bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNSC-40. HARNESSING EVOLUTIONARY CONSTRAINT IDENTIFIES POTENTIAL NON-CODING DRIVERS IN BRAIN TUMORS
Authors: Roy Ananya , Pensch Raphaela , Sakthikumar Sharadha , Kozyrev Sergey V , Nordin Jessika , Mäkeläinen Suvi , Jansson Ylva , Pettersson Mats , Karlsson Elinor , Lindblad-Toh Kerstin , Forsberg-Nilsson Karin 
Published: November 2023

Abstract
The somatic mutational landscape of brain tumors has primarily focused on coding mutations for driver gene discovery. Non-coding mutations can drive cancer by targeting regulatory elements and be valuable biomarkers and therapeutic targets. However, their identification and functional impact have been elusive. Here, we apply evolutionary constraint (phyloP scores, a constraint metric from sequence alignment of 241 mammals) to whole genome sequencing data from three different brain tumors; pilocytic astrocytoma (PA), medulloblastoma (MB), and glioblastoma (GBM) to identify non-coding constraint mutations (NCCMs) with regulatory potential. NCCM rates (phyloP ≥ 1.2) differ significantly between these cancers, with low rates of NCCMs in PA reflecting its benign feature and high rates in MB and GBM, in support of their aggressivity and heterogeneity. Many of the NCCMs affect genes that are developmentally regulated and expressed in the brain, hence they could be potential drivers. In PA, a high NCCM frequency only affects the BRAF locus, while in MB, over 500 genes have high levels of NCCMs. Intriguingly, many of these genes are associated with different age of onset, such as NUAK1 in adult patients and HOXB1 in young patients, pointing to different molecular pathways in patient groups. NCCMs in the HOXB locus altered the expression of multiple genes of the cluster in MB cells. In GBM NCCMs with regulatory potential cluster as hotspots in PTEN, LRFN5 and MIR99AHG. We observe an enrichment of NCCMs in the regulatory regions of transcription factors including FOXA1, HOXA9 and EBF1. We conclude that since evolutionary constraint is agnostic to cell type or disease stage, it is a powerful predictor of function. Understanding changes in the non-coding cancer genomes will lead to more robust patient stratification of future treatment.
STEM-14. TARGETING HAUSP IN GLIOMA STEM CELLS INHIBITS MALIGNANT GROWTH AND OVERCOMES RADIORESISTANCE OF GLIOBLASTOMA
Authors: Huang Zhi , Wu Lian , Huang Qian , Zhai Kui , Lathia Justin , Rich Jeremy , Yu Jennifer , Bao Shideng 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most lethal and common type of primary brain tumor highly resistant to current treatments including radiotherapy. GBM contains heterogeneous cancer cells including glioma stem cells (GSCs) that promote malignant growth and therapeutic resistance, indicating that targeting GSCs may effectively improve GBM therapy. Here, we show that HAUSP (USP7, a deubiquitinase) is preferentially expressed by GSCs in the perivascular niches in human GBMs. Disrupting HAUSP by shRNA or its inhibitor P22077 promoted GSC differentiation, impaired GSC growth, and potently inhibited GBM malignant growth, indicating that HAUSP is required for maintaining the self-renewal and tumorigenic potential of GSCs. Moreover, pharmacological inhibition of HAUSP synergized with irradiation (IR) to suppress GBM tumor growth, suggesting that targeting HAUSP may effectively overcome GSC-driven radioresistance to improve therapeutic efficacy for GBM. Our findings uncover a novel role of HAUSP in maintaining GSC phenotypes and tumorigenic potential, and thus offer a promising druggable target for developing anti-GSC therapeutics to improve GBM treatment. Furthermore, our preclinical data suggest that inhibiting HAUSP alone or in combination with IR may prolong the survival of GBM patients.
STEM-17. IMPLICATING ASTROCYTE PROGENITOR SIGNATURES FROM THE DEVELOPING HUMAN SUBVENTRICULAR ZONE IN GLIOBLASTOMA PROGRESSION AND RECURRENCE
Authors: Ramos Susana Isabel , Chang Wan Sze , Zaslavsky Elena , Tsankova Nadejda 
Published: November 2023

