bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-44. INTERIM RESULTS OF PHASE 2 STUDY TO EVALUATE PI3K/mTOR INHIBITOR PAXALISIB (GDC-0084) GIVEN TO NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE PROMOTER
Authors: Wen Patrick , de Groot John , Battiste James , Goldlust Samuel , Damek Denise , Garner James , Simpson Jeremy , Olivero Alan , Cloughesy Timothy 
Published: December 2020

Abstract

BACKGROUND
Paxalisib (GDC-0084) is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR). Paxalisib crosses the blood-brain barrier and achieves a brain / plasma ratio of approximately 1.0. An MTD of 60mg per day has been identified in newly diagnosed glioblastoma (GBM) patient with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status. Paxalisib has shown encouraging indications of clinical activity.

METHODS
This study has a 2-part design: an open-label, dose-escalation phase (Stage 1) to define MTD, followed by an expansion cohort (Stage 2) at the MTD and patients are randomized to take paxalisib, in fed or fasted states. Pharmacokinetic data will be analysed and compared by dose and fed/fasted status.

RESULTS
Stage 2 (expansion cohort) is fully enrolled and patients are in follow-up. Adverse event profile seems broadly consistent with prior clinical experience and with other PI3K-targeting agents. With analysis including all patients, a sustained PFS signal of 8.5 months is seen and this compares favourably with historical controls.

CONCLUSION
Paxalisib displays a safety profile consistent with previous data and promising efficacy signals in newly diagnosed GBM. A pivotal study in GBM is planned to commence recruitment later this year.
CTNI-62. CLINICAL FEATURES AND PROGNOSTIC FACTORS OF NONGERMINOMATOUS GERM CELL TUMORS IN 111 CONSECUTIVE PATIENTS IN A SINGLE INSTITUTION: IMPACT OF IRRADIATION AND CHEMOTHERAPY CYCLES ON SURVIVAL
Authors: Wen Lei , Li Juan , Hu Qingjun , Lai Mingyao , Zhou Cheng , Shan Changguo , Cai Linbo 
Published: December 2020

Abstract

BACKGROUND
Limited data is available in intracranial nongerminomatous germ cell tumors (NGGCTs) in Chinese population. Here we aimed to retrospectively assess the clinical-pathological and prognostic factors of NGGCTs in a single large institution in China.

METHODS
From June 2003 to December 2018, 111 consecutive NGGCTs were treated in Guangdong Sanjiu Brain Hospital, China.

RESULTS
The median follow-up was 36.2 months (range, 1.2 to 131.2 months). Three-year EFS and OS for 111 NGGCTs patients were 78.5%±4.5% and 82.8%±4.0%, respectively. 98 patients received CSI plus boost yielded better survival than those who received reduced-volume radiotherapy or no radiotherapy (3y OS, 86.7% vs. 51.4%, p=0.007). Patients had at least four cycles of chemotherapy were strongly associated with improved 3-year OS, compared to those received less than 4 cycles (94.1% vs. 63.6%, p＜0.001). There was no significant difference in survival of patients stratified by age, surgery, hydrocephalus, as well as tumor diameter. Multivariate analysis identified chemotherapy cycles less than 4 was the only prognostic factor that conferring a worse OS (p=0.003). Patients both received CSI and at least 4 courses of chemotherapy were correlated with lower incidence of relapse (p=0.044).

CONCLUSIONS
Multimodal approach including CSI and enough courses of chemotherapy was effective and should be recommended for the treatment of newly diagnosed NGGCTs in Chinese population.
CTNI-70. LONG-TERM SURVIVAL IN GLIOBLASTOMA PATIENTS AFTER TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: Rulseh Aaron , Derner Adam , Sroubek Jan , Klener Jan , Vymazal Josef 
Published: December 2020

Abstract

PURPOSE
Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor and traditionally has a median survival of only 10 to 14 months, with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only 5 to 7 months with optimal therapy. Thus, advances in treatment that may improve survival in these patients are highly desirable.

METHODS
Tumor treating fields (TTFields) therapy (Novocure Ltd., Haifa, Israel) is an approved antimitotic treatment for patients with newly diagnosed and recurrent GBM. TTFields are low-intensity (1–3 V/cm), intermediate-frequency (100–300 kHz) alternating electric fields that selectively kill or arrest the growth of rapidly dividing cells by inhibiting the proper formation of the mitotic spindle and by causing rapid membrane breakdown during cytokinesis.

