bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-31. ERK1/2 PHOSPHORYLATION PREDICTS SURVIVAL FOLLOWING ANTI-PD-1 IMMUNOTHERAPY IN RECURRENT GLIOBLASTOMA
Authors: Arrieta Víctor , Chen Andrew X , Kane J Robert , Kang Seong Jae , Kassab Cynthia , Dmello Crismita , Zhao Junfei , Burdett Kirsten , Upadhyayula Pavan , Chang Catalina , Shilati Joseph , Jaishankar Dinesh , Chen Li , Gould Andrew , Zhang Daniel , Yuan Jinzhou , Zhao Wenting , Ling Xiaoyang , Burks Jared K , Laffleur Brice , Amidei Christina , Bruce Jeffrey N , Lukas Rimas V , Yamaguchi Jonathan T , Cieremans David , Rothschild Gerson , Basu Uttiya , McCord Matthew , Brat Daniel , Zhang Hui , Cooper Lee A D , Zhang Bin , Sims Peter , Cloughesy Timothy , Prins Robert , Canoll Peter , Stupp Roger , Heimberger Amy B , Horbinski Craig , Iwamoto Fabio , Rabadan Raul , Sonabend Adam M 
Published: November 2021

Abstract
PD-1 checkpoint inhibition has led to remarkable clinical responses in several cancer types. Whereas PD-1 blockade has not shown an overall survival (OS) benefit for glioblastoma (GBM) patients, a subset of them exhibit long-term responses to this immunotherapy. Previously, we reported an enrichment of BRAF/PTPN11 activating mutations in 30% of recurrent GBMs that responded to PD-1 blockade, but the molecular profile of the majority of responders remained elusive. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in recurrent GBM, including patients that do not harbor BRAF/PTPN11 mutations. Immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, was performed in a discovery cohort including pre-treatment specimens of 29 recurrent GBM patients treated with adjuvant PD-1 blockade, and 33 patients who did not undergo immunotherapy. p-ERK was predictive of response and OS following PD-1 blockade. Yet p-ERK was not associated with OS in patients not treated with immunotherapy. p-ERK was also associated with OS in a validation GBM cohort treated with adjuvant anti-PD-1 therapy. Single-cell RNA-seq and multiplex-immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and high p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. Thus, our findings indicate that ERK1/2 activation in recurrent GBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.
BIOM-36. SERIAL ASSESSMENT OF MEASURABLE RESIDUAL DISEASE IN MEDULLOBLASTOMA LIQUID BIOPSIES
Authors: Liu Anthony Pak-Yin , Smith Kyle , Kumar Rahul , Paul Leena , Lin Tong , Maass Kendra , Pajtler Kristian , Bihannic Laure , Orr Brent , Ellison David , Gilbertson Richard , Onar-Thomas Arzu , Gajjar Amar , Robinson Giles , Northcott Paul 
Published: November 2021

Abstract
Medulloblastoma is the most common malignant brain tumor in children. Despite the use of contemporary multi-modal therapy, up to one-third of patients will succumb to disease progression. Conventional response monitoring is based on magnetic resonance imaging and cerebrospinal fluid (CSF) cytology and a marker for measurable residual disease (MRD) is lacking. In this study, we show the clinical utility of profiling CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD based on a sizable cohort of children with medulloblastoma enrolled on a prospective, multi-center, risk-adapted trial (SJMB03; NCT00085202). A total of 476 CSF samples were serially collected from 123 patients by lumbar puncture at post-operative baseline, during therapy, and at regular surveillance after completion of therapy. Using low-coverage whole-genome sequencing (lcWGS), tumor-associated copy-number alterations in CSF-derived cfDNA were investigated as an MRD surrogate for correlation with clinical features and outcomes. MRD was detected in post-operative baseline CSF samples for 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients declined with therapy, yet those with persistent MRD detected at the end of therapy (20 of 68 CSFs at this timepoint) had significantly higher risk of disease progression (hazard ratio 8.94, 95%CI 4.10-19.49; log-rank p&lt; 0.0001). Importantly, MRD-positivity from routine surveillance samples often preceded radiographic progression by more than 3 months. Comparative analyses of copy-number variations obtained from serial CSF samples enabled identification of relapse-specific alterations and early detection of relapse-dominant clones. Overall, our findings advocate for the routine incorporation of CSF-derived liquid biopsies in future medulloblastoma trials.
BIOM-40. TARGETED GENE EXPRESSION PROFILING PREDICTS MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES
Authors: Chen William , Choudhury Abrar , Vasudevan Harish , Lucas Calixto , Nguyen Minh , Young Jacob , Yu Theresa , Lam Tai-Chung , Pu Jenny , Li Lai-Fung , Leung Gilberto , Chan Jason , Oberheim-Bush Nancy Ann , Villanueva-Meyer Javier , Schulte Jessica , Braunstein Steve , Butowski Nicholas , Sneed Penny , Berger Mitchel , Perry Arie , Solomon David , McDermott Michael , Magill Stephen , Raleigh David 
Published: November 2021

