bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDDR-31. TARGETING CANCER STEM CELLS WITH A CDK2 INHIBITOR IN GLIOBLASTOMA
Authors: Mahmoudian Elham , Qu Dianbo , Jahani-Asl Arezu 
Published: November 2023

Abstract
Glioblastoma (GB) is the most common and aggressive adult brain tumor with no cure. Brain tumor stem cells (BTSCs) are a rare population of self-renewing multipotent stem cells in GB that contribute to tumorigenesis, therapeutic resistance and tumour recurrence. Here, we report a CDK2 inhibitor that suppresses BTSCs via OSM/OSMR/STAT3 signalling pathway. To begin with we performed high throughput screening (HTS) of ~8400 compounds including FDA-approved drugs in patient derived human BTSCs that naturally harbour EGFRvIII mutation and elevated STAT3 phosphorylation, in search of compounds that can suppress EGFRvIII/OSMR/STAT3 oncogenic pathway. The screen led to the identification of a panel of CDK inhibitors that possessed important characteristics including a) ability to cross the blood-brain barrier with mall molecular weights of 277-566 kDa, b) low Topological Polar Surface Area (TPSA) of 76-115 A°, c) a low number of Hydrogen Bond Donors (HBDs) (1-4), and d) cLogP values ranging from 2-4. Following counter screens, we focused on a CDK2 inhibitor that significantly and most efficiently reduced OSM/OSMR signalling and STAT3 activation. Importantly, we found that the compound inhibited the self-renewal and growth of BTSCs in EGFRvIII subtype of BTSCs. This research has led to future investigation on in vivo assessment of this CDK2 inhibitor in combination with ionizing radiation and chemotherapy in preclinical models of GB.
DDDR-33. TNG908, A BRAIN-PENETRANT MTA-COOPERATIVE PRMT5 INHIBITOR, IS EFFICACIOUS IN PRECLINICAL MTAP-DELETED MODELS INCLUDING GLIOBLASTOMA
Authors: Zhang Minjie , Tsai Alice , Cottrell Kevin , Wilker Erik , Davis Charles , DiBenedetto Heather , Weitzman Ron , Huang Alan , Maxwell John , Briggs Kimberly 
Published: November 2023

Abstract
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) with standard of care therapies, demonstrating the significant need for the development of novel therapeutics. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that is selectively active in MTAP-deleted cells by leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors have MTAP loss due to a co-deletion event with the proximal tumor suppressor gene, CDKN2A. In preclinical in vitro studies, TNG908 was 15-fold more potent in MTAP-deleted cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is neither a substrate for P-glycoprotein nor Breast Cancer Resistant Protein (BCRP) efflux transporters. Consistent with these favorable attributes, TNG908 demonstrated in vivo brain penetration in multiple preclinical models, including non-human primates and mice. TNG908 on-target pharmacodynamic activity was determined by dose-dependent decreases in SDMA-modified protein levels in a GBM subcutaneous xenograft model. TNG908 demonstrated dose-dependent antitumor activity in multiple hyper- and hypomethylated GBM subcutaneous models, including cell lines and patient-derived xenograft models. Despite 6-fold reduced Kpuu in rodents (Kpuu ~0.15) relative to non-human primates (Kpuu 0.9), oral administration of TNG908 drove near tumor stasis and increased median survival by 3-fold in a highly aggressive murine GBM orthotopic model. In summary, TNG908 is a potent, brain-penetrant, MTA-cooperative PRMT5 inhibitor that drives strong antitumor activity in preclinical models of MTAP-deleted GBM. TNG908 is currently enrolling patients with MTAP-deleted tumors including glioblastoma in a Phase I/II clinical trial (NCT05275478).
EPID-03. SEX DIFFERENCES IN ODDS OF BRAIN METASTASIS AND OUTCOMES BY BRAIN METASTASIS STATUS AFTER ADVANCED MELANOMA DIAGNOSIS
Authors: Cioffi Gino , Ascha Mustafa , Dmukauskas Mantas , Waite Kristin , Wang Xiaoliang , Royce Trevor , Calip Gregroy , Waxweiler Timothy , Rusthoven Chad , Kavanagh Brian , Barnholtz-Sloan Jill 
Published: November 2023

