bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSIG-13. CLINICAL IMPACT OF CDKN2A/B DELETIONS IN IDH-MUTANT ASTROCYTOMAS
Authors: Yuile Alexander , Satgunaseelan Laveniya , Alexander Kimberley L , Thavaneswaran Subotheni , Krasovitsky Michael , Buckland Michael , Lee Maggie , Wei Grace , Kastelan Marina , Wong Mark , Wilson Isabella , Bayly Angela , Varikat Winny , Sim Hao-Wen , Kong Ben , Lwin Zarnie , Turner Cassie , Back Michael , Miller Samuel , Lee Adrian , Wheeler Helen 
Published: November 2022

Abstract

BACKGROUND
IDH-mutant astrocytomas with CDKN2A/B homozygous deletions (HD) are now categorized as grade 4 astrocytomas. It is unclear how these HD astrocytomas should be treated. We aimed to compare 3-year outcomes for HD versus heterozygous deleted (HeD) IDH-mutant astrocytomas, describe the prognostic impact of deletions relative to histologic grade and describe differences in outcomes based on treatment regimen.

METHODS
Molecular and clinical data concerning IDH-mutant glioma patients +/-CDKN2A/B deletions were retrieved across four neuro-oncology centers and two tumor banks from 01/2016-07/2021.

RESULTS
48 patients with HD or HeD were identified. Median follow-up time was 4.0 years, median age 33 (range 20-74) years. Sixteen astrocytomas were histologic grade 4, remainder were grade 2 (n= 9) and grade 3 (n= 23). HD were detected in 16 patients. Survival data were unavailable in n= 1 HD and n= 2 HeD patients. 3-year OS for CDKN2A/B HD and HeD groups were 47% versus 67% (log-rank p= 0.004). For grades 2, 3 and 4, 3-year OS for HD were 100% (n= 1), 57% (n= 7) and 29% (n= 7) respectively, 3-year OS for HeD were 100% (n= 7), 56% (n= 16) and 57% (n= 7) respectively. In HD patients, six were treated with concurrent temozolomide-radiotherapy (3-year OS 50%) and five with radiotherapy and sequential temozolomide only (3-year OS 80%, log-rank p= 0.38). Treatment data were unavailable in two patients and three were treated with “other” regimens. Sequential regimens were preferentially used in histologic grade 2 and 3 cases.

CONCLUSION
Preliminary data are in keeping with current literature and are one of the first to describe outcomes based on clinical regimen. There was insufficient evidence of OS differences between concurrent and sequential therapy, though conclusions are limited by sample size and data maturity. Additional follow-up data are required to further define optimal treatment for these patients.
CSIG-14. THE PDGFRA-REGULATING LNCRNA LINC02283 IS AMPLIFIED IN HIGH-GRADE GLIOMA AND FACILITATES GLIOMAGENESIS
Authors: Goenka Anshika , Song Xiao , Tiek Deanna , Hu Bo , Cheng Shi-Yuan 
Published: November 2022