Abstract
Although astrocyte-like progenitors in the adult subventricular zone (SVZ) have been put forward as the glioblastoma (GBM) cell of origin, the mechanisms that trigger astrogenesis in the developing SVZ are poorly understood. We previously reconstructed astrocyte lineages using computational tools and identified PDGFRβ+ astrogenesis-committed radial glia (RG-A) and EGFR+ gliogenic intermediate progenitor cells (gIPCs). We have, however, yet to identify the transcription factors (TFs) that drive the differentiation of these progenitors in the pre- and postnatal SVZ. As malignant cells are known to co-opt neurodevelopmental pathways, the exploitation of TF driver vulnerabilities in malignant cells could bring novel therapeutic strategies to hinder GBM progression or recurrence. Here, we integrated single nucleus RNA- (snRNA-seq) and ATAC-sequencing (snATAC-seq) datasets from 1) surgically resected GBMs (n = 5), 2) the subventricular zone and neocortex from non-pathological adult cortices (n = 3) and 3) the corresponding germinal matrix and cortical plate of non-pathological cortices ranging from 17 to 41 gestational weeks (n = 17) and 21 to 301 postnatal days in age (n = 9). To prioritize candidate drivers of astrogenesis computationally, we correlated motif enrichment with gene expression over pseudotime in gIPC and RG-A lineages. Subsequently, we projected transcriptional signatures from non-pathological neocortices onto GBMs. Interestingly, we observed high proportions of tumor cells with preferentially enriched prenatal gIPC-like signature in EGFR amplified GBMs and with preferentially enriched postnatal RG-A-like signature in GBMs with PFGFRα or FGFR3 amplification. As tumor recurrence is associated with a mesenchymal-like switch, we were intrigued to find that RG-A-like cells exhibited a mesenchymal-like phenotype in a recurrent GBM. Currently, we are developing an in vitro assay to manipulate the expression of astrogenic drivers and force the differentiation of patient-derived, primary GBM cells into astrocytes; a strategy that we will later apply in patient-derived xenograft models.
STEM-19. POTENTIAL THERAPEUTIC EFFECTS OF NOVEL HISTONE DEACETYLASE INHIBITORS ON HUMAN-DERIVED GLIOBLASTOMA TUMORSPHERES
Authors: Choi Seonah , Kim Seo Jin , Park Junseong , Choi Ran Joo , Moon Ju Hyung , Kim Eui-Hyun , Teo Wan-Yee , Chang Jong Hee , Jeon Raok , Kang Seok-Gu 
Published: November 2023

Abstract

BACKGROUND
Histone deacetylase (HDAC) inhibitor is a promising anticancer drug targeting epigenetic alterations on tumor cells, however, failed to prove its feasibility on glioblastoma (GBM) in several trials. We developed new HDAC inhibitors and applied them to human-derived GBM tumorsphere(TS)s to confirm its therapeutic efficacy to overcome the current limitations. Materials and

METHODS
The expression level of HDAC in GBM versus normal brain tissue was evaluated with RNA sequencing and its knock-down effects were evaluated through western blot, WST, and luciferase assay. The most potential drugs were selected among the candidates through dose-escalation WST assays, and their capacities on HDAC were evaluated through western blot and HDAC activity/inhibition direct assay. The results of the sphere-formation assay, 3D matrix invasion assay, and transcriptome data analysis were compared between the drugs, and bioluminescence images and Kaplain-Meier survival cure were obtained through a mouse model.

RESULTS
HDAC 8 is more expressed in GBM tissue and TSs than normal ones, and the knock-down of HDAC 8 shows decreases in viability, ATP levels, and related proteins. Two potential HDAC 8 inhibitors were selected and compared with suberoylanilide hydroxamic acid (SAHA) through the experiment, which discovered that they not only reduced HDAC’s expression and its activity but also stemness and invasiveness of GBM TSs to comparable levels despite the differences in transcriptional profile changes, with meaningful survival rates in a mouse model.