RESULTS
Our center was the first in the world to apply TTFields treatment to histologically proven GBM in a pilot study of 20 individuals (10 GBM and 10 RGBM) in 2004 and 2005, and 4 of the original 20 patients are still alive today (2 GBM, 2 RGBM), in good health and no longer receiving any treatment roughly 15 years (range 14.2–15.9 years) after initiating TTFields therapy, with no clinical or radiological evidence of recurrence. The diagnosis of GBM was confirmed in all patients in two independent laboratories. Two of the 4 surviving patients exhibited radiological signs of tumor growth initially, before the tumor regressed in size after a median of 4 months of continuous treatment.

CONCLUSIONS
Our results indicate that TTFields treatment may be remarkably successful for both newly diagnosed and recurrent GBM patients. We recommend that TTFields treatment should be applied for a sufficient amount of time, and that initial radiologic progression following treatment initiation should not be considered a reason to discontinue treatment.
DDRE-10. IMMUNE PROFILES ASSOCIATE WITH OUTCOMES IN HLA-A*02:01+, H3.3K27M+ PATIENTS WITH DIFFUSE MIDLINE GLIOMAS TREATED WITH H3.3K27M PEPTIDE VACCINE COMBINED WITH POLY-ICLC: A PNOC REPORT
Authors: Mueller Sabine , Taitt Jared M , Villanueva-Meyer Javier , Bonner Erin R , Nejo Takahide , Lulla Rishi R , Goldman Stewart , Banerjee Anurhada , Chi Susan , Whipple Nicholas S , Crawford John R , Gauvain Karen , Nazemi Kellie , Watchmaker Payal , Almeida Neil D , Okada Kaori , Salazar Andres , Gilbert Ryan , Nazarian Javad , Molinaro Annette , Butterfield Lisa H , Prados Michael , Okada Hideho 
Published: December 2020

Abstract

BACKGROUND
Patients with diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+ H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine.

PATIENTS AND METHODS
Newly diagnosed patients aged 3–21 years with positive HLA-A*02.01+ and H3.3K27M+ status were enrolled into two strata after completion of radiation therapy: Stratum A for DIPG (n=19); Stratum B for non-pontine DMG (n=10). Vaccine was administered in combination with poly-ICLC every three weeks for eight cycles, followed by once every six weeks. Immunological responses were assessed in peripheral blood mononuclear cells using mass cytometry.

RESULTS
19 patients enrolled in Stratum A (median age=11 years) and 10 in Stratum B (median age=13 years). There were no grade 4 treatment-related adverse events (TRAE). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22% to 73%) for Stratum A and 39% (95% CI, 16% to 93%) for Stratum B. The median OS was 16.1 months in patients exhibiting an expansion of H3.3K27M-reactive CD8+ T-cells compared to 9.8 months for their counterparts (p=0.05). DIPG patients with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared to their counterparts (p&lt; 0.1). Immediate pre-treatment dexamethasone administration inversely associated with H3.3K27M-reactive CD8+ T-cell responses. However, neither tumor size or bulk CD8+ T-cell status was significantly associated with OS.

CONCLUSION
Administration of the H3.3K27M-specific vaccine is well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared to non-responders.
DDRE-11. DEVELOPMENT OF THE FIRST-IN-CLASS INHIBITOR OF CHD4 - SENSITIZING RESISTANT GLIOMAS
Authors: Nurmemmedov Elmar , Kesari Santosh 
Published: December 2020

Abstract
Glioblastoma is a lethal brain tumor with high recurrence rate. CHD4 overexpression, which drives resistance to DNA damage, is one of the major sources of recurrence. Since standard GBM treatments like radiation and temozolomide chemotherapy create DNA damage, inhibition of CHD4 offers a new therapeutic option for resensitizing GBM. CHD4 is a ubiquitously expressed ATP-dependent chromatin remodeler, which plays a crucial role in epigenetic regulation of gene expression and in DNA damage repair. Structurally, CHD4 contains an HMG-like domain, PHD domains, two chromodomains, a catalytic ATPase module, two domains of unknown function (DUF) and a C-terminal domain CHDCT2. Currently, no specific inhibitors targeting this chromatin remodeler have been reported yet. We aim to develop the first-in-class inhibitor targeting chromo-domain of CHD4. We have performed in silico screens to identify small molecules binding to the chromo-domains of CHD4. We present our growing in vitro data demonstrating biophysical properties and mechanism-of-action of these novel inhibitors. We expect that the experiments proposed here will result in the development of the first-in-class CHD4 inhibitor which can be used in the future not only to better study the physiological role of CHD4 but also to determine its potential as a novel targeted therapy for GBM.
DDRE-12. PNOC001 (NCT01734512): A PHASE II STUDY OF EVEROLIMUS FOR RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMAS (pLGG)
Authors: Mueller Sabine , Aboian Mariam , Nazemi Kellie , Gauvain Karen , Yoon Janet , Minturn Jane , Leary Sarah , AbdelBaki Mohamed , Goldman Stewart , Elster Jennifer , Resnick Adam , Molinaro Annette , Phillips Joanna , Prados Michael , Haas-Kogan Daphne 
Published: December 2020

