bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDDR-13. MGMT FUNCTION DETERMINES THE DIFFERENTIAL RESPONSE OF ATR AND PARP INHIBITORS WITH DNA DAMAGING AGENTS FOR GBM THERAPY
Authors: Koul Dimpy , Wu Shaofang , Li Xaolong , Khan Sabbir , Balasubramaniyan Veerakumar , Yung W K Alfred 
Published: November 2022

Abstract
The most common cancer therapies including chemo- and radiation therapy are designed to induce cell death by DNA damage. However, DNA damage response (DDR) repair pathways initiated by tumor cells can resist the effect of anticancer drugs thus providing the rationale for combining DNA repair pathway inhibitors with radiation and DNA damaging anticancer drugs. The reliance of different cancer to different DDR mechanism can guide for targeted use of specific DDR inhibitor to maximize tumor cell killing. Here, we show the differential activities of two classes of DDR pathway inhibitors, Ataxia Telangiectasia- and Rad3-related kinase (ATRi) and poly(ADP-ribose) polymerases inhibitors (PARPi) across 20 glioma stem cell (GSC) lines. Using a panel of 3 ATRi, we identified a subgroup of GSCs, showing significant synergism with TMZ combination but resistant to ATRi single agent monotherapy. Interestingly, majority of the synergistic cell lines are associated with MGMT promoter methylation, suggesting that only tumor cells with no MGMT repair will benefit from ATR inhibition. Moreover, we also observe that PARPi + TMZ showed synergism only in MGMT unmethylated GSC cells suggesting that this synergism is a result of the dual function of PARPi in blocking BER repair and blocking MGMT PARylation thus abolishing MGMT mediated repair. Altogether, we believe MGMT methylation status in primary GBM could function as a strong biomarker for patient selection for ATRi or PARPi combination with TMZ in the clinic. We are currently exploring the activity of the triple combination of TMZ + PARPi + ATRi for the small subgroup of GSCs that do not show response to either TMZ + ATRi or PARPi + TMZ combinations.
DDDR-14. YAP/TAZ TRANSCRIPTIONAL CO-ACTIVATORS DRIVE NEURO-GLIAL STEM/PROGENITOR CELL IDENTITY IN HIGH GRADE GLIOMAS
Authors: Read Renee , Oh Se-Yeong , Vigneswaran Krishanthan , Boyd Nathaniel , Young Elizabeth , Read William , Olson Jeffrey 
Published: November 2022

Abstract
High-grade gliomas (HGGs), neoplasms derived from neuro-glial stem/progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults and children, with a median survival time of 14 months with current treatments. HGG tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases (RTKs), such as EGFR, and the Pi-3 kinase (PI3K) signaling pathway. Using Drosophila, mouse, and human HGG model systems of RTK-PI3K mutant HGGs, we identified the YAP and TAZ transcription co-activators, which regulate gene expression via TEAD co-factors, as key drivers of HGG tumorigenicity downstream of oncogenic RTK signaling. YAP and TAZ are highly expressed in RTK-mutant human HGG cells, and regulate TEAD-mediated transcription of several transcription factors, neurodevelopmental genes, and receptors, including the EGFR RTK, that together create a feedforward loop with RTKs to maintain a radial-glia-like stem/progenitor cell fate in HGG cells. Inhibition of YAP and TAZ in self-renewing stem-cell-like RTK mutant HGG cells can inhibit proliferation, block stem/progenitor cell fate, and elicit apoptosis. In particular, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD mediated transcription, specifically induced apoptosis of cultured patient-derived HGG cells, suppressed expression of YAP/TAZ transcriptional targets, including RTKs, and conferred significant survival benefit in an orthotopic xenograft HGG model. Our efforts led us to initiate phase 0 and phase 1/2 clinical trials of Visudyne, an FDA-approved liposomal formulation of verteporfin, in which we have verified verteporfin uptake into tumor cells and are now testing the therapeutic efficacy of verteporfin in human patients. Finally, we have examined mechanisms of response and resistance to verteporfin, and we have evidence that stem-like HGG cells can escape the effects of YAP/TAZ inhibition by recapitulating neuro-glial developmental cell fate transitions. Together, our data indicate that targeting YAP/TAZ functionality is a promising therapeutic approach for HGG.
DDDR-25. CO-INHIBITION OF KINASE SIGNALING PATHWAYS AND EPIGENETIC REGULATORS OVERCOMES COMPENSATORY EFFECTS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Adams Jack , Stitzlein Lea , Singh Melissa , Su Xiaoping , Lu Yue , Bailey Cavan , Monje Michelle , Whitehead Christopher , Sebolt-Leopold Judith , Chandra Joya 
Published: November 2022