Abstract

BACKGROUND
Surgery is the mainstay of meningioma treatment, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. DNA methylation profiling, copy number variants (CNVs), exome sequencing, and RNA sequencing have improved understanding of meningioma biology, but have not superseded histologic grading, or revealed biomarkers for radiotherapy responses. To address these unmet needs, we optimized and validated a targeted gene expression biomarker predicting meningioma outcomes and responses to radiotherapy.

METHODS
Targeted gene expression profiling was performed on a discovery cohort of 173 meningiomas (median follow-up 8.1 years) and a validation cohort of 331 meningiomas (median follow-up 6.1 years) treated with surgery (n=504) and postoperative radiotherapy (n=73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). Optimized targeted gene expression models predicting clinical outcomes (34 genes) or radiotherapy responses (12 genes) were developed from the discovery cohort, and compared to histologic and molecular classification systems by performing DNA methylation profiling, CNV analysis, exome sequencing, and RNA sequencing on the same meningiomas.

RESULTS
Targeted gene expression profiling achieved a concordance-index of 0.75 ± 0.03 (SEM) for local freedom from recurrence (LFFR) and 0.72 ± 0.03 for overall survival (OS) in the validation cohort, outperforming WHO grade (5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p=0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p=0.01) for LFFR, disease-specific survival, and OS. The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and identified meningiomas benefiting from radiotherapy (interaction p-value=0.0008), suggesting postoperative radiotherapy could be refined in 30.2% of cases.

CONCLUSIONS
Targeted gene expression profiling of 504 meningiomas improves discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and predicts radiotherapy responses.
STEM-17. THE GLIOMA STEM CELL PLATELET INTERACTION DRIVES GBM ONCOGENESIS IDENTIFYING A NOVEL THERAPEUTIC APPROACH
Authors: Sloan Anthony , Hoffman Harry , Harris Peggy , Lee-Poturalski Christine , Elder Theresa , Kerstetter-Fogle Amber , Cioffi Gino , Desai Ansh , Rich Jeremy N , Barnholtz-Sloan Jill , Gupta Anirban Sen , Jankowsky Eckhard , Sloan Andrew 
Published: November 2021

Abstract
The effect of platelets on oncogenesis has been studied extensively in cancer metastasis, but not in glioblastoma (GBM), where metastasis is rare. Here we identify the unique crosstalk between glioma stem cells (GSCs) and platelets within GBM solid tumors that enhance disease progression. Targeting GSCs is considered a promising therapeutic approach; however, no clear method has been identified. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Immunofluorescence, qPCR, and western blot were used to evaluate the presence of GSCs and platelets and their colocalization in GBM patient tissue at University Hospitals-Seidman Cancer Center. Functional assays followed by RNA sequencing were conducted to determine the functional effect of healthy and GBM platelets on growth of patient derived, autologous GSCs. Our clinical studies suggest elevated platelet counts positively correlate with GSC proliferation and negatively correlate with overall survival in patients with GBM. Patients with high platelet counts ( &gt;350k/µl) had a median survival time of 9 months compared to 16 months median survival for patients with normal platelet count (150-350/µl) (p&lt;0.05). We demonstrate platelet and GSC co-localization in GBM solid tissue and platelet exposure to patient derived GSCs cell lines results in a ≥ 3-fold increase in GSC proliferation compared to GSCs not exposed to platelets (p&lt;0.0005). Similarly we found that platelets increased the self-renewing capacity by enhancing the average sphere size (p &lt; 0.005), and increasing the GSC “Stem-like” transcriptional pattern (P&lt; 0.05). Conversely, pharmacologic inhibition of platelet activation reversed the effect of platelets on GSC proliferation (p ranging from 0.05-0.005). These studies suggests the platelet-GSC interactions appear to stimulate GBM oncogenesis, identifying a potential therapeutic target for the treatment of GBM.
CBIO-10. TARGETING HISTONE H4 Lys 20 MONOMETHYLATION IN THE TREATMENT OF GLIOBLASTOMA
Authors: Han Mingzhi , Li Xingang 
Published: November 2021