Abstract
Long non-coding RNAs (lncRNAs) regulate numerous physiological processes and the etiology of diseases including cancers. However, lncRNA-based therapies are limited because the mechanism of action of many lncRNAs and their interaction with binding partners is not completely understood. We have identified LINC02283, a novel oncogenic lncRNA, highly expressed in the PDGF Receptor A (PDGFRA)-mutation driven cohort of high-grade glioma (HGG) patients which accounts for ~8% of glioma cases. LINC02283 gene co-amplifies with the PDGFRA locus and is upregulated in HGG. LINC02283 expression and copy number variation were highly correlated to that of PDGFRA expression and amplification respectively, and high LINC02283 levels leads to worse survival in HGG patients. We found that LINC02283 transcription is essential for the survival of Glioma Stem cells (GSCs) with PDGFRA amplification mutation, and its inhibition significantly improves survival in orthotopic HGG xenograft models. Interestingly, overexpression of LINC02283 in GSCs with wild type (wt) - PDGFRA, enhance PDGFRA signaling, increases cell proliferation and worsens survival in orthotopic HGG xenograft models. Inhibition of PDGFRA signaling using AG1296, represses the high endogenous LINC02283 levels in PDGFRA-mutant GSCs, reduces LINC02283 induced signaling in PDGFRA-wt GSCs, and suppresses cell proliferation in both the cellular models of HGG. Moreover, LINC02283 co-localizes and interacts with the wild-type and mutant PDGFRA to enhance its signaling and that of its downstream targets Akt and Erk. In a feedback regulation, dysregulated PDGFRA signaling induces LINC02283 levels to enhance cell proliferation in GSC and GBM cellular models through activating its downstream, Akt and Erk signaling pathways, as their inhibition reduces the lncRNA induction and function. Thus, blocking the LINC02283-PDGFRA interaction could be a plausible therapeutic strategy in HGG. Altogether, our results provide strong evidence of lncRNAs as drivers of PDGF Receptor A activity and HGG progression and support the potential of lncRNAs as possible therapeutic targets.
CSIG-17. SCD5 PROTECTS GLIOBLASTOMA STEM CELLS FROM DEATH AND DIFFERENTIATION BY MODULATING INTRACELLULAR LIPID COMPOSITION
Authors: Mnatsakanyan Hayk , Pechdimaljian Caline , Jha Roshani , Sammarco Alessandro , Su Baolong , Williams Kevin J , Bensinger Steven J , Badr Christian E 
Published: November 2022

Abstract
Glioblastoma (GBM) is the most common malignant brain cancer in adults, enriched in a small subpopulation of glioma stem cells (GSC), which can drive tumor recurrence and therapeutic resistance. Considerable evidence suggests that the endogenous levels of unsaturated fatty acids (FA) are crucial regulators of GSCs survival and self-renewal. Stearoyl-CoA desaturase-1 (SCD-1) is the most abundant desaturase in humans. We have previously shown that SCD1 activity is required for GSCs self-renewal and brain tumor initiation. However, SCD1 orthologous isoform, SCD5, has been poorly characterized and its potential role in GBM has not been previously reported. We have observed that SCD5 is highly enriched in GSC both at the mRNA and protein levels. Genetic downregulation of SCD5 in GSCs led to a remarkable decrease in stem cell markers, impaired cell viability and the ability to form neurospheres. Further, the downregulation of SCD5 in GSCs orthotopically implanted in mice resulted in delayed tumor growth and extended overall survival. Shotgun lipidomics in GSCs after either SCD1 or SCD5 knock-down revealed a largely distinctive lipidome profile, highlighting the divergent role of these two isoforms in GBM lipid metabolism. Surprisingly, lipidomics analysis showed that both SCD1 and SCD5 are required to synthesize a variety of lipid species involved in receptor tyrosine kinase (RTKs) and GPCRs signal transduction, directly linking FA synthesis with the oncogenic signaling. We confirmed these results by immunoblot analysis. Using specific tagging and immunofluorescence analysis, we observed that, despite a spatial overlap in SCD1 and SCD5 expression, SCD5 is uniquely present in some subcellular locations. This suggests that different functions of these isoforms could be related to different subcellular localization. Altogether, our results underscore a novel function of SCD isoforms in GSCs metabolism and highlight SCD5 as a potential therapeutic target for GBM.
CSIG-18. ANTI-TUMOR EFFECTS OF VERTEPORFIN AND PHOTODYNAMIC THERAPY IN COMBINATION WITH STANDARD OF CARE ON PATIENT-DERIVED GBM CELL LINES
Authors: Sudhir Sweta , Anastasiadou Maria , Price Gabrielle , Hadjipanayis Constantinos 
Published: November 2022

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of approximately 15 months. GBM tumorigenicity frequently arises from aberrant signaling transduction pathways involving receptor tyrosine kinases (RTKs), such as EGFR and PI3K. Amplification of the Epidermal Growth Factor Receptor (EGFR) gene upregulates Hippo pathway transcription factors YAP1 and TAZ, leading to tumor cell proliferation, radiation resistance, and poor survival. Verteporfin (VP), also known as Visudyne, is an FDA-approved macular degeneration photosensitizer that has photodynamic effects when combined with 489 nm of light. Additionally, VP is a small-molecule inhibitor of the YAP/TAZ/TEAD complex that has been shown to reduce tumor migration and is in phase I clinical trial as a chemotherapeutic for patients with recurrent GBM. We now investigate if VP is an effective photosensitizer for PDT in GBM and if it enhances the effects of TMZ and RT. Compared to VP alone, VP+PDT reduced the IC50 of VP treatment in GBM cells +/- EGFR amplification. Light activation of VP has a significant antitumor effect as observed with cytotoxicity in comparison to vehicle and VP treated cells (p&lt; 0.01). Compared to control, VP, VP+PDT+TMZ, and CRT show significantly less intravasation (p&lt; 0.01). Furthermore, Western blot analysis shows differential expression of YAP, TAZ and TEAD compared to Control and VP after treatment with VP+PDT. Differential YAP signaling is observed via IF staining in EGFR+ GBM cells treat with VP+PDT. Our research supports the use of VP as a photosensitizer in GBM cells. We found downregulation of the hippo pathway and decrease tumorigenicity of GBM cells. Application of VP-PDT treatment in combination with standard of care may be proven beneficial in GBM patients. We plan to further explore these in vitro findings in mice models and investigate other pathways including immune response with NanoString analysis.
CSIG-22. THE MOLECULAR NETWORK OF CAMTA-1 IN GLIOMA CELLS
Authors: Haeusser Lara , Kuhlburger Laurence , Czemmel Stefan , Govindarajan Parameswari , Merk Daniel , Nahnsen Sven , Tabatabai Ghazaleh 
Published: November 2022

Abstract
Calmodulin-binding transcription activator 1 (CAMTA1) is a transcription factor located on chromosome 1p, and we have recently reported that CAMTA1 expression reduced neurosphere formation and tumor growth in nude mice, suggesting that CAMTA1 can function as tumor suppressor in experimental glioma. In the present study, we investigated the molecular network of CAMTA-1 in glioma cells. We established glioma cell lines with a doxycycline-inducible overexpression of CAMTA1. We performed a cap analysis of gene expression (CAGE) on these overexpressing cell lines to identify differentially regulated transcriptional start sites. We particularly focused on regulated target genes encoded on chromosome 19q. We identified an interaction of CAMTA1 overexpression with changes in the differential expression of Zink finger (ZNF) genes located on 19q. We will present novel data on a potential molecular interaction between chromosomes 1p and 19q.
CSIG-23. ALTERATIONS IN THE TRANSSULFURATION PATHWAY DRIVE GLIOBLASTOMA INVASION IN THE PERITUMORAL WHITE MATTER
Authors: Garcia Joseph , Jain Saket , Akins Erin , Carrete Luis , Zheng Allison , Gill Sabraj , Kumar Sanjay , Aghi Manish 
Published: November 2022

Abstract
Glioblastoma is the most common and lethal adult brain tumor with a median survival under two years. The poor prognosis glioblastoma carries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. Although numerous molecular factors have been proposed as driving glioblastoma invasion, the search for targetable pathways to mediate glioblastoma invasion has been largely unfruitful. Despite a well-established relationship between metabolic reprogramming and cancer cell survival, little attention has been paid to the metabolic alterations needed for invading tumor cells to thrive in peritumoral white matter. To address this knowledge gap, we defined the links between tumor metabolism and invasion using metabolomics, transcriptomics, and CRISPR screens in biomimetic 3D hydrogels and regional biopsies of patient glioblastomas. Metabolomic and lipidomic screening of 315 metabolites and 691 lipids revealed cystathionine, a cysteine precursor in glutathione synthesis in the transsulfuration pathway, as well as hexosylceramides and glucosyl-ceramides, which counteract oxidative stress, to be enriched in invasive tumor cells in hydrogels and patient samples. Immunostaining confirmed elevated secondary ROS markers in invasive GBM cells in hydrogels and patient specimens. While adding ROS promoted GBM invasion in hydrogels, ROS sequestration had no effect. A CRISPR screen of 3000 metabolic genes revealed cystathionine gamma lyase (CTH), which catalyzes the last step in the transsulfuration pathway, to be essential for glioblastoma invasion. Genetic and pharmacologic CTH inhibition suppressed glioblastoma invasion in hydrogels in a manner rescued by exogenous cysteine. Thus, invasive glioblastoma cells exhibit high ROS levels, metabolic adaptations to ROS, and increased invasion in response to ROS. While targeting ROS directly did not slow invasion, targeting metabolic adaptations to ROS in the transsulfuraton pathway suppressed invasion. Our work defines the first link between metabolic adaptations and glioblastoma invasion, intriguing findings warranting future exploration.
CSIG-24. EPIGENETIC SUPPRESSION ALLOWS GBM TO MAINTAIN P53 WILD-TYPE STATUS
Authors: Park Jung , Schulder Michael , Boockvar John 
Published: November 2022

