hiroaki , Kamenecka Theodore , Solt Laura , Cope Jamie , Moats Rex , Hirota Tsuyoshi , Rich Jeremy , Kay Steve
Published: November 2023

Glioblastoma multiforme (GBM) is the most common primary brain tumor, with an average survival time of less than one year following diagnosis. Treatment success remains challenging despite aggressive, multimodal current standard-of-care consisting of maximal surgical resection followed by concurrent temozolomide (TMZ) chemotherapy and radiation. The presence of GBM stem cells (GSCs) is thought to make treatment exceptionally difficult as they are highly invasive, resistant to chemoradiation, promote angiogenesis, support an immune suppressive environment, and can recapitulate the primary tumor following surgical resection. We have reported that GSCs, however, are dependent on core circadian clock proteins, Brain and Muscle ARNTL-Like 1 (BMAL1) and Circadian Locomoter Output Cycles Protein Kaput (CLOCK), which is not observed in differentiated GBM cells or normal neuronal stem cells. In this study, we explore the anti-GSC effects of multiple families of novel small molecule circadian clock compounds that either lower BMAL1 transcription (REV-ERB agonists) or inhibit BMAL1::CLOCK heterodimer transcriptional activity (Cryptochrome (CRY) stabilizers or Casein Kinase (CK) 1/2 inhibitors). Here we report that compared to compared to non-cancerous cells, U2OS human osteosarcoma cells, and differentiated GSCs (DGCs), GSCs display increased sensitivity to clock compounds at single agent and combinatory doses of clock compounds. Additionally, clock compounds are significantly more effective in targeting GSCs than TMZ and combinations of clock compounds with TMZ can lower TMZ IC50 value in different GBM cell lines and types. Application of the CRY stabilizer SHP1705 in GBM PDX patient derived xenograft (PDX) models resulted in decreased tumor growth rate and increased survival time compared to vehicle control. These results highlight the therapeutic potential of circadian clock compounds as single agents, in combinations and as adjuvants to existing therapies by specifically targeting the GSC population in GBM.
DDDR-08. DISCOVERY OF ER STRESS-INDUCING COMPOUNDS FOR GBM: A PROMISING APPROACH TOWARDS THERAPEUTIC DEVELOPMENT
Authors: Veliz Eduardo , Sansalone Lorenzo , Maldonado Amanda , Leblanc Roger , Steven Vanni , Graham Regina
Published: November 2023

The unfolded protein response (UPR) is a pro-survival mechanism triggered by cellular stresses encountered by tumor cells, such as hypoxia, acidosis, reactive oxygen species and even radiation and chemotherapy. In response to increased unfolded or mis-folded proteins in the endoplasmic reticulum (ER), the UPR initiates specific cell signaling pathways aiming to alleviate ER stress and restore ER proteostasis which include increasing the expression of chaperones to aid in protein folding, enhancing protein degradation and reducing global protein synthesis. However, if homeostasis cannot be restored, the UPR switches from survival to cell death. The UPR is a relatively novel therapeutic target for glioblastoma (GBM), and specifically GBM stem-like cells (GSCs) which maintain tumor heterogeneity, drive GBM tumor growth and therapy resistance. Here we tested a series of curcumin derivatives against three GSC lines and identified a trimethoxy bis-chalcone which promotes robust GSC death with an average IC50 of just below 300 nM, a 100-fold increase in activity compared to curcumin. Furthermore, this bis-chalcone was non-toxic to normal human mesenchymal stem cells. Western blot analysis indicated that the bis-chalcone induced robust activation of UPR pro-death protein C/EBP Homologous Protein (CHOP) while simultaneously decreasing the expression of pro-survival chaperone GRP78/Bip. Lastly our bis-chalcone induced caspase 7 expression and PARP cleavage indicating apoptosis. Most ER stress inducing agents promote both the survival, upregulation of Grp78, and cell death arms of the UPR. Here we identified a compound that only promotes UPR cell death signaling and is highly toxic to radiation and temozolomide resistant GSCs while demonstrating no toxicity to non-tumor cells. This is a promising lead compound for the development of UPR targeted GSC/GBM therapeutics.
DDDR-09. FUNCTIONAL GENOMICS AND CHEMOTHERAPY RESISTANCE SCREENING IDENTIFIES BIOMARKERS AND TARGETABLE MECHANISMS OF CCNU RESISTANCE IN GLIOMAS
Authors: Hajal Cynthia , Dalin Simona , Raskind Greg , Cusick Margaret , Malinowski Seth , Ito Jakob , Bossi Connor , Vogelzang Jayne , Bellamy Charlotte , Salhi Lisa , Bielle Franck , Getz Gad , Bandopadhayay Pratiti , Touat Mehdi , Beroukhim Rameen , Ligon Keith
Published: November 2023