Abstract
Pediatric high-grade gliomas (pHGG) confer poor survival outcomes with minimal treatment options due to a high rate of therapeutic resistance and few surgical options. One subgroup of pHGG is diffuse intrinsic pontine glioma (DIPG). Patient-derived cell lines, such as SU-DIPG-XIII, SU-DIPG-VI, and SU-DIPG-IV, recapitulate epigenetic mutations seen in patients. In these lines, lysine-specific demethylase 1 (LSD1) is overexpressed and knockdown/inhibition slows growth, therefore, optimizing LSD1 inhibitor treatment regimens is promising. In other models, MEK kinase activation acts as a mechanism of resistance to LSD1 inhibitors. This is relevant to DIPG due to the frequency of dysregulated and mutated upstream kinase pathways. Thus, we sought to identify the connection between LSD1 and kinase signaling as a therapeutic co-inhibition strategy in DIPG. Pharmacologically relevant catalytic LSD1 inhibitors were assessed using the alamarBlue viability assay and demonstrated wide ranges of IC₅₀ values with ORY-1001(19 μM to &gt; 150 μM), ORY-2001( &gt; 50 μM), GSK-LSD1(134 μM to &gt; 500 μM), and IMG-7289(1.6 μM-179 μM) in the SU-DIPG lines. Resistance mechanisms from kinase modulation were investigated via Western Blot to determine if kinase inhibition could sensitize these cells to LSD1 inhibition. We discovered that LSD1 inhibition caused an unexpected increase in pAKT and pERK, suggesting enhanced activity of protumorigenic kinases. To overcome kinase activation from LSD1 inhibition, MEK or PI3K inhibitors, including selumetinib, trametinib, and BKM120, were tested. A novel dual kinase inhibitor directed against EGFR and PI3K, MTX-241F, was also assessed. Several combinations caused a significant increase in efficacy measured by cell viability. We further observed that the addition of kinase inhibitors with LSD1 inhibition decreased phosphorylated kinases. Overall, the combination enhanced in vitro efficacy in contrast to single-agent inhibition supporting an interplay between LSD1 and kinase signaling in pHGG. Future studies will assess this combination utilizing orthotopic xenograft models of DIPG
EOLP-02. THE EFFECT OF CLINICAL TRIAL ENROLLMENT ON SPECIALTY PALLIATIVE CARE RECEIPT IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH HIGH GRADE GLIOMAS
Authors: Roberts Holly , Franson Andrea , Wang Yujie 
Published: November 2022

Abstract

BACKGROUND
Palliative care has been shown to provide numerous benefits to children with cancer. Pediatric patients with high grade glioma (HGG) are particularly well suited for early involvement of palliative care given their high symptom burden and relatively poor prognosis. However, a recent study revealed that pediatric patients with primary central nervous system malignancies missed multiple opportunities for appropriate palliative care involvement. We hypothesize that clinical trial enrollment may adversely impact palliative care involvement for children and young adults with HGG.

METHODS
We identified a cohort of 43 deceased patients with HGG treated at our institution. IRB exemption was obtained. For each patient, the electronic medical record was reviewed to collect demographic, diagnostic, clinical trial, treatment, and palliative care information. Statistical analysis was performed, employing Fisher exact and t tests.

RESULTS
Overall, 72% (31/43) of patients had at least one visit with a specialty palliative care provider. 56% (24/43) of patients enrolled in a clinical trial with HGG-directed therapy, with 71% (17/24) of patients who enrolled in a clinical trial receiving specialty palliative care compared to 74% (14/19) of patients who were not on a trial (p = 1.000). Among patients who received palliative care, there was no statistically significant difference in the timing of palliative care involvement, measured from the date of first palliative care contact to date of death, for patients who enrolled in a clinical trial (mean = 177 days) compared to those who did not (mean = 113 days, p = 0.180).

CONCLUSIONS
As our understanding of the genomic landscape of pediatric brain tumors increases, it can be expected that patients electing to enroll in targeted therapy clinical trials will also increase. As such, it is reassuring that our data suggest trial participation does not adversely impact the receipt of palliative care in children with HGG.
EPID-11. NATIONAL EPIDEMIOLOGY AND SURVIVAL OF ADULT-TYPE DIFFUSE GLIOMAS IN THE UNITED STATES BY IDH, 1P/19Q, MGMT, AND WHO CNS GRADE
Authors: Iorgulescu Bryan , Sun Chuxuan , Cioffi Gino , Neff Corey , Shoaf Madison , Waite Kristin , Kruchko Carol , Wen Patrick Y , Brat Daniel , Ostrom Quinn , Barnholtz-Sloan Jill 
Published: November 2022

Abstract

BACKGROUND
Histomolecularly-defined adult-type diffuse gliomas—including IDH-wildtype glioblastoma, IDH-mutant astrocytoma, and IDH-mutant 1p/19q-codeleted oligodendroglioma—were incorporated into U.S. cancer registry reporting for individuals with brain tumors beginning in 2018. We therefore assessed their epidemiology and overall survival (OS) patterns.

METHODS
Individuals histopathologically diagnosed with diffuse gliomas in 2018 and had brain molecular marker data were identified within the National Cancer Database; Surveillance, Epidemiology, and End Results Incidence; and Central Brain Tumor Registry of the United States databases. Age-adjusted incidence rates per 100,000 population with 95% confidence intervals (95CI) were estimated. OS was estimated using Kaplan Meier methods and stratified by WHO CNS grade, age, sex, tumor size, treatment, extent of resection, and MGMT promoter methylation. WHO CNS grade was additionally examined among individuals with IDH-wildtype diffuse astrocytic gliomas.

RESULTS
IDH-wildtype glioblastomas’ incidence rate was 1.74 (95CI = 1.69-1.78); as compared to 0.14 (95CI = 0.12-0.15), 0.15 (95CI = 0.14-0.16), and 0.07 (95CI: 0.06-0.08) WHO grade 2, 3, and 4 IDH-mutant astrocytomas. Irrespective of grade, IDH mutation prevalence was highest in adolescents & young adults, and IDH-mutant astrocytomas were more frequently MGMT promoter methylated. For OS analysis, 8,651 individuals were identified: one-year OS was 53.7% for WHO grade 4 IDH-wildtype glioblastomas (95CI = 52.5-54.9); 98.0% (95CI = 96.1-99.0), 92.4% (95CI = 89.6-94.5), and 76.3% (95CI = 70.1-81.3) for grade 2, 3, and 4 IDH-mutant astrocytomas; 97.9% (95CI = 95.9-98.9) and 94.4% (95CI = 90.9-96.6) for grade 2 and 3 IDH-mutant 1p/19q-codeleted oligodendrogliomas. Among IDH-wildtype glioblastomas, median OS was 17.1 months (95CI = 16.1-18.6) and 12.4 months (95CI = 12.0-12.9) for methylated and unmethylated MGMT promoters. IDH-wildtype diffuse astrocytic gliomas reported as WHO grade 2 or 3 demonstrated longer adjusted OS compared to grade 4 tumors (both p &lt; 0.001). A significant association was not observed between chemotherapy and OS (HRadjusted 0.95, 95CI = 0.41-2.22, p = 0.91) for radiotherapy-treated grade 3 IDH-wildtype diffuse astrocytic gliomas.

CONCLUSIONS
Our findings provide the initial U.S. epidemiological estimates for histomolecularly-defined adult-type diffuse gliomas.
EPID-24. TIMING OF STANDARD-OF-CARE CHEMO-RADIATION THERAPY FOLLOWING SURGICAL RESECTION OR STEREOTACTIC BIOPSY
Authors: Zhu Ping , Chen Clark 
Published: November 2022

Abstract

OBJECT
The literature examining the optimal timing for initiating post-surgical therapy after glioblastoma surgery is brimming with inconsistencies, with reports of both deleterious effects and benefits in the delay of post-surgical therapy at various time intervals. Moreover, there is currently limited data pertinent to the post-Stupp regimen era. Here, we use the National Cancer Database (NCDB) to explore this matter, with a focus on patients who underwent the standard-of-care (SOC) Stupp regimen.

METHODS
The study cohort included newly glioblastoma patients from the NCDB, with exclusion of patients age &lt; 40 [as proxy for isocitrate dehydrogenase (IDH) mutated astrocytoma] and stratified for Methyl-guanine-methyl transferase (MGMT) promotor methylation. Timing of initiating SOC was grouped by 0-2, 2-4, 4-6, 6-8, and &gt; 8 weeks from surgery. Biopsy and craniotomy patients were analyzed separately. The Kaplan-Meier method and Cox proportional hazards regression were applied for survival analysis.