Abstract

OBJECTIVE
To estimate the 6-month Progression Free Survival (PFS6) associated with everolimus for progressive/recurrent pLGGs and to determine if activated PI3K/Akt/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) status was associated with response.

METHOD
Patients 3–21 years of age with recurrent or progressive pLGG were enrolled. Everolimus was administered orally at 5 mg/m2 daily. Tissue availability for molecular analysis was mandatory. Immunohistochemistry (IHC) for p-RPS6 was performed centrally. An adaptive Simon two-stage design was employed based on p-RPS6 status. Based on results of the first stage, enrollment in the second stage was either limited to pathway activated patients or open to all subjects.

RESULTS
From December 2012 to July 2019 a total of 65 subjects enrolled [median age 9 years (range 3–19); 43% female]. As of December 15, 2019 median number of treatment cycle is 8 (range 1–24); 7 patients remain on treatment. Toxicity profile is similar to published reports with rash and elevated lipid profiles as most common adverse events. PFS6 for the entire cohort is 63%; PFS6 is 64% for the activated and 61% for the non-activated patients. Central imaging review (n=52) revealed 1 partial response, 1 complete response, 33 stable disease, and 17 progressive disease at the end of study treatment. Initial molecular analysis identified BRAF alterations in 35/65 patients.

CONCLUSION
Everolimus is well tolerated and active in a subset of pLGGs. Ongoing analyses will assess predictive biomarkers of response and will be reported at the meeting.
DDRE-15. THE COMBINATION THERAPY OF PARP INHIBITOR AND TMZ IN DIFFUSE MIDLINE GLIOMA HARBORING H3 K27M-MUTANT
Authors: Ohba Shigeo , Hashizume Rintaro , Hirose Yuichi 
Published: December 2020

Abstract
Diffuse midline glioma harboring H3 K27M-mutant (DMG) is a newly defined entity, and the prognosis of DMG is very poor. Combined of radiotherapy and chemotherapy is a standard therapeutic approach, because surgical debulking for providing relief to patients is not an option. Temozolomide (TMZ) is often used for the treatment of gliomas. TMZ is an alkylating agent that adds a methyl group to DNA (O6-guanine, N7-guanine, and N3-adenine). TMZ-induced cytotoxicity is mainly derived from O6-methylguanine, which is repaired by O6-methylguanine DNA methyltransferase (MGMT). Unfortunately, most DMG lacks MGMT promoter hypermethylation, which contributes to less effectiveness of TMZ in DMG. Because N7-methylguanine and N3-methyladenine are repaired via base excision repair, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor combined with TMZ was considered to be effective to suppress the proliferation of DMG. The purpose of the study is to evaluate whether PARP inhibitor sensitizes DMG to TMZ. A patient-derived DMG cell line, SF8628, showed the expression of MGMT, resulted in resistant to TMZ. We evaluated the effects of multiple PARP inhibitors: talazoparib, olaparib, niraparib, A-966492 in SF8628 DMG cells. These PARP inhibitors suppressed the proliferation of SF8628 cells in a dose dependent manner. Moreover, PARP inhibitors enhanced TMZ-induced cytotoxicity in SF8628. The combined treatment of PARP inhibitor and TMZ induced apoptosis. These results would support a possibility that the combination treatment of PARP inhibitor and TMZ is an effective approach in DMG.
DDRE-27. LMNA-PRKDC AXIS PROMOTES CHEMORESISTANCE IN RECURRENT GBM BY STABILIZING DNA REPAIR FOCI
Authors: Saathoff Miranda , Shireman Jack , Savchuk Sol , Baisiwala Shivani , Park Cheol , James Charles , Ahmed Atique 
Published: December 2020