Abstract

BACKGROUND
Glioblastoma (GBM) is the most malignant primary tumor of the central nervous system, while the pathogenesis remains unclear. Protein lysine methyltransferase SETD8, which is responsible for the modification of histone H4K20me1, has been shown to play an important role in cellular transcriptional regulation and the development of a variety of tumors, yet its role in the malignant progression of GBM has not been elucidated. MATERIAL AND

METHODS
In the present study, we used primary GBM cell lines, intracranial xenograft model, transcriptome sequencing together with ChIP-sequencing, aiming to elucidate the molecular mechanism of SETD8-mediated H4K20me1 transcriptional regulation in promoting GBM progression. Furthermore, we evaluated the potential therapeutic significance in GBM using SETD8 small molecule inhibitor, UNC0379.

RESULTS
We found that SETD8 is aberrantly expressed in GBM tissues, accompanied by the dysregulation of H4K20me1 modification, which is associated with tumor pathology and prognosis. Using SETD8 inhibitor UNC0379 or knockdown of SETD8 significantly inhibited GBM cell proliferation in vitro and in vivo, and downregulated H4K20me1 modification level as well as transcriptome expression.

CONCLUSION
In summary, our work provide a novel insight into the role of SETD8/H4K20me1 axis. SETD8 overexpression mediated aberrant H4K20me1 modification act as a novel "transcriptional switch" in the malignant progression of glioma.
CBIO-11. HISTONE H3.3 G34R/V MUTATIONS STIMULATE PEDIATRIC HIGH-GRADE GLIOMA FORMATION THROUGH THE INDUCTION OF CHROMOSOMAL INSTABILITY
Authors: Day Charles , Grigore Florina , Langfald Alyssa , Hinchcliffe Edward , Robinson James 
Published: November 2021

Abstract
H3.3 G34R/V mutations are drivers of high-grade pediatric glioma (pHGG). H3.3 G34R/V mutations are linked to altered H3.3 K36 trimethylation (H3K36me3); implicating epigenetic gene regulation as a possible contributor to pHGG formation. Here we show that H3.3 G34R/V also induces chromosomal instability (CIN); a hallmark of pHGG. If CIN promotes pHGG formation is unknown. We observed that H3.3 G34 mutant pHGG cells have reduced mitotic H3.3 S31 phosphorylation compare to WT H3.3 cell lines. And, H3.3 G34R reduced Chk1 phosphorylation at S31 by &gt;90% in an in vitro kinase assay. Chk1 regulates chromosome segregation through phosphorylation of pericentromeric H3.3 S31 during early mitosis. Overexpression of H3.3 G34R or non-phosphorylatable S31A in H3.3 WT, diploid cells caused a significant increase in CIN. Likewise, H3.3 G34 mutant pHGG cells have significantly elevated rates of CIN as compare to H3.3 WT pHGG cells. During normal cell division, phospho-S31 is lost in anaphase. However, following chromosome missegregation, phospho-S31 spreads and stimulates p53-induced cell cycle arrest. Here we show that WT p53 cells expressing mutant G34 fail to arrest following chromosome mis-segregation. These studies demonstrate that H3.3 G34R/V mutations are sufficient to transform normal, diploid cells into proliferating CIN cells. To determine if this process contributes to tumorigenesis, we used RCAS Nestin-TVA mice to overexpress H3.3 WT, G34R, or S31A – P2A-linked to PDGFB expression in glial precursor cells of newborn mice. Over 100 days, S31A and G34R mice had drastically reduced survival (averaging 77, 81, and 100 days for S31A, G34R, and WT). Furthermore, most G34R and S31A mice developed HGG, while H3.3 WT mice remained tumor-free. Our work implicates CIN as a driver of H3.3 G34 mutant pHGG formation. Our ongoing studies utilize K36M and double mutants to further define the contributions of S31 phosphorylation (CIN) and H3K36me3 (epigenetic gene regulation) to tumorigenesis.
CBIO-22. PARP INHIBITION SYNERGIZES WITH DNA DAMAGING DRUGS IN PEDIATRIC CNS TUMORS
Authors: Laemmerer Anna , Kirchhofer Dominik , Madlener Sibylle , Loetsch-Gojo Daniela , Jaunecker Carola , Schrempf Anna , Reisecker Johannes , Vician Petra , Gabler Lisa , Mayr Lisa , Loizou Joanna , Slavc Irene , Berger Walter , Gojo Johannes 
Published: November 2021

Abstract

BACKGROUND
Central nervous system (CNS) tumors are the second most common childhood cancer. Despite innovations in surgery and chemo-/radiotherapy, CNS tumors remain the major cause of cancer-related death in children. Previous sequencing analyses in a pediatric cancer cohort identified BRCA and DSB repair signatures as potentially targetable events. Based on these findings, we propose the use of PARP inhibitors (PARPi) for aggressive CNS tumor subtypes, including high-grade glioma (HGG), medulloblastoma (MB) and ependymoma (EPN).