CONCLUSION
We have newly developed meaningful HDAC inhibitors in the tumorsphere stage, and believe it could be a fundamental result for improving future treatment methods.
CSIG-27. FLUID SHEAR STRESS ACTIVATES A MECHANO-METASTATIC CASCADE TO PROMOTE MEDULLOBLASTOMA METASTASIS
Authors: Min Hyun-Kee , Zhao Hongyu , Huang Xi 
Published: November 2023

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Dissemination of MB cells into cerebrospinal fluid (CSF) and blood initiates metastasis in the central nervous system, which significantly worsens patient prognosis. Disseminated MB cells survive the nutrient-deprived CSF environment and are subjected to fluid shear stress (FSS) by CSF flow. Whether and how FSS contributes to MB metastasis is completely unknown. We computationally simulated FSS dynamics in MB patients using MRI-informed CSF flow models. Based on CSF flow rates and force magnitudes in patients, we engineered two FSS application systems: (1) an orbital shaker system that applies FSS to large populations of cells, and (2) a microfluidic system compatible with live-cell and high-resolution imaging. By applying physiologically relevant FSS to MB cells, we discovered that FSS-treated MB cells metastasize more frequently and form larger metastatic tumors along the spinal cords of mice. Mechanistically, FSS induces actomyosin contraction, which promotes cell clustering, glucose transporter 1 (GLUT1) localization at the cell surface, and GLUT1-dependent glucose uptake. FSS elevates intracellular calcium through mechanosensitive ion channel PIEZO2, which is required for FSS-induced actomyosin contraction, cell clustering, and GLUT1 activity. Genetically perturbing PIEZO2 or pharmacologically inhibiting GLUT1 robustly suppresses MB metastasis in mice. Collectively, we discover that MB cells perceive FSS, define an FSS-activated mechano-metastatic cascade, and demonstrate that this cascade is clinically targetable to mitigate MB metastasis.
CSIG-30. FUNCTIONAL CHARACTERISATION OF A NOVEL MUTATION IN PRKCA, THE MAJOR DRIVER OF CHORDOID GLIOMAS
Authors: Bellamy Charlotte , Tovell Hannah , Dingli Florent , Liva Stephane , Loew Damarys , Stefan Eduard , Schwaighofer Selina , Newton Alexandra , Sanson Marc , Bielle Franck 
Published: November 2023

Abstract
Chordoid gliomas (ChG) are a rare low-grade brain tumour, believed to be derived from Tanycytes. An analysis by the team previously identified a novel mutation present in all ChGs: PRKCA p.D463H. This mutation involves a D463H amino acid substitution at the kinase domain of the Protein kinase C alpha (PKCα) and represents the hallmark of ChG. PKCα is a serine/threonine kinase, that carries out the regulation of various functions in the cell. The aim of the project is to identify novel and biologically relevant PKCα D463H signalling pathways, which will demonstrate the involvement and the role of this mutated kinase in cellular functions implicated in the development of ChGs. The D463H mutation affects a critical residue of the kinase domain of PKCα, suggesting that such change may modify substrate affinity and specificity. Following the purification of the mutated form of PKCα, we have shown it is an inactive kinase, that has a dominant negative effect over the wild type (WT) PKCα. The mutation affects the tertiary structure of the protein, resulting in a more open, unstable protein. Phosphoproteomic analysis of HEK cells overexpressing the mutant protein has shown a global loss of PKCα substrate phosphosites compared to the WT condition. By understanding these changes, integrated with our snRNAseq and bulk RNAseq data of ChGs, we hope to elucidate the mechanism by which the mutation leads to tumorigenesis. Finally, the candidates will be explored in a representative context, by exploring the PKCɑ D463H mutation in primary rat Tanycyte culture and in vivo model. These models will allow us to study the effect of the mutation on cellular processes involved in the development of this rare tumour.
RADT-01. BASELINE HIPPOCAMPAL VOLUME AS A PREDICTOR OF NEUROCOGNITIVE CHANGES AFTER WBRT OR HA-WBRT: SECONDARY ANALYSIS OF NRG ONCOLOGY CC001
Authors: Abraham Christopher , Pugh Stephanie , Brown Paul , Gondi Vinai , Bovi Joseph , Robinson Clifford , Wefel Jeffrey , Roberge David , Kundapur Vijayananda , Devisetty Kiran , Shah Sunjay , Usuki Kenneth , Baschnagel Andrew , Stea Baldassarre , Yoon Harold , Li Jing , Laack Nadia , Jindal Saurahb , Borges Monica , Kachnic Lisa 
Published: November 2023

Abstract

PURPOSE
Hippocampal volume (HV) is a predictor of neurocognitive function (NCF) in neurodegenerative disease. The role of patient-specific anatomic variables has not been well investigated in patients with brain metastases. This work aimed to evaluate HV at baseline and 6 months as a predictor of NCF and differential benefit from HA-WBRT for patients enrolled on CC001.

MATERIALS
HV was calculated at baseline and 6 months. HV at baseline and 6 months were correlated with baseline and 2, 4, and 6-month NCF scores (HVLT-R Total and Delayed Recall, Delayed Recognition, TMT Parts A and B, and COWA) using Pearson correlation. Correlation was defined as weak if ρ ≤0.35. A cox proportional hazards model was used to determine the impact of baseline HV on time to NCF failure.

RESULTS
Of 518 patients randomized on CC001, 277 had baseline imaging, and 135 had 6-month imaging. However, only 87 patients were analyzable at both baseline and 6-month periods. At baseline, HV was not significantly associated with NCF score for any measure (p-value range: 0.06-0.72). Additionally, there was no association between baseline HV and time to NCF failure (p = 0.16). Additionally, the impact of treatment arm allocation on HV was examined but found to be non-significant (p = 0.06). Lastly, baseline HV and NCF scores were noted to have weak correlation at 2, 4, 6, and 12 month timepoints (ρ: range, -0.17-0.15; P-value range, 0.04-0.98). At 6 months, the correlation between HV, baseline NCF change, and 6 month standardized NCF change were also noted to be weak (ρ: range, 0.05-0.16; P-value range, 0.06-0.76).

CONCLUSIONS
Radiotherapy is known to have deleterious effects on neurocognition. In neurodegenerative disease, HV and rate of HV change are known predictors for NCF. However, baseline HV is not an independent predictor of neurocognitive changes after WBRT or HA-WBRT for patients with brain metastases.
RADT-07. CLINICAL OUTCOMES OF MELANOMA BRAIN METASTASES TREATED WITH NIVOLUMAB AND IPILIMUMAB ALONE VERSUS NIVOLUMAB AND IPILIMUMAB WITH STEREOTACTIC RADIOSURGERY
Authors: Tang Joseph , Mills Matthew , Dohm Ammoren , Khushalani Nikhil , Forsyth Peter , Vogelbaum Michael A , Wuthrick Evan , Yu Hsiang-Hsuan Michael , Oliver Daniel , Liu James , Ahmed Kamran 
Published: November 2023

Abstract

BACKGROUND
Upfront dual checkpoint blockade has demonstrated efficacy in new melanoma brain metastases (MBM) of asymptomatic patients. Whether combination stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual checkpoint blockade alone is unknown. We evaluated clinical outcomes of new MBM receiving nivolumab and ipilimumab, with and without SRS.

METHODS
52 patients with 171 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and toleration of therapy were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), distant intracranial control (DIC), and intracranial control (ICC). Time-to-event analysis was conducted with the Kaplan-Meier method.

RESULTS
25 patients with 74 MBM received nivolumab and ipilimumab alone. 27 patients with 97 MBM received concurrent SRS. No differences in age (p = 0.72), KPS (p = 0.94), presence of symptoms (p = 0.87), prior MBM (p = 0.90), prior MBM-directed surgery (p = 0.77) or SRS (p = 0.65), MBM size (p = 0.36), MBM number (p = 0.36), or treatment completion (p = 0.12) were seen. Median follow-up was 22.7 months. There was a trend towards higher rates of nivolumab and ipilimumab course completion in the combination group (44% vs. 24%; p = 0.12). The combination therapy group received prior immunotherapy more often than the monotherapy group (52% vs. 8.0%; p = 0.0003). OS, DIC, and ICC were similar (p = 0.16, p = 0.32, p = 0.57, respectively) with overall 12-month OS 70.7%, DIC 56.8%, and ICC 49.4%. The combination therapy group had higher 12-month LC compared to the monotherapy group (91% vs. 64%; p = 0.001).

CONCLUSION
In our analysis, SRS with nivolumab and ipilimumab shows superior LC compared to nivolumab and ipilimumab alone despite our combination cohort being more advanced with higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.
RADT-08. IS THERE A CORRELATION BETWEEN ANEMIA AND RADIATION NECROSIS IN BREAST CANCER PATIENTS WITH BRAIN METASTASES UNDERGOING RADIOSURGERY? A PRELIMINARY SINGLE-INSTITUTION COHORT STUDY
Authors: Wilding Hannah , De Macedo Filho Leonardo Jose Monteiro , Bhanja Debarati , Husain Rabab , Hong Jinpyo , Moeckel Camille , Mansouri Alireza 
Published: November 2023

Abstract

INTRODUCTION
Stereotactic radiosurgery (SRS) is a highly effective treatment for brain metastases. Radiation necrosis (RN) is a prominent dose-limiting toxicity, occurring in 5-10% of patients. Data on differences in RN incidence based on tumor molecular markers and the potential correlation with anemia have not been explored. The objective of this study was to 1) report our institutional rates of RN in patients with breast cancer brain metastases (BCBM) undergoing radiosurgery; and 2) investigate the correlation of anemia with RN rates.

METHODS
A retrospective review of patients with BCBM treated with SRS between May 2006 and October 2020 was conducted. To ensure homogeneity, only patients with oligometastatic disease (1-4 BM) and only 1 session of SRS were included. Hemoglobin (Hb) was assessed from 3 months before or 6 months post SRS, and diagnosis of anemia was made for Hb &lt;13 g/dL in males and Hb &lt;12 g/dL in females. Logistic regression was used to analyze correlation of anemia and RN.

RESULTS
44 patients were included (82 total lesions treated by SRS, median 2). Seventy-seven lesions were treated with SRS to a median dose of 20 Gy (15-24 Gy). Five lesions were treated with fractionated SRS (30Gy, 3-5 fractions). Five patients (11.4%) developed RN based on imaging; two went on to biopsy with one having pathological confirmation of RN. Anemia was identified in twenty-eight (63.7%) patients; 1 was treated with iron supplementation. Although anemia was not significantly associated with RN, patients with anemia did have significantly lower OS than those without (p = 0.04).

CONCLUSION
Our institutional data suggest similar RN rates in BCBM patients as the literature. Our sample size was too small to investigate correlation between anemia and RN, though survival may be impacted. Larger, multi-institutional studies are underway to further study this possibility.
RADT-27. BONE MARROW SUPPRESSION AFTER REIRRADIATION THERAPY WITH PROTON VERSUS PHOTON THERAPY FOR RECURRENT GLIOMA
Authors: Subramaniam Varun , Zhou Alexander , Rios Carlos Ortega , Hadjipanayis Constantinos , Lazarev Stanislav , Press Robert 
Published: November 2023

Abstract

INTRODUCTION
High grade radiation-induced lymphopenia has been implicated to worse prognostic outcomes and overall survival in numerous malignancies. Understanding factors which influence lymphopenia can help optimize radiation delivery and overall patient care. Proton therapy (PRT), due to its distinct dose fall-off, spares tissues and organ-contained blood pools from excess radiation compared to conventional photon radiation (XRT) and may thereby reduce hematologic toxicity.

