bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-72. CREATION, CHARACTERIZATION AND CATALOGUING NEXT-GENERATION DIPG PATIENT-DERIVED CANCER CELL LINES: THE DIPG C3 PROJECT
Authors: Bhatia Sonam , Quinn Thomas , Chow Kin-Hoe , Vogelzang Jayne , Shetty Aniket , Yerrum Smitha , Monje Michelle , Raabe Eric , Filbin Mariella , Hulleman Esther , Ligon Keith L , Warren Katherine 
Published: June 2024

Abstract

BACKGROUND
Preclinical studies of diffuse intrinsic pontine glioma (DIPG) have increased significantly over the past 15 years due to the development of DIPG disease-specific tools including cell lines and animal models. We now know that DIPG is a molecularly heterogeneous tumor. While &gt;80% of these tumors have H3K27M alterations, partner mutations can vary. Many DIPG cell lines used for pre-clinical assessments of new therapies have not been fully characterized, therefore, comparing preclinical results across studies has been impeded. We sought to Create, Characterize and Catalogue DIPG cell lines and animal models with the aim of expanding contemporary resources and providing a public database for DIPG researchers.

METHODS
Existing DIPG cell lines in the Center for Patient-Derived Models (CPDM) were utilized; additional patient-derived cell lines were created in CPDM, and obtained from collaborators. The assembled collection was characterized by whole genome (WGS) and RNA-sequencing (RNAseq).

RESULTS
To date, we have 21 growth-verified DIPG models with the majority grown as 3D neurospheres in-vitro and capable for long-term culture. Fourteen (14) of these patient-derived models were genomically verified with WGS and RNA-seq platform. Data will be made publicly available to researchers on cBioPortal.

CONCLUSIONS
Systematic characterization and cataloguing of pre-clinical DIPG models is important to allow more stringent comparison across studies and ensure their utility and impact. These DIPG-specific tools can thus be used in applications such as drug discovery and testing.
DIPG-77. SOMATICTP53,PIK3R1, NF1 ORTERT MUTATIONS ARE ASSOCIATED WITH INFERIOR CLINICAL OUTCOME IN H3K27M-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Nguyen Thien , Lerman Benjamin , Stoller Schuyler , Müller Timothy , Comfort Lion , Lyons Samantha , Holman Lynette , Junior Calixito Hope Lucas , Banerjee Anu , Reddy Alyssa , Gupta Nalin , Whipple Nicholas , Gerber Nicolas , Stuecklin Ana , Areza Esha , Marion Rizo , Knowles Truman , Solomon David , Franson Andrea , Koschmann Carl , Partap Sonia , Monje Michelle , Prolo Laura , Cheshier Samuel , Antony Reuben , Bhatia Aashim , Foster