RESULTS
We identified 6511 glioblastoma patients who underwent SOC therapy with available MGMT methylation status. SOC was initiated in 228 (3.5%), 2478 (38.1%), 2954 (45.4%), 646 (9.9%), and 205 (3.2%) patients at 0-2, 2-4, 4-6, 6-8, and &gt;8 weeks after surgery. For craniotomy patients, initiation of SOC at 0-2 weeks was associated with an increased risk of death relative to SOC initiation at 4-6 weeks (HR: 1.19, p = 0.036). These results remain robust after controlling for the extent of resection, tumor size, and tumor location (HR: 1.19, p = 0.044). Such association was not observed in patients who underwent stereotactic biopsy (HR: 1.27, p = 0.148). Patients who received SOC at 6-8 weeks post-craniotomy (HR: 0.96, p = 0.420) or biopsy (HR: 0.93, p = 0.628) did not appear to worsen survival outcomes.

CONCLUSION
Optimal timing for initiation of SOC differ for craniotomy and needle biopsy patients. Initiating SOC within 2 weeks after craniotomy could lead to worse survival outcomes for GBM patients.
EPCO-08. CONSERVED FEATURES OF TERT PROMOTER DUPLICATIONS REVEAL AN ACTIVATION MECHANISM THAT MIMICS HOTSPOT MUTATIONS IN CANCER
Authors: Suwala Abigail , Barger Carter , Soczek Katarzyna M , Wang Albert S , Kim Min Y , Hong Chibo , Doudna Jennifer A , Chang Susan M , Phillips Joanna J , Solomon David A , Costello Joseph F 
Published: November 2022

Abstract
Mutations in the TERT promoter are the single most common non-coding mutation in cancer and represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, G228A and G250A, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants in the TERT promoter are unknown. We identified duplications of wildtype sequence within the core promoter region of TERT in 7 different cancer types that have strikingly similar features including size, insertion position, and inclusion of one of the native ETS motifs. Each duplication activates the TERT promoter to a similar level as G228A and G250A and is critically dependent on the insertion site. The GABP tetramer binds to the TERT duplicated promoter sequence by virtue of the native ETS motif and its duplicated version with precise spacing, and it is necessary for the transcriptional activation by all duplications tested. Spatiotemporal analysis in a multifocal glioblastoma shows the duplication is clonal and its activation of TERT is readily detectable at the single cell level and in bulk tumor tissue. We conclude that recurrent TERT promoter duplications of the native ETS sequence are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.
EPCO-11. GATEKEEPER INACTIVATION DRIVES TUMOR PROGRESSION TO GRADE IV ASTROCYTOMA
Authors: Hartewig Anja , Granberg Kirsi , Jaatinen Serafiina , Tiihonen Aliisa , Annala Matti , Vuorinen Elisa , Kivinen Anni , Rauhala Minna , Maass Kendra , Pajtler Kristian , Yli-Harja Olli , Helén Pauli , Haapasalo Joonas , Zhang Wei , Haapasalo Hannu , Nykter Matti 
Published: November 2022

Abstract
IDH-mutant low-grade diffuse astrocytomas frequently progress to grade IV astrocytomas with implications for patient prognosis. To better understand this process, we applied whole-genome and transcriptome sequencing to matched tumor samples collected before and after progression to grade IV astrocytomas from five patients. All tumors carried an IDH1 mutation. The number of chromosomal rearrangements was increased between 1.3 and 3.5-fold in the tumors upon progression, with the exception of one case, in which the increase was only 1.03-fold. This case exhibited a hypermutation signature caused by homozygous deletion of the MSH2 gene, which encodes a member of the DNA mismatch repair complex. The most common genomic alterations acquired at progression were homozygous deletions in the CDKN2A/ RB1 -pathway or hemizygous deletion of PTEN. Additionally, PDGFRA was amplified in two grade IV tumors, with concordantly increased expression. For one of these cases, a PDGFRA-amplified subclone is likely to be present already in the low-grade astrocytoma. We further detected intrachromosomal rearrangements closeby the genes NRG3 in the progressed tumors as well as in the The Cancer Genome Atlas (TCGA) cohort. The expression of NRG3 decreased with increasing grade in the TCGA cohort and the gene was frequently deleted. Lower NRG3 expression was associated with shorter survival in the TCGA cohort. Several miRNAs showed differential expression upon progression. For two miRNAs the predicted targets were associated with cell cycle regulation and we detected inverse correlation between miRNA and target mRNA expression. While progression seems to occur via different pathways, the predicted outcome for many of the alterations was the inactivation of tumor suppressor genes and further dysregulation of cell proliferation.
EPCO-24. MULTI-OMIC PROFILING OF PATIENT-DERIVED SUBCLONES IDENTIFIES AGGRESSIVE CELLULAR SUBPOPULATIONS IN PAEDIATRIC DIFFUSE HIGH GRADE GLIOMAS (PDHGGS)
Authors: Kessler Ketty , Grabovska Yura , Burford Anna , Temelso Sara , Tari Haider , Molinari Valeria , Crampsie Shauna , Yu Lu , Choudhary Jyoti , Proszek Paula , Hubank Mike , Mackay Alan , Jones Chris 
Published: November 2022