Abstract

Introduction
Glioblastoma (GBM) is the most common primary brain malignancy in adults. The vast majority of GBM cases maintain wild-type status of p53, the protein considered to be the most critical tumor suppressor. How GBM displays such a malignant phenotype despite retaining normal p53 protein is unknown. We also aim to translate these molecular findings into therapeutics via a randomized clinical trial.

METHODS
A variety of molecular biological techniques were employed. These include CRISPR-CAS, next generation sequencing, stereotactic mouse brain injections, and histological analyses of human GBM tumors. Approval for a small, single site, blinded, randomized clinical trial for newly diagnosed GBM is underway. Overall survival, recurrence-free survival, immunohistochemical analyses will be assessed.

RESULTS
Human p53 wild-type GBM cell lines express Brd at higher levels compared to p53 mutant cell (~10 fold, p &lt; 0.05). Cell viability assays show that deletion of Brd leads to a ~50% decrease (p &lt; 0.05) in cell survival. Critically, this effect is abrogated upon deletion of p53 itself, showing that Brd functions through the inhibition of p53’s tumor suppressive effects. Furthermore, immunoprecipitation of Brd shows that it is a member of a complex of proteins that bind to p53 target genes. The importance of these findings are corroborated in vivo, as mice stereotactically injected with human GBM cells that lack Brd survive ~2-fold longer (p &lt; 0.05) than mice that retain Brd. We have begun the process to start clinical trials with an already FDA-approved drug (currently used for the treatment of lymphoma and sarcoma) that blocks the Brd pathway.

CONCLUSION
Brd is the key suppressor of p53 target genes in GBM. Brd binds to a multimeric protein complex, which inhibits p53 target genes. Thus, the tumor suppressive effects of p53 are prevented in GBM. Inhibition of this pathway in GBM patients is underway.
CSIG-34. LIN28B-LET-7-PBK PATHWAY IS AN IMPORTANT REGULATOR OF GROUP 3 MEDULLOBLASTOMA PROLIFERATION
Authors: Shahab Shubin , Sun Jessica , Kunhiraman Haritha , Schneiderjan Matthew , Juraschka Kyle , Kumar Sachin , Taylor Michael , MacDonald Tobey , Kenney Anna 
Published: November 2022