The bifunctional alkylator lomustine (CCNU) remains widely but heterogeneously used as one of the few effective treatments in glioblastoma (GBM) and IDH mutant gliomas. Despite its widespread use, mechanisms of response and resistance to this agent are controversial and patients who benefit are poorly understood. To address this with next-generation patient models and functional genomics approaches, we generated and characterized CCNU response in a large cohort of 71 patient-derived glioma cell lines (PDCLs, spheroids/organoids). Models had fully defined clinical and molecular characteristics (WES, RNAseq, and patient and model MGMT). Patient models, including those derived from patients who acquired resistance to CCNU, exhibited a surprisingly wide range of differential response to CCNU (median IC50: 21.66uM; range: 1.52uM-159uM) using metabolic (CTG) as well as cell death readouts, with no lines showing complete resistance (EC100 < 291uM). MGMT promoter methylation status but not mismatch repair (MMR) trended, but did not reach, statistical significance as a predictor of CCNU sensitivity (p=0.053), in striking contrast to TMZ (p=0.01). Chronic CCNU exposure of two PDCLs led to acquired resistance to CCNU (IC50 increase from 5uM to 50uM on average). RNA sequencing showed 194 significantly differentially expressed genes while no mutations acquired in resistant models were identified in DNA sequencing. PRISM pooled screening of over 900 barcoded cancer cell lines and correlation with DepMap whole genome CRISPR-knockout data showed unique patterns of CCNU response and strong upregulation of DNA repair targets in the resistant state, which differed from TMZ. Shared targets were also identified in a CRISPR-activator screen performed on a CCNU sensitive cell line in the presence and absence of CCNU and converged on multiple mTOR pathway genes as top enriched targets and biomarkers of resistance in CCNU-resistant models. These druggable targets are currently being investigated for combination therapies with CCNU and potential to overcome resistance.
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

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

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

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

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

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

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

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 > 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

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

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

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.
EPID-04. EVOLVING SURVIVAL IN PATIENTS WITH LEPTOMENINGEAL METASTASES FROM SOLID TUMORS
Authors: Chabot Kiana , Osei-Gyening Isaiah , Estrera Rachel , Yang Jonathan , Pentsova Elena , Boire Adrienne , Wilcox Jessica
Published: November 2023

BACKGROUND

The prognosis for patients with leptomeningeal metastases (LM) has been historically bleak, with an average survival < 4 months and limited treatment options. As modern therapeutics prolong the lives of cancer patients, the life expectancy of those with LM may also improve. This study aims to demonstrate survival trends in patients with LM over a 20-year time span.

METHODS

This is a single-institution retrospective analysis of patients diagnosed with solid tumor LM, excluding primary brain tumors, between 2002-2022. LM diagnosis was determined via unequivocal radiographic enhancement, CSF cytology, and CSF circulating tumor cell enumeration (CSF-CTC, cells/3mL). Patient characteristics, CSF-CTC enumeration at diagnosis, and therapeutic interventions post-LM were collected. Median overall survival (OS) with IQRs were calculated.

RESULTS

A total of 626 patients with LM were identified. The median age at LM diagnosis was 59 years (range, 13-86) with a female predominance (72.5%). Primary malignancy consisted of lung (45.2%), breast (35.7%), melanoma (4.0%), and other (15.1%). The 20-year median OS in patients with lung cancer was 4.8 months (1.9-13.0), breast cancer was 6.1 months (2.0-13.7), and melanoma was 7.1 months (2.8-14.5). Median OS was prolonged in patients with a CSF-CTC count ≤ 50 versus > 50 (8.9 vs 3.4 months, p< 0.0001). Patients who received LM-directed proton craniospinal irradiation (17.1%), photon involved-field radiation (45.5%), and no radiation (37.4%) had a median OS of 8.7 months (4.3-20.2), 4.3 months (1.5-9.1), and 3.4 months (1.2-12.5), respectively. Patients diagnosed with LM between 2017-2022 trended towards superior median OS (6.2 months, 2.2-14.0) compared to those diagnosed between 2002-2016 (5.3 months, 2.2-12.2).