Abstract
Sex differences in cancer are well-established. However, less is known about sex differences in diagnosis of brain metastasis and outcomes among individuals with advanced melanoma. Using the nationwide Flatiron Health electronic health record-derived deidentified database, we evaluated individuals diagnosed with advanced melanomafrom 1/1/11-07/30/22 who received oncologist-defined rule-based first line of therapy (N = 7,969, 33% female according to EHR, 35% w/ documentation of brain metastases). Odds of documented brain metastasis diagnosis were calculated using multivariable logistic regression adjusted for age, practice type, diagnosis period (pre/post-2017), ECOG performance status, anatomic site of melanoma, group stage, documentation of non-brain metastases prior to first-line of treatment, and BRAF positive status. Real-world overall survival (rwOS) and progression-free survival (rwPFS) starting from first-line initiation were assessed by sex, accounting for brain metastasis diagnosis as a time-varying covariate using the Cox proportional hazards model, with the same adjustments as the logistic model, excluding group stage, also adjusting for race, socioeconomic status, and insurance status. Adjusted analysis revealed males with advanced melanoma were 22% more likely to receive a brain metastasis diagnosis compared to females (aOR: 1.22, 95% CI:1.09, 1.36). Males with brain metastases had worse rwOS (aHR: 1.15, 95% CI:1.04, 1.28) but not rwPFS (aHR: 1.04, 95% CI: 0.95, 1.14) following first-line treatment initiation. Among individuals with advanced melanoma not diagnosed with brain metastases, survival was not different by sex (rwOS aHR: 1.06 [95% CI: 0.97, 1.16], rwPFS aHR: 1.02 [95% CI: 0.94, 1.1]). This study showed that males had greater odds of brain metastasis and, among those with brain metastasis poorer rwOS compared to females, while there were no sex differences in clinical outcomes for those with advanced melanoma without brain metastasis.
EPID-10. CNSONTRK STUDY: CLINICAL CHARACTERISTICS AND OUTCOME OF CENTRAL NERVOUS SYSTEM TUMORS HARBORING NTRK GENE FUSIONS
Authors: Lamoureux Audrey-Anne , Fisher Michael , Lemelle Lauriane , Pfaff Elke , De Wilde Bram , Pfister Stefan , Sturm Dominik , Orbach Daniel , Raskin Scott , Drilon Alexander , Zapotocky Michal , Barritault Marc , Leblond Pierre , Tabori Uri , Hawkins Cynthia , Hansford Jordan , Erker Craig , Gottardo Nicholas , Nørøxe Dorte , Goto Hiroaki , Ziegler David , Liu Yen-Lin , Hwang Eugene , Aguilar-Bonilla Ana , Cheng Sylvia , Cacciotti Chantel , Massimino Maura , Wood Paul , Hoffman Lindsey , Lassaletta Alvaro , Gerber Nicolas , Ceruso Mariella Spalato , Bendel Anne , Abadi Christina Coleman , Mueller Sabine , Aguilera Dolly , Robison Nathan , O’Halloran Katrina , Abbou Samuel , Geoerger Birgit , Øra Ingrid , Moertel Christopher , Razis Evangelia , Seizeur Romuald , Clarke Matthew , Doz François , Laetsch Theodore , Perreault Sébastien , Ellezam Benjamin , Alves Mélanie 
Published: November 2023

Abstract

BACKGROUND
TRK fusions are detected in less than 2% of central nervous system (CNS) tumors. There are limited data on the clinical course of affected patients.