Abstract
Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and many do not survive beyond 5 years. Several drivers for Group 3 MB have been identified but none have resulted in targeted therapy to date. LIN28B is a stem cell factor upregulated in Group 3 MB and is associated with worse survival. Here we investigate the role of the LIN28B pathway in Group 3 MB development. Pharmacologic inhibition of the LIN28B pathway is feasible and may provide a unique opportunity to target this tumor. Using LIN28B knockdown and overexpression in Group 3 MB cells we test LIN28B’s effect on proliferation, self-renewal and metastasis. We investigate the effect of LIN28B knockdown on survival as well as proliferation and apoptosis markers using orthotopic xenografts in vivo. We also investigate the role of let-7 and its downstream target PBK on Group 3 MB proliferation. Finally, we use a LIN28 inhibitor 1632 and a PBK inhibitor HITOPK032 to treat Group 3 MB cell lines and then assess their impact on proliferation and apoptosis. We find that down-regulation of LIN28B or PBK using shRNA results in significant reduction in cell proliferation. In contrast overexpression of LIN28B increases Group 3 cell proliferation and tumor sphere formation. LIN28B knockdown also significantly (p&lt; 0.01) increases survival in mice with orthotopic Group 3 tumors. The LIN28 inhibitor 1632 also leads to significant reduction in MB growth through decreased cell cycle entry and increased apoptosis. In addition, HITOPK032 also demonstrates significant reduction in Group 3 MB cell proliferation at low micromolar concentration. We also demonstrate that HITOPK032 in combination with CDK 4/6 inhibition can additively inhibit proliferation of Group 3 MB cells. Our study establishes a critical role for the LIN28B-let-7-PBK pathway in Group3 MB and provides encouraging preliminary preclinical results for drugs that target this pathway.
CSIG-36. NOTCH3 DRIVES MENINGIOMA TUMORIGENESIS AND RESISTANCE TO RADIOTHERAPY
Authors: Cady Martha , Choudhury Abrar , Lucas Calixto-Hope , Phillips Joanna J , Palikuqi Brisa , Bush Nancy Ann Oberheim , Klein Ophir , Hervey-Jumper Shawn L , Dickinson Peter , Magill Stephen , Bhaduri Aparna , Crouch Elizabeth , Raleigh David 
Published: November 2022

Abstract
There are no approved targeted therapies for meningiomas and the cell types underlying meningeal tumorigenesis are incompletely understood. To address these limitations, we performed single-cell RNA sequencing of 57,114 cells from 8 human meningiomas and 54,607 cells from 3 canine meningiomas. Pseudotime, gene ontology, and copy number variant analyses revealed a population of pericyte-like meningioma cells that were conserved across human and canine tumors and were enriched in expression of Notch3 and other cancer stem cell genes. Deconvolution of cell types from bulk RNA sequencing and DNA methylation profiling of 200 human meningiomas integrated with immunohistochemistry (IHC), immunofluorescence (IF), and RNAScope demonstrated Notch3+ pericytes and Notch3 expression were enriched in high grade or Immune-enriched meningiomas, which were distinguished from other meningioma DNA methylation groups by genes driving vasculature development. IHC and IF of human meninges integrated with lineage tracing approaches using Notch3-CreERT2 ROSAmT/mG alleles in mice demonstrated Notch3 expression was restricted to the perivascular stem cell niche during meningeal development and homeostasis. Mice harboring Notch3-CreERT2 Nf2fl/fl alleles developed meningeal hyperproliferation. Overexpression of constitutively activated Notch3 (Notch3AICD) in Immune-enriched human meningioma cells increased the expression of cancer stem cell genes, driving clonogenic growth in vitro, limiting dilution tumor-initiating capacity in vivo, and resistance to radiotherapy in vivo. A selective Notch3 neutralizing antibody (αNRR3) blocked meningioma cell proliferation and expression of Notch3 target genes, inhibiting meningioma xenograft growth and prolonging overall survival. Single-cell RNA sequencing of 187,366 cells from meningioma xenografts after αNRR3 or radiotherapy treatment ± Notch3AICD overexpression revealed distinct meningioma cell-intrinsic or cell-extrinsic mechanisms driving responses to radiotherapy or αNRR3, respectively. Combined treatment with αNRR3 and radiotherapy additively blocked meningioma xenograft growth and extended survival benefit. In sum, these data shed light on a novel cell type, molecular mechanism, and therapeutic vulnerability in the most common primary intracranial tumor.
CSIG-39. PROSTAGLANDIN-SCULPTING; REPRODUCTIVE DRIVERS OF THE GBM TUMOR IMMUNE LANDSCAPE
Authors: Sharpe Martyn , Baskin Alexandra , Baskin David 
Published: November 2022

Abstract

Introduction
We have reported that GBM utilize sex-steroids and reproduction-specific proteins to hijack the granting of immune-privilege to male/partner-specific antigens/epitopes. We have extended upon this foundation to examine other examples of immunosuppressive tissue-mimicry mechanisms that GBM deploy. The generation of prostaglandins D2, E2 and F2 and reproductive proteins are used by GBM tumors to activate discrete immune-cell types and to drive vascularization and growth.

METHODS
Three GBM-transcriptome databases were mined and analyzed utilizing pathway, stratification, correlation and survival analysis.

RESULTS
PGD2 and PGF2 synthesis is driven by C3AR1 microglial signaling, in response to complement C3a activation by GBM expression of C3 and CFB. PGD2 is expressed in hypoxic tumors and PGF2 is expressed in normoxic ones. PGF2 drives the hematopoietic stem cell angiogenic pathway, via TPBG/CXCL12/CXCR4. This is the primary pathway promoting early placental vascularization and vascular development/repair of mucosal tissues. Microglial synthesized PGD2 drives the CCL5/CCR5 axis, a pathway central to cyclic vascularization of uterine tissues and in wound healing, via VEGFA. Generation of CCL5 also recruits CCR5-positive monocytes, which are then driven into M2-TAM phenotype. CCL5 also recruits and drive myeloid cells into MDSCs. SOX9 drives masculinization of embryonic gonads. GBM expression of SOX9 correlates with seminal heat shock protein expression. These reproductive HSPs are associated with neutrophil generation of PGE2 in GBM tumors, mirroring their role in the semenized female reproductive tract, where they support PGE2 synthesis and aid EGFR driven vascularization

CONCLUSIONS
The ability of GBM to modulate the anti-tumor response is central to their lethality. The discrete, cell-specific mechanisms revealed will allow personalized medicine using off-the-shelf drug therapy.
RADT-04. SINGLE SESSION GAMMA KNIFE RADIOSURGERY TO TREAT PATIENTS WITH 20 OR MORE BRAIN METASTASES
Authors: Wei Zhishuo , Luy Diego , Yavan Sila , Jose Shalini , Worrell Stephen , Belkhir J Raouf , Deng Hansen , Niranjan Ajay , Lunsford L Dade 
Published: November 2022

Abstract

BACKGROUND
Stereotactic Radiosurgery (SRS) has become a primary management option for brain metastases (BMs). This present study aims to review outcomes in patients with ≥ 20 BMs treated in a single session SRS and to identify predictors of local tumor control (LTC) and overall survival (OS).

METHODS
We identified 75 patients including 26 non-small cell lung cancer (NSCLC), 21 small cell lung cancer (SCLC), 14 breast cancer (BC), and 14 melanoma patients who underwent SRS for ≥ 20 BMs between 2014 and 2020. The median number of tumors was 24 (range 20 – 52), and the median cumulative tumor volume was 3.70 cc (0.13 – 62.49 cc). The median margin dose was 16 Gy (14 – 20 Gy). Median skull integral dose was 5492 mJ (range 1372 – 11243 mJ). The median treatment time for each session was 160 min. Outcome variables were assessed using univariate and multivariate analyses with p &lt; 0.05.

RESULTS
Median OS after SRS was 5.8 months (range 0.1 – 73.2 months). Primary cancer type and concurrent immunotherapy were significant predictive factors for patient OS after SRS (p = 0.01, 0.05, and 0.02, respectively). LTC rate at 6 and 12 months after SRS was 95.7% and 83.7%, respectively. Thirty (40.0%) patients underwent additional SRS and 3 patients (4%) received post-SRS WBRT due to distant tumor recurrence. The median time to distant recurrence was 5 months (range 2-28 months). SRS-induced adverse radiation effects (ARE) events were observed in 3 patients (4.0%; 1 NSCLC, 1 SCLC, and 1 melanoma).

CONCLUSIONS
Our results suggest that patients with ≥ 20 BMs can be safely treated with SRS with an excellent LTC rate and a low risk of ARE. Newly developed BMs can be treated with repeat SRS. This single-session SRS allows patients to proceed with systemic cancer care without interruption.