CONCLUSION

In this largest known series of patients with LM, outcomes show signs of improvement. Superior survival trends emerge based on primary malignancy, early detection, and modern treatment modalities. Further analyses will define survival trends by patient characteristics, cancer subtypes, and systemic therapies.
EPID-05. PATTERNS OF RECOMMENDATION FOR SURGICAL INTERVENTION IN GRADE II, III, AND IV ASTROCYTOMAS: IMPLICATIONS FOR DELAYED DIAGNOSIS AND TREATMENT
Authors: Yekula Anudeep , Zhu Ping , Chen Clark
Published: November 2023

INTRODUCTION

Timely surgical acquisition of tumor tissue for definitive diagnosis forms the foundation for early cancer diagnosis and treatment. Here we examined the pattern of surgical recommendations in the treatment of intracranial astrocytoma.

METHODS

Grade 2, 3, and 4 astrocytoma (abbreviated as A2, A3, and A4) patients who underwent biopsy for histologic diagnosis were identified in NCDB (2010-2021) and SEER (2004-2019) and divided into those who received recommendation for biopsy on initial presentation and those who received recommendation against surgery but ultimately underwent biopsy. Demographic, clinical characteristics, and survival outcomes of these cohorts were compared.

RESULTS

In both the NCDB and the SEER, patients ultimately diagnosed with A2 (NCDB: aOR=1.88, p< 0.001; SEER: aOR=1.77, p< 0.001) and A3 (NCDB: aOR=1.97, p< 0.001; SEER: aOR=1.78, p< 0.001) were less likely to receive recommendation for biopsy during initial encounter relative to patients with glioblastoma after adjusting the covariates. Other factors associated with decreased likelihood of recommendation for biopsy included: advanced age, deep cortical/infratentorial location, and smaller tumor size. These findings remain robust after accounting for dehydrogenase (IDH) mutation status, which was available in the NCDB after 2018. In a multivariable model accounting for survival-pertinent variables, including medical comorbidities, A2 (NCDB: aHR=1.23, p=0.006; SEER: aHR=1.15, p=0.039) and A3 (NCDB: aHR=1.44, p< 0.001; SEER: aHR=1.53, p< 0.001) patients who received recommendation against biopsy during initial encounter exhibited worse survival.

CONCLUSION

Patients with A2 and A3 are more likely to receive recommendation against surgical intervention on initial encounter. The associated survival pattern bears relevance to the potential impact of delayed diagnosis and treatment.
EPID-07. DISTANT PROGRESSION TO THE POSTERIOR FOSSA IN SUPRATENTORIAL GLIOBLASTOMA: A REPORT OF THREE CASES DURING TUMOR TREATING FIELDS THERAPY
Authors: Kiyokawa Juri , Tamura Kaoru , Shimizu Kazuhide , Ota Tetsuo , Imae Shogo , Sakashita Mai , Yamamoto Shinji , Maehara Taketoshi
Published: November 2023

BACKGROUND

Distant progression of supratentorial glioblastoma (GBM) to the posterior fossa is rare. We report three cases in which such distant progression was observed during Tumor Treating Fields (TTFields) therapy. CASES: All three cases involved solitary supratentorial tumors. Biopsy was performed in case 1 (61-year-old male) and partial resection in cases 2 (69-year-old female) and 3 (73-year-old male). The diagnosis was IDH-wildtype GBM in all three cases. TTFields therapy was performed following chemoradiotherapy. In case 1, distant progression was observed in the dorsal side of the medulla oblongata at 7 postoperative months and in the left cerebellum at 23 postoperative months. The patient died 5 months later. In case 2, distant progression was evident in the pons at 41 postoperative months and the patient died 3 months later. In case 3, distant progression was observed in the cerebellum at 5 postoperative months and the patient died 3 months later. Autopsy was performed in case 1 and revealed multiple separate GBM lesions in the supra- and infratentorial space. Although there was histological heterogeneity within lesions, there was no clear histological difference between supra- and infratentorial lesions.

DISCUSSION

In the EF-14 trial, although there were no cases of GBM progression to the posterior fossa in the control group who did not receive TTFields therapy (0/122 cases), such progression occurred in 3.6% (11/306) of cases in the TTFields-treated group (p< 0.001). Even though TTFields therapy affords good local control of GBM, distant progression might occur in the posterior fossa, where the electric field effect is poor. Further accumulation and analysis of such cases is warranted.
EPID-11. THE IMPACT OF THE COVID-19 PANDEMIC ON TREATMENT PATTERNS IN GLIOBLASTOMA
Authors: Neff Corey , Price Mackenzie , Cioffi Gino , Waite Kristin , Kruchko Carol , Bryan Iorgulescu J , Barnholtz-Sloan Jill , Ostrom Quinn
Published: November 2023

BACKGROUND

The COVID-19 pandemic and subsequent shutdowns led to significant disruptions in medical care and access to treatment for all medical conditions in the US in 2020. Institutional cohorts and survey-based studies have shown that there was significant care disruption for individuals diagnosed with primary brain tumors. In this analysis, we utilized a database containing ~80% of brain tumor diagnoses to assess the national impact of the pandemic on treatment patterns for glioblastoma.