Abstract
Tumors in patients with recurrent GBM are resistant to standard therapies. Available models for testing experimental therapies to treat GBM are primarily derived from or representative of primary, untreated GBM. We have developed a clinically relevant model of recurrent, therapy-resistant glioblastoma (GBM6R) from a patient-derived xenograft (PDX) of primary glioblastoma (GBM6) that underwent multiple rounds of temozolomide (TMZ) treatment following intracranial engraftment in a host mouse. Initial characterizations of GBM6R revealed a significant decrease in sensitivity to TMZ both in vitro (p&lt; 0.008) and in vivo (p=0.0079). An unbiased screen to identify proteins with altered expression in GBM6R, relative to treatment naïve GBM6, revealed nuclear lamina protein LMNA as highly expressed in GBM6R. From in silico analysis we found that high LMNA expression is associated with poor survival for GBM patients (p=0.0001, Gravendeel; p=0.0078, TCGA_GBM; p&lt; 0.0001, CCGA; GlioVis). GBM5 and GBM43 PDX explant cultures treated with multiple doses of TMZ increased their expression of LMNA. We found that in TMZ treated and TMZ resistant tumors, that LMNA preferentially localizes to the nuclear lamina (p&lt; 0.001), which is not observed in primary, untreated tumors (p&lt; 0.005). Analysis of LMNA by immunoprecipitation revealed that LMNA interacts with DNA-PK and γH2AX. From these results, we hypothesize that LMNA may be acting to stabilize DNA damage foci at the nuclear periphery, which results in enhanced DNA repair. Our observations support the testing of selective DNA-PK inhibitors for treating GBM, which would inhibit TMZ-induced DNA damage repair, and enhance the cytotoxic effects of TMZ.
DDRE-29. SMOOTHENED-ACTIVATING LIPIDS DRIVE RESISTANCE TO CDK4/6 INHIBITION IN HEDGEHOG-ASSOCIATED MEDULLOBLASTOMA
Authors: Daggubati Vikas , Hochstelter Jordan , Bommireddy Ani , Choudhury Abrar , Krup Alexis , Kaur Pervinder , Tong Pakteema , Li Amy , Xu Libin , Reiter Jeremy , Raleigh David 
Published: December 2020

Abstract

BACKGROUND
Medulloblastoma is an aggressive pediatric brain tumor that is associated with misactivation of the Hedgehog (HH) pathway. Our lab has shown that CDK6, a critical activator of the cell cycle, is a direct transcriptional target of oncogenic HH signaling, and that inhibiting CDK6 blocks the growth of HH-associated medulloblastoma in mice. A clinical trial exploring the efficacy of CDK6 inhibition in medulloblastoma patients is underway, but prior attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to molecular monotherapy. Thus, we sought to identify mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma.

METHODS
We performed orthogonal CRISPR and CRISPR interference screens in HH-associated medulloblastoma cells treated with pharmacologic inhibitors of CDK6 in vitro, and RNA-sequencing of HH-associated medulloblastomas with genetic deletion of CDK6 in vivo. Mechanistic and functional validation of resistance pathways was performed using CRISPR interference, immunoblotting, immunofluorescence, genetics, and pharmacology. Lipid quantification was carried out by ultra-high performance liquid chromatography-tandem mass spectrometry.

RESULTS
Our results reveal that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to endoplasmic reticular (ER) stress and activation of the unfolded protein response (UPR). We show that ER stress and the UPR increase the activity of enzymes producing Smoothened-activating sterol lipids that sustain oncogenic HH signaling in medulloblastoma despite CDK6 inhibition. These discoveries suggest that combination molecular therapy against CDK6 and HSD11ß2, an enzyme producing Smoothened-activating lipids, may be an effective treatment for HH-associated medulloblastoma. In support of this hypothesis, we demonstrate that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2 additively blocks the growth of multiple models of HH-associated medulloblastoma in mice.