METHODS
We conducted an international retrospective cohort study of patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, TRK gene fusion, treatment modalities and outcomes. The growth modulation index (GMI) was calculated as a ratio of time to progression with TRK inhibitors to time to progression with the prior line of therapy.

RESULTS
119 patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 4.5 years (range 0.0–78.3); 101 (85.6%) were &lt; 18 and 45.3% were &lt; 3 years of age. The most frequent tumor location was hemispheric (63.8%). Tumor types included 68 high-grade gliomas (HGG; 57.1%), 33 low-grade gliomas (LGG; 27.7%), 5 embryonal tumors (4.2%) and 13 others (10.9%). Median follow-up was 38.5 months (range 0.03–229.3). Pediatric patients had a better prognosis with a median OS of 185.5 months compared to 24.8 months in adults (p&lt; .0001). Patients with LGG also had a better outcome with median OS that was not reached for LGG compared to 99.5 months for HGG and 38.5 months for embryonal tumors (p=0.0012). Out of 16 evaluable treatment regimens with larotrectinib an objective response was reported in 11 (11/16 (68.8%)-4 CR, 5 PR and 2 MR) compared to 38.1% for non-targeted treatment regimens (24/63 (38.1%)-10 CR, 13 PR and 1 MR). The GMI was 2.11 for pediatric patients treated with larotrectinib.

CONCLUSIONS
We report a large cohort of patients with TRK fusion-driven primary CNS tumors. Children with LGG glioma had a favorable outcome compared to adult and HGG. Larotrectinib appears to be associated with a better response rate and longer duration of response compared to non-targeted therapy.
EPID-15. SEX-SPECIFIC DIFFERENCES IN GLIOBLASTOMA IN THE RESPOND CONSORTIUM
Authors: Gongala Sree , Garcia Jose , Korakavi Nisha , Patil Nirav , Akbari Hamed , Tippareddy Charit , Sloan Andrew , Barnholtz-Sloan Jill , Bakas Spyridon , Kazerooni Anahita Fathi , Sako Chiharu , Baid Ujjwal , Brem Steven , Lustig Robert A , Capellades Jaume , Nasrallah MacLean , O'Rourke Donald M , LaMontagne Pamela , Marcus Daniel S , Balana Carmen , Puig Josep , Waite Kristin , Colen Rivka , Choi Yoon Seong , Lee Seung-Koo , Dicker Adam P , Flanders Adam E , Shi Wenyin , Griffith Brent , Poisson Laila M , Rogers Lisa R , Booth Thomas C , Jain Rajan , Chakravarti Arnab , Palmer Joshua , Mohan Suyash , Tiwari Pallavi , Aboian Mariam , Ahn Sung Soo , Davatzikos Christos , Badve Chaitra 
Published: November 2023

Abstract

AIM
The goal of this study was to understand sex-specific differences in the molecular, clinical and radiological tumor parameters and survival outcomes of Glioblastoma (GBM) patients within the international GBM dataset, known as the ReSPOND (Radiomic Signatures for PrecisiON Diagnostics) consortium.

METHODS
Sex-based differences were retrospectively studied in 1922 GBM patients from the ReSPOND consortium which includes information from over 14 institutions across 3 continents. The parameters include age, Methylguanine-DNA Methyltransferase (MGMT) promoter methylation status, isocitrate dehydrogenase 1 (IDH1) mutation status, Karnofsky performance status (KPS), extent of resection (EOR), tumor epicenter, volumes, laterality and spatial extent. Non-parametric tests, log-rank test and cox-proportional hazard analysis were performed to understand sex-based differences in tumor parameters, survival rates and hazard ratios. Spatial atlases were generated to understand radiological parameters such as tumor spatial extent.