METHODS

Data on newly diagnosed glioblastoma were obtained from the National Cancer Database, which includes hospital registry data from Commission on Cancer accredited facilities, for diagnosis years 2018-2020. Logistic regression was used to generate odds ratios (OR) of receiving resection, chemotherapy, or radiation after diagnosis in 2020 as compared to 2018-2019, after adjustment for potential confounders, including age at diagnosis, sex, race and ethnicity, insurance status, income, patient distance from diagnosing facility, Charlson comorbidity score, facility type and location, and MGMT methylation.

RESULTS

There were 7,184 glioblastoma, of which 5,873 were IDH-wt, diagnosed in 2020, a 3% decrease from the 2018-2019 average. For individuals with any newly diagnosed glioblastoma, there was a decrease in odds of resection (OR=0.91, p=0.047). Among those with any glioblastoma and a subset with IDH-wt glioblastoma there was a reduction in odds of radiation (OR=0.87, p=0.004 and 0.85, p< 0.001, respectively) and chemotherapy (OR=0.87, p=0.002 and 0.89, p=0.026, respectively). No decrease in odds of treatment was associated with a prior positive SARS-CoV-2 PCR test.

CONCLUSIONS

The COVID-19 pandemic caused significant disruption to health care for cancer patients in the US in 2020. For individuals with glioblastoma, in-person treatments decreased in frequency for individuals diagnosed in 2020 as compared to prior years. Further research is required to determine the impact this treatment disruption had on outcomes.
EPID-12. SURVIVAL IS ASSOCIATED WITH CIRCULATING B-CELLS AND AGE AMONG OLIGODENDROGLIOMA PATIENTS
Authors: Taylor Jennie , Warrier Gayathri , Hansen Helen , McCoy Lucie , Rice Terri , Guerra Geno , Francis Stephen , Clarke Jennifer , Bracci Paige , Kelsey Karl , Wrensch Margaret , Molinaro Annette , Wiencke John
Published: November 2023

BACKGROUND

Though patients with oligodendroglioma have improved outcomes versus astrocytomas, there remains marked variability in their survival experience that is unexplained by known prognostic factors. Immunomethylomics uses DNA methylation as a substitute for flow cytometry to characterize immune cells in whole blood.

METHODS

We applied immunomethylomics to archived blood samples from patients enrolled in the UCSF Adult Glioma Study including oligodendrogliomas (141); other adult diffuse glioma subtypes (347); and controls (454).

RESULTS

Median age of oligodendrogliomas was 44 years (range 19 – 83), 57% male, 75% white, and 60% received chemotherapy prior to blood draw. Oligodendroglioma patients had lower percent of B cell fractions (total, memory, naïve) than people without glioma. They also had higher percent of B cell (total, memory) and lymphocyte fractions (total, CD4-total and memory), basophil, eosinophil, and NK cells versus other glioma subtypes. Median overall survival in oligodendrogliomas was 17.5 years (95% CI 16.9 - NA) with median follow-up of 12 years (95% CI 11 – 14). Recursive partitioning analysis delineated two survival groups for oligodendroglioma patients based on age and percent B naïve cells. Best outcome, with median survival of 24.2 years (95% CI 20.4 – NR), was seen in patients < /= 42 years of age with a higher percent of B naïve cells ( >1.91%) (N = 37). Worst outcome, with median survival of 16.9 years (14.8 – NR), was seen in patients < /= 42 years of age with a lower percent of B naïve cells (< /= 1.91%) (N = 28) OR patients > 42 years of age (N = 76) (p = 0.00032).

CONCLUSIONS

An interaction between age and B naïve cell percentages may predict survival for oligodendroglioma patients. Immunomethylomics is a powerful tool for assessing immune status and these findings suggest that blood-immune profiles may be prognostic glioma patients.
EPID-14. ASSOCIATION OF ELEMENTAL IRON WITH GLIOBLASTOMA PATIENT OUTCOMES
Authors: Shenoy Ganesh , Kuhn Madison , Sahu Aurosman , Khristov Vladimir , Heebner Madison , Wilding Hannah , Clegg Taylor , Bhanja Debarati , Wade Quinn , Liermann Laura , Wang Dongxiang , Smith Nataliya , Khunsriraksakul Chachrit , Palsa Kondaiah , Slage-Webb Becky , Zacharia Brad , Proctor Elizabeth , Connor James R
Published: November 2023

Very few studies have examined the role of trace metals, such as iron, in glioblastoma biology and patient outcomes. Here we directly measured iron content in matched glioblastoma tumor and plasma samples using inductively coupled plasma mass spectroscopy (ICP-MS) or inductively coupled plasma atomic emission spectroscopy (ICP-AES), and then studied associations of iron with clinical parameters such as median overall survival (mOS). Elemental iron analysis was performed on a total of 31 glioblastoma samples, 21 of which had matched plasma samples that were analyzed together. Plasma samples from age-matched healthy volunteers were used as a control for comparisons against plasma from glioblastoma patients. Plasma samples from glioblastoma patients had higher levels of iron compared to age-matched healthy control samples (1307.2 ng/mL vs. 575.2 ng/mL, P = .000013). Among glioblastoma patients, higher levels of plasma iron were associated with prolonged survival (mOS: 20.7 months vs. 12.4 months, P = 0.0063). Plasma iron levels, however, were not significantly correlated with tumoral iron levels (R = 0.095, P = 0.70), indicative of regulation between plasma and brain iron. Unsurprisingly, high tumor iron content failed to significantly associate with survival. To gain insights into whether iron may be associated with immune function, we analyzed plasma samples with multiplexed immunoassays. Glioblastoma plasma samples that contained higher levels of iron were associated with increased IFN-β (10.91 pg/mL vs 7.43 pg/mL, P = 0.004) and PDGF-AB/BB (1275.3 pg/mL vs 492.8 pg/mL, P = 0.009), whereas no such association was observed in healthy plasma samples. Our results demonstrate that plasma iron is associated with clinical outcomes and potentially with alterations in IFN-β and/or PDGF-AB/BB signaling in glioblastoma patients. These findings illustrate the importance of iron in glioblastoma biology and demonstrate its potential prognostic value.
EPID-16. A MULTI-CENTER, PROGRESSION-FREE SURVIVAL ANALYSIS IN IDH-MUTANT GLIOMAS WITH CDKN2A DELETION: IMPLICATIONS FOR PROGNOSIS AND CLINICAL TRIAL DESIGN
Authors: Miller Julie , Hsieh Annie , Nohman Amin , Reuss David , Eyuepoglu Ilker , Cahil Daniel , Jungk Christine , Juratli Tareq
Published: November 2023

Homozygous deletion of CDKN2A is an important predictor of poor prognosis in patients with IDH-mutant gliomas. The updated 2021 WHO classification now recognizes this alteration as sufficient for the designation of an astrocytoma, IDH-mutant, WHO Grade 4, which otherwise requires histological observation of necrosis or microvascular proliferation. While overall survival patterns associated with CDKN2A deletion have been well-described, we sought to characterize progression-free survival (PFS) in this patient population. Across three institutions (Massachusetts General Hospital, Boston; University Hospital Heidelberg, Heidelberg; TU Dresden, Dresden), we identified 48 patients with IDH-mutant gliomas in which CDKN2A deletion was detected at the time of diagnosis, followed for a median of 15.2 years. The average age of the cohort is 35 years, with 60% of the patients identified as male. Most patient received immediate treatment after surgery, with 81% of the cohort undergoing radiation therapy and 73% receiving chemotherapy. Based on RANO criteria, the median progression-free survival of this patient population is 2.8 years (95% CI 1.4 – 3.3 years) and median overall survival is 4.3 years (95% CI 2.1 – 6.6 years). A positive T2/FLAIR mismatch sign or lack of contrast enhancement on MRI at the time of diagnosis are both associated with improved PFS in univariate regression analysis. For comparison, we identified a control cohort of 51 patients with astrocytoma, IDH-mutant, grade 4 without CDKN2A deletion from MGH, achieving grade 4 by histologic criteria. Demographics were similar to the CDKN2A-deleted cohort, with median age (37 years) and percentage of male patients (60%). Notably, however, PFS for the grade 4, CDKN2A-intact, IDH-mutant glioma comparison group is estimated at 5.9 years (95% CI 3.3 – 7.9 years). Overall, these data reinforce the accelerated disease course associated with deletion of CDKN2A in IDH-mutant gliomas, providing an important reference for clinical trial design.