METHODS
Patients with confirmed glioma diagnosis who underwent reirradiation with either PRT or XRT were retrospectively analyzed. Complete blood counts (CBCs) within one month of reirradiation start, and CBCs within one month of reirradiation completion were reviewed. Values of interest included total white blood cell (WBC), absolute neutrophil count (ANC), and absolute lymphocyte count (ALC). Dosimetric data was collected to assess whole brain mean dose (WBMD), and volume of brain tissue receiving 5-50 Gy (V5-V50).

RESULTS
16 patients receiving either PRT (n = 8) or XRT (n = 8) were included. Treatment doses ranged from 35-59.4 Gy. Across all patients there was a decrease in WBC, ANC, and ALC after reirradiation in both PRT and XRT (p &lt; 0.05). Compared to reirradiation with XRT, patients who underwent PRT had significantly lesser reductions in WBC (PRT: 8.60% decrease, XRT: 22.58% decrease; p &lt; 0.05). PRT reirradiation also resulted in lesser ANC and ALC reductions, though did not reach statistical significance. On dosimetric comparison of XRT and PRT plans, PRT demonstrated significant reductions in V5, V10, V20, and V30 (p &lt; 0.05). V5 through V40 and WBMD were significantly correlated with decreased WBC, ANC, and ALC (p &lt; 0.01).

CONCLUSION
Preliminary results show PRT reirradiation leads to decreased WBMD and volumes of brain tissues receiving 5 to 30 Gy. Given that these parameters are associated with greater reductions in lymphocytic counts, PRT reirradiation may confer reduced hematologic toxicity in patients seeking adjuvant radiation therapy.
CTIM-05. RESULTS OF SAFETY LEAD IN OF PHASE II TRIAL OF COMBINATION OLAPARIB, TEMOZOLOMIDE, AND PEMBROLIZUMAB FOR PATIENTS WITH IDH-MUTANT GLIOMA
Authors: Fortunato John , Newton Adam , Gonzalez Ashley , Gavrilovic Igor , Miller Alexandra , Grommes Christian , Lin Andrew , Pentsova Elena , Mellinghoff Ingo , Kaley Thomas , Schaff Lauren 
Published: November 2023

Abstract

BACKGROUND
Recurrent gliomas are universally fatal with few adequate treatment options. IDH-mutant gliomas may be susceptible to PARP inhibition, thus combination therapy using alkylating agents and checkpoint inhibition could be synergistic.

METHODS
This is an open label, phase II study of olaparib, temozolomide, and pembrolizumab for patients with recurrent IDH-mutant glioma, grade 2 or 3, with measurable enhancing disease per RANO. Patients received pembrolizumab 200mg IV on day 1 of each 21-day cycle. Oral olaparib 200mg twice daily and temozolomide 50mg/m2 daily were given days 1-7 of cycles 3-11. Here, we report the results of our safety lead in, consisting of the first 6 patients to complete cycle 3.

RESULTS
A total of seven patients were enrolled to the safety lead-in: 2 women; 5 patients with astrocytoma, 2 oligodendroglioma. Patients had a median age of 45 (range 29-63) and median KPS 90 (range 80-100). Median number of recurrences was 3.5 (range 1-5). All had received prior alkylating therapy and all but 1 patient had received prior RT. No patients were taking steroids at the time of enrollment. Six patients completed the dose-limiting toxicity (DLT) period without any DLTs. One patient experienced clinical progression on pembrolizumab monotherapy prior to the start of combination therapy and was thus replaced. No grade 3 or 4 toxicities were seen through the DLT period. The most common clinical toxicities at least possibly related to treatment were grade 1 and 2 fatigue (n = 4), nausea (n = 3) and constipation (n = 2). Hematological toxicities include grade 1 anemia (n = 2) and decreased platelet count (n = 1).

CONCLUSIONS
The combination of olaparib, temozolomide, and pembrolizumab was well tolerated in this cohort. Following completion of the safety lead-in, the trial was redesigned to minimize the length of pembrolizumab monotherapy and introduce combination therapy in cycle 1. Enrollment is ongoing. NCT05188508.