RESULTS
GBM in was diagnosed at a median age of 62.6 years in females compared to 61 years in males (p = 0.001). Additionally, 44% females compared to 37% males (p = 0.04) had methylated MGMT and 79% females compared to 73% males (p = 0.004) had IDH1 wildtype. The tumor volumes were smaller in females (necrotic core, edema, and enhancing tumor) compared to males. Females exhibited a higher prevalence of right hemisphere (39.6%) and right temporal lobe tumors (19.7%), while males showed a higher prevalence of left hemisphere (40.3%) left temporal lobe tumors (23.7%). No significant sex-based differences in OS and PFS was observed in overall sample, although longer PFS was observed in elderly (above 60 years) female patients.

CONCLUSION
This is a first international large cohort study looking at sex-based differences in GBM patients using the ReSPOND consortium data. Several sex-specific differences in the distribution of various tumor phenotypes were noted, however sex was not a contributing factor in OS and PFS.
EPID-29. ASSOCIATIONS BETWEEN PM2.5, VEGETATION DENSITY AND CHILDHOOD BRAIN TUMORS: A CASE-CONTROL REGISTRY-BASED STUDY FROM TEXAS 1995-2011
Authors: Williams Lindsay , Haynes David , Sample Jeannette , Hossaini Ali , McGuinn Laura , Hoang Thanh , Lupo Philip , Scheurer Michael 
Published: November 2023

Abstract

BACKGROUND
Air pollution has been reported to be associated with childhood leukemia, and increasing vegetation density (greenness) has been inversely associated with adult cancer incidence. However, the interplay between air pollution and greenness in childhood brain tumor (CBT) etiology is unclear. We sought to estimate the association between prenatal exposure to air pollution, greenness, and CBTs in Texas (1995-2011). Materials and

METHODS
We included 1,316 individuals with a CBT diagnosed ≤ 16 years of age and 109,762 age- and sex-matched controls. We linked birth certificate residential address to census tract annual average particulate matter 2.5 µg/m³ (PM2.5) and Normalized Difference Vegetation Index (NDVI) to approximate prenatal exposure to air pollution and greenness. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) between CBTs, PM2.5 and NDVI interquartile range (IQR) increases. Models were adjusted for birth year, sex, race/ethnicity, and area-level socioeconomic status.

RESULTS
Ependymoma (n=136), astrocytoma (n=619), medulloblastoma (n=187), PNET (n=57), ATRT (n=54), and other gliomas (n=263) were included. Average birth year PM2.5 and NDVI exposure levels were similar in cases and controls, 11 µg/m³ and 0.4, respectively. Each IQR increase (2.6µg/m³) in PM2.5 was associated with ependymoma (OR: 1.27, 95% CI: 1.01-1.60), adjusting for NDVI. After adjusting for PM2.5 quartiles, each IQR increase in NDVI (0.13) was inversely associated with ependymoma in those diagnosed at 0-4 years of age (OR: 0.75, 95% CI: 0.56-0.97) and medulloblastoma in those aged 0-16 years at diagnosis (OR: 0.75, 95% CI: 0.62-0.91). There was no evidence of statistical interaction for any CBT.

CONCLUSIONS
Increasing air pollution during the prenatal period increased risk of childhood ependymoma, independent of greenness. Conversely, increasing greenness prenatal exposure decreased the risk of ependymoma and medulloblastoma, independent of PM2.5. These findings highlight the complex relationship between air pollution and greenness in CBT etiology.
EPID-33. MORTALITY AND CAUSE OF DEATH RELATED TO CLINICAL AND GENETIC SEVERITY IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2 – SCHWANNOMATOSIS
Authors: Weigert Lisa , McLean Anna Lawson , Freier Anna , Farschtschi Said , Rosahl Steffen 
Published: November 2023

Abstract

OBJECTIVES
This study aimed to investigate the circumstances of death in NF2 patients, focusing on clinical and genetic severity.

METHODS
Data from three major German NF2 centers were analyzed retrospectively. A total of 199 patients were included, with follow-up periods ranging from 6 months to 30 years. Disease severity was assessed using clinical and genetic classification scales with three grades each. At the time of data analysis, 36 patients had died in all three centers combined.

RESULTS
Of the 36 deceased patients, 47.2% had moderate clinical severity, 38.9% had severe disease, 13,9% were classified as grade 1. Genetic severity could be determined for 15 patients with 66.7% categorized as a moderate NF2 and 20.0% as genetically severe NF2. Only 13.3% had tissue mosaicism associated with a mild genetic severity. Patients with moderate clinical severity died at a mean age of 44.5 years (± 20.97), patients in grade 3 died at 46.89 years (± 11.71), and grade 1 patients died at 35.1 years (± 31.36) in this cohort. Patients with the highest genetic severity score died earlier (mean age = 35.5 years ± 2.29) than those with a moderate severity (51.3 years ± 21.65). The most common causes of death were malignant neoplasms, cerebral insults, and pneumonia, each accounting for three of the cases. Other causes of death included road traffic fatalities, septic shock, cerebral compression, and suicide, with 16.6% of cases involving attempted suicide.

CONCLUSIONS
The study emphasizes the need for a wider registry to assess prognosis, to stratify major risk factors causing mortality in NF2 and to verify correlations to clinical and genetic severity scales. Increased suicide and attempted suicide rates among NF2 patients highlight the importance of psychological counseling in patient management.
EPCO-29. SEXUALLY DIMORPHIC EFFECT OF H-FERRITIN GENETIC MANIPULATION ON SURVIVAL AND IMMUNE CELL INFILTRATION IN A MOUSE MODEL OF GLIOBLASTOMA
Authors: Shesh Bhavyata (Pandya) , Walter Vonn , Slage-Webb Becky , Neely Elizabeth , Connor James R 
Published: November 2023

Abstract
Iron plays a crucial role in promoting tumor growth. Recent research has shown that H-ferritin (FTH1), traditionally recognized as an iron storage protein, can transport iron to GBM cancer stem cells, reducing their invasion activity. Moreover, binding of extracellular FTH1 to human GBM tissues, and brain iron delivery in general, has been found to have a sex bias. This raises questions addressed in this study about whether H-ferritin levels extrinsic to the tumor can affect tumor cell pathways and if this impact is sex-specific. Systemic Fth1+/- mice were orthotopically implanted with mouse GBM cells (GL261). Littermate Fth1 +/+ mice were controls. Survival was evaluated and the tumors were subjected to next-generation sequencing protocols. We analyzed resulting data utilizing murine Microenvironment Cell Population (mMCP) method. mMCP estimates abundance of tissue infiltrating immune and stromal populations based on cell-specific gene signatures. Female Fth1+/- mice had significantly poorer survival than control females. Fth1 genetic status had no effect on survival in males. mMCP analysis revealed a significant reduction in T cells and CD8+ T cell infiltration tumors of Fth1+/- females as compared to Fth1+/+. Mast and fibroblast cell infiltration was increased in females and males with Fth1+/- background, respectively, compared to Fth1+/+ mice. Genetic manipulation of Fth1 which leads to reduced systemic levels of FTH1 protein had a sexually dimorphic impact on survival. Fth1+/- significantly worsened survival in females but not in male GBMs. Furthermore, genetic manipulation of Fth1 significantly affected tumor infiltration of T-cells, CD8+ T cells, fibroblasts, and mast cells in a sexually dimorphic manner. These results demonstrate a role for FTH1 and presumably iron status in establishing the tumor cellular landscape that ultimately impacts survival and further reveals a sex bias that may inform the population studies showing a sex effect on the prevalence of brain tumors.
EPCO-39. CLARIFYING THE MOLECULAR CONSEQUENCES OF ONCOGENIC MUTATIONS THROUGH MULTISCALE AND MULTIOMIC ANALYSIS OF INDIVIDUAL TUMORS
Authors: Schupp Patrick , Shelton Samuel , Brody Daniel , Eliscu Rebecca , Johnson Brett , Mazor Tali , Kelley Kevin , Potts Matthew , McDermott Michael , Huang Eric , Lim Daniel , Pieper Russell , Berger Mitchel , Costello Joseph , Phillips Joanna , Oldham Michael 
Published: November 2023

Abstract
Understanding the molecular consequences of oncogenic mutations is an important goal that may reveal essential features of malignant cells and new therapeutic targets for diverse cancers. However, this task is complicated by substantial inter- and intra-tumoral heterogeneity, which obscure the molecular consequences of oncogenic mutations in malignant cells. Although single-cell methods hold promise for this task, it remains non-trivial to isolate DNA and RNA from the same cell at scale. Here we describe a statistically motivated strategy that controls for inter-tumoral heterogeneity and exploits intra-tumoral heterogeneity to reveal the most consistent molecular phenotypes of malignant cells. By combining deep, multiscale sampling of IDH-mutant astrocytomas with integrative, multiomic analysis, we reconstruct and validate the phylogenies, spatial distributions, and molecular profiles of distinct malignant clones. Importantly, by genotyping nuclei for driver mutations, we show that existing strategies for inferring malignancy from gene expression profiles of single cells may be inaccurate. We identify genes that are consistently upregulated in the truncal clone of IDH-mutant astrocytomas, which are significantly enriched with genes involved in RNA splicing, mRNA transport and the nuclear pore, and WNT / MYC signaling. Furthermore, we find that expression phenotypes of malignancy persist despite loss of the mutant IDH1 protein following chr2q deletion in a subset of malignant cells. More broadly, our work provides a generalizable strategy for precisely deconstructing intra-tumoral heterogeneity and determining the most robust molecular consequences of oncogenic mutations in any kind of solid tumor.
EPCO-45. CELLULAR HIERARCHIES OF ETMR ARE SHAPED BY ONCOGENIC MICRORNAS AND RECEPTOR-LIGAND INTERACTIONS
Authors: Gabler Lisa , Beck Alexander , Cruzeiro Gustavo , Lambo Sander , Englinger Bernhard , Shaw McKenzie L , Hack Olivia , Chi Susan , Alexandrescu Sanda , Gojo Johannes , Kool Marcel , Hovestadt Volker , Filbin Mariella 
Published: November 2023

Abstract
Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive brain tumor that predominantly occurs in children under the age of four years. Most children succumb within 10 months of diagnosis, typically due to invasive tumor growth and therapy-refractory behavior. 95% of ETMR harbor activating genetic alterations of the chromosome 19 microRNA cluster (C19MC). Despite the identification of this presumed oncogenic driving event, its biological consequences remain understudied and targeted therapy options are lacking. Here, we set out to further explore the intracellular heterogeneity of ETMR and shed light onto its oncogenic mechanisms with the goal to identify novel therapeutic targets for this dismal disease. We have compiled and analyzed a cohort of 11 ETMR tumors using single-cell RNA sequencing and multiplexed spatial imaging. We reveal a common, spatially distinct cellular hierarchy, closely resembling physiological brain development. This hierarchy spans a highly proliferative neural stem cell-like population that gives rise to more differentiated neuron-like cells. C19MC, predominantly expressed in the malignant stem-like population, controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA interactions. Targeting specific C19MC members by antisense oligonucleotides results in reduced cell proliferation, suggesting potent new avenues for future therapeutic approaches. Seeking more immediate therapeutic targets, we performed comprehensive cell-cell interaction analyses and reveal that FGF-FGFR and Delta-Notch interactions are important to maintain oncogenic signaling across malignant cell populations. These interactions were successfully targeted using small molecule inhibitors in preclinical models and in one ETMR patient. Taken together, we identify different malignant ETMR cell populations that follow a common developmental hierarchy, explore the regulatory reach of C19MC activation, and identify an oncogenic receptor-ligand interaction network. Targeting this interaction network opens a powerful new rationale for more effective ETMR therapies.