Abstract
Paediatric-type diffuse high-grade gliomas are classified into distinct subgroups based upon their location and defining molecular alterations, with very poor clinical outcomes in patients &gt;3yrs. This extensive inter-tumour heterogeneity is further complicated by a wide diversity of genotypically- and phenotypically-distinct subclonal populations within individual tumours, providing a substantial barrier to developing effective treatments. We aimed to understand the dynamic cellular make-up of PDHGGs such that novel strategies aimed at targeting specific subpopulations based upon their contribution to disease progression as whole may be employed. Two complementary approaches have been undertaken to address this – first by carrying out single-cell profiling of bulk specimens, and the second isolation and propagation of single-cell-derived stem cell-like cultures in vitro. To-date we have studied 10 cases and a total of 218 subclonal colonies from both DMG-H3K27 and DHG-WT. In a spinal metastatic case of DMG-H3K27, lpWGS/FISH highlighted subpopulations driven by mis-segregation of amplified oncogenic ecDNA, and mutually exclusive subpopulations defined by MYCN, PDGFRA and CCND1. Through integrated analysis of scRNA-seq and scATAC-seq, we show distinct chromatin accessibility profiles to underlie gene expression signatures defining unique subpopulations of cells. In addition to cycling populations and those associated with lineage-specificity, we identified ‘aggressive’ subpopulations defined by significant upregulation of immediate early response genes such as FOS/FOSL1/JUN, those associated with promotion of invasion/migration such as SERPINs and MMPs. These subpopulations could be mapped to isolated single-cell-derived subclones with highly proliferative and/or motile phenotypes, defined by comprehensive profiling of expressed and secreted proteins. Differential cis-regulation driving cell identity/tumorigenesis was found in one example to occur via a trans-histone mechanism mediated by an H4-lysine-methyltransferase, KMT5B. Application of functionally-defined interventional strategies aimed at disrupting the interactions between these subpopulations based upon evolutionary biology principles may offer a novel approach to treat these otherwise incurable tumours in children and young adults.
EPCO-31. AI-BASED PROGNOSTIC STRATIFICATION OF GLIOBLASTOMA USING H&E-STAINED WHOLE SLIDE IMAGES
Authors: Baheti Bhakti , Nasrallah MacLean , Bakas Spyridon 
Published: November 2022

Abstract

BACKGROUND
Glioblastoma is the most common and aggressive malignant adult brain tumor, with median overall survival (OS) of 14 months. Despite optimizations in the treatment regime and technological advancements, patient OS has remained unchanged for the last 20 years. Here we seek the prognostic stratification of glioblastoma patients, by virtue of distinct morphological patterns apparent in histopathology H&E-stained whole slide images (WSI) alone.

METHODS
We selected 271 (ntraining/nhold-out-test= 216/55) frozen digitized tissue sections, at 10x magnification, of untreated primary glioblastoma (IDH-wildtype) adult cases from the TCGA-GBM collection, without history of previous glioma and with post-operative OS &gt; 30 days. The median OS across cases was used to divide them into short- (&lt; 324 days) and long- ( &gt; 390 days) survivors, after excluding 5 percentiles of cases around this median. Each WSI was partitioned in non-overlapping 256x256 patches. A pre-trained VGG16 AI model automatically extracted a 512-dimensional feature vector from each patch. Dimensionality was reduced, from 512 to 8, using principal component analysis, and distinct groups of morphological patterns were identified with unsupervised clustering. The number of distinct groups was decided based on the silhouette coefficient, assessing goodness of clustering. The proportions of these patterns within each WSI, describing the tumor’s spatial heterogeneity, were used to distinguish between short- and long-survivors using gradient boosting.

RESULTS
We identified morphological patterns of 5 distinct groups, descriptive of cellularity differences as well as artifactual content. Quantification of these patterns’ proportions resulted in a classification accuracy of 72.72% (short- vs long-survivors).

CONCLUSIONS
We identified morphologic patterns within a WSI, associated with shorter and longer OS. These may allow the clinical neuropathologist to i) provide additional prognostic information gleaned during microscopic assessment to the treating team, and ii) suggest avenues for further biological investigations towards contributing to our mechanistic understanding and potentially treating of glioblastoma.