CONCLUSIONS
Smoothened-activating lipid biosynthesis underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, revealing a novel combination therapy to treat the most common malignant brain tumor in children.
EPCO-14. DECIPHERING DIFFERENTIATION HIERARCHIES, HERITABILITY AND PLASTICITY IN HUMAN GLIOMAS VIA SINGLE-CELL MULTI-OMICS
Authors: Gaiti Federico , Chaligne Ronan , Silverbush Dana , Schiffman Joshua , Weisman Hannah , Kluegel lloyd , Gritsch Simon , Deochand Sunil , Richman Alyssa , Klughammer Johanna , Biancalani Tommaso , Muus Christoph , Sheridan Caroline , Alonso Alicia , Izzo Franco , Rozenblatt-Rosen Orit , Regev Aviv , Suva Mario , Landau Dan 
Published: December 2020

Abstract
Human diffuse gliomas are incurable malignancies, where cellular state diversity fuels tumor progression and resistance to therapy. Single-cell RNA-sequencing (scRNAseq) studies recently charted the cellular states of the two major categories of human gliomas, IDH-mutant gliomas (IDH-MUT) and IDH-wildtype glioblastoma (GBM), showing that malignant cells partly recapitulate neurodevelopmental trajectories. This raises the central questions of how cell states are encoded epigenetically and whether unidirectional hierarchies or more plastic state transitions govern glioma cellular architectures. To address these questions, we generated multi-omics single-cell profiling, integrating DNA methylation (DNAme), transcriptome and genotyping of 1,728 cells from 11 GBM and IDH-MUT primary patient samples. Direct comparison of the methylomes of distinct glioma cell states revealed Polycomb repressive complex 2 (PRC2) targets DNAme as a key switch in the differentiation of malignant GBM cells. In contrast, dissecting aberrant circuits of hyper-methylation and gene expression in IDH-MUT gliomas, we observed a decoupling of the promoter methylation-expression relationship, with disruption of CTCF insulation and enhancer vulnerability which increases with cellular differentiation. To define cell state transition dynamics directly in patient samples, we generated high-resolution lineage histories of glioma cells using heritable DNAme changes, and projected the scRNAseq-derived cell states onto the lineage trees. This analysis demonstrated that cell states are heritable across malignant gliomas and, while in IDH-MUT differentiation far outpaces de-differentiation, GBM harbors a higher degree of cell state plasticity allowing reversion of GBM cells from a differentiated to a stem-like state. Overall, our work provides detailed insights into gliomagenesis, dissecting the epigenetic encoding, regulatory programs, and dynamics of the cellular states that drive human gliomas. Importantly, it also carries significant translational implication, as the high degree of de-differentiation in GBM challenges the paradigm of therapeutically targeting glioma stem-like cells to deprive tumors of their ability to regenerate.
EPCO-26. PROJECT HOPE: “PEDIATRIC AND AYA HIGH-GRADE GLIOMA OMICS PROJECT”- A LONGITUDINAL MOLECULAR LANDSCAPE OF HIGH-GRADE GLIOMAS RESOLVED AT SINGLE-CELL LEVEL
Authors: Jiang Li , Hack Olivia , Babikir Husam , Shamardani Karin , Liu Ilon , Shaw McKenzie , Cunliffe-Koehler Kennedy , Resnick Adam , Prados Michael , Monje Michelle , Diaz Aaron , Filbin Mariella 
Published: December 2020

Abstract
High-grade gliomas (HGG) are among the most prevalent and fatal cancers in pediatric, adolescent, and young adult (AYA) patients. Especially understudied are older children and young adults, aged 16–39 years. Previously, we profiled primary pediatric HGGs through single-cell transcriptomics and identified the genetic, epigenetic and developmental programs that drive their malignant progression. However, the questions of how these programs compare to those in older HGG patients, what the mechanisms are by which these tumors ultimately evolve to drive recurrence and treatment resistance, and how distinct tumor cell subpopulations bidirectionally communicate with their microenvironment remain to be elucidated. In order to investigate these questions, we use single-nucleus RNA sequencing to compare 11 paired, matched high-grade gliomas at diagnosis and recurrence and 15 additional H3K27M primary and recurrent DMG samples in pediatric and AYA patients. In all tumors, we find both undifferentiated and differentiated tumor cells recapitulating distinct glial lineages, as well as diverse microenvironmental cell populations. When longitudinally comparing this tumor architecture within matched pairs, we find substantial differences in transcriptional program expressions. In particular, recurrent samples showed a higher proportion of cells expressing heat- shock proteins (HSPs) and a novel cancer cell program characterized by synaptic formation and neurotransmitter secretory processes, suggesting tumor progression- and treatment-related shifts. Ongoing sequencing and analysis will allow for unprecedented insight into the evolutionary dynamics of pediatric and AYA high-grade gliomas as well as delineate differences in the biology of DMGs occurring in different age groups. This multi-institutional project was funded by the National Institute of Health.