METHODS
We tested multiple PARPi in tumor cell lines (n=8) as well as primary patient-derived models (n=11) of pediatric HGG, MB, EPN and atypical teratoid/rhabdoid tumors (ATRTs). Based on PARPi sensitivity, selected models were further exposed to a combination of PARPi and DNA-damaging/modifying agents. The mode of action was investigated using Western blot and flow cytometry.

RESULTS
We show that a fraction of pediatric MB, EPN and ATRT demonstrate sensitivity towards PARP inhibition, which is paralleled by susceptibility to the DNA damaging drugs cisplatin and irinotecan. Interestingly, talazoparib, the most potent PARPi, showed synergistic cytotoxicity with DNA-damaging/modifying drugs. In addition, cell cycle blockade and increased DNA damage combined with reduced DNA repair signaling, such as activation of the ATR/Chk1 pathway were observed. Corroboratively, talazoparib exhibited a synergistic anti-cancer effect in combination with inhibitors of ATR, a major regulator of DNA damage response.

CONCLUSION/OUTLOOK
To sum up, we demonstrate that PARP inhibition synergizes with DNA damaging anti-cancer compounds or DNA repair inhibitors and, thus, represents a promising therapeutic strategy for a defined subgroup of pediatric high-risk CNS tumors patients. More in depth characterization of the underlying molecular events will most likely allow the identification of predictive biomarkers for most efficient implementation of this strategy into clinical application.
CBIO-28. IDENTIFYING THE ROLE OF MISMATCH REPAIR IN TEMOZOLOMIDE-INDUCED ATR ACTIVATION FOR MGMT-METHYLATED GLIOBLASTOMA MULTIFORME
Authors: Ganesa Sachita , Sule Amrita , Sundaram Ranjini , Bindra Ranjit 
Published: November 2021

Abstract
The methylation status of the O6-methyl guanine methyltransferase (MGMT) gene promoter is a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ) in many solid tumors including gliomas and colorectal cancers. It is well established that patients with a methylated MGMT promoter (MGMT-) who are treated with the TMZ have a better overall survival than patients with an unmethylated MGMT promoter (MGMT+). The enzyme produced by the MGMT gene is responsible for removing cytotoxic O6-methylguanine (O6-meG) lesions formed by TMZ. In the MGMT- setting, the O6-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Published work from our group reported differential activation of the ataxia telangiectasia and RAD3 related protein (ATR) in MGMT- and MGMT+ glioblastoma multiforme (GBM) cells in response to TMZ treatment, as demonstrated through the phosphorylation of CHK1. Though it is known that MMR proteins are involved in ATR activation, the specific MMR proteins required for ATR activation by TMZ-induced alkyl lesions remain unknown in the MGMT- setting. Here, we demonstrate that specific mismatch repair proteins, including MSH2, MSH6, and PMS2 play a role in ATR activation in the presence of O6-meG lesions. We show that there is potent synergy with ATRi and TMZ in the MGMT- MMR- proficient GBM cell line, which is abrogated in an shMMR MGMT- GBM cell line. Additionally, we observe decreased levels of pCHK1 in the shMMR MGMT- setting compared to the MGMT- MMR-proficient cells, suggesting that MMR is integral in the activation of ATR upon TMZ treatment. Mechanistic understanding of how the MMR system is involved in ATR activation by TMZ can ultimately be exploited for therapeutic gain.
CSIG-03. GBP5 DRIVES MALIGNANCY OF GLIOBLASTOMA
Authors: Li Ming , Chen Clark 
Published: November 2021

Abstract
Guanylate binding proteins (GBPs), a family of interferon-inducible large GTPase, play a pivotal role in cell-autonomous immunity and tumor malignant transformation. Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults. Here we show that GBP5 was highly expressed in GBM cell lines and in clinical samples, especially in the mesenchymal subtype. The expression levels of GBP5 were negatively correlated with the prognosis of GBM patients. Overexpression of GBP5 promoted the proliferation, migration, and invasion of GBM cells in vitro and in vivo. In contrast, silencing GBP5 by RNA interference exhibited the opposite effects. Consequently, targeting GBP5 in GBM cells resulted in impaired tumor growth and prolonged survival time of mice with GBM tumors. We further identified that the Src/ERK1/2/MMP3 axis was essential for GBP5-promoted GBM aggressiveness. These findings suggest that GBP5 may represent a novel target for GBM intervention.
CSIG-14. PTEN AS A SIGNATURE OF VULNERABILITY OF GBM TO NEDDYLATION INHIBITION
Authors: Taylor Brett , Ferdosi Shayesteh , Lee Matthew , Tang Nanyun , Peng Sen , Bybee Rita , Hartman Lauren , Reid George , Garcia-Mansfield Krystine , Sharma Ritin , Pirrotte Patrick , Ma Jianhui , Parisian Alison , Furnari Frank , Dhruv Harshil , Berens Michael 
Published: November 2021

Abstract
Neddylation is a specific pathway within the ubiquitin/proteasome system that is overactive in GBM, and whose upregulation has been associated with glioma progression and worse survival. Pevonedistat (MLN4924) is a first-in-class small-molecule neddylation inhibitor shown to inhibit growth of GBM cells by impacting protein degradation in culture and orthotopic xenografts. However, the determinants of vulnerability are not fully understood. Because the molecular heterogeneity within and across GBM patients obscures therapeutic targets and obfuscates signals of efficacy in clinical trials, we pursue the use of molecular “signatures of vulnerability” to targeted agents in subsets of preclinical models. Selective vulnerability to pevonedistat was shown in a subset of GBM; notably, models with mutations or copy number deletions of PTEN are associated with de novo resistance to pevonedistat. Time-course studies of sensitive and non-sensitive GBM cells using transcriptomics and proteomics/phosphoproteomics uncovered additional determinants of response to pevonedistat. Our results demonstrate that in GBM, resistance to pevonedistat is driven by reduced PTEN-chromatin binding (loss-of-function or lower expression) that is also independent of PTEN’s lipid phosphatase activity (i.e., PI3K/AKT signaling). Across 25 glioma cell lines, we found that PTEN signaling, DNA replication, and chromatin instability pathways are the most significant differentiators between pevonedistat sensitive vs. non-sensitive models. In GBM models with modest to low sensitivity to pevonedistat, TOP2A expression was elevated. Combination treatment with the TOP2A inhibitor, etoposide, proved synergistic with pevonedistat. We report that PTEN status both serves as a novel biomarker for GBM sensitivity to pevonedistat and reveals a synergistic vulnerability to TOP2A inhibitors in combination with pevonedistat. Paired use of GBM PDX models of varying sensitivity with drug development testing allows the advancement of a promising agent as well as a patient-enrollment “signature of vulnerability” likely to increase the likelihood of demonstrating therapeutic efficacy in early stage clinical trials.
RADT-25. PROTON THERAPY FOR YOUNG ADULT MEDULLOBLASTOMA: ACUTE TOXICITY AND DISEASE CONTROL OUTCOMES
Authors: Liu I-Chia , Holtzman Adam , Rotondo Ronny , Indelicato Daniel , Gururangan Sridharan , Cavaliere Robert , Morris Christopher , Tavaniepour Daryoush , Rutenberg Michael 
Published: November 2021

Abstract

BACKGROUND
Report disease control, survival outcomes, and acute radiotherapy related toxicity among young adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy. We reports the completion rates of planned adjuvant chemotherapy.

METHODS
All adult medulloblastoma patients (≥ 22 years old) who received postoperative proton CSI +/- chemotherapy at our institution between 2008 and 2020 were included. Patient, disease, and treatment details along with prospectively obtained patient-reported acute CSI toxicities were collected (CTCAE v3 or v4). Acute hematologic data were analyzed.

RESULTS
Twenty young adult medulloblastoma patients were included. The median age at diagnosis was 27 years (range, 22–30). 45% had high-risk disease. 75% received chemotherapy, most of whom (65%) received post-CSI chemotherapy. Eight patients (40%) received concurrent vincristine with CSI. The median CSI dose was 36 GyE (range, 23.4-36) with a median tumor bed boost of 54 GyE (54-55.8). The median duration of radiotherapy was 44 days (range, 40-49). There were no acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI (during or within 4 weeks after completion of RT). Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively. Acute grade 2 hematologic toxicity affected 36% of patients. Among patients planned to receive adjuvant chemotherapy (n=13), 100% completed at least 4 cycles and 85% completed all planned chemo cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, DFS, and OS were 90% (95% CI 53-99), 90% (95% CI 53-99), and 95% (95% CI 72-99), respectively. Two patients had disease recurrence, both with local failures in the high dose boost volume in the tumor bed.

CONCLUSIONS
Proton radiotherapy for CSI in young adult medulloblastoma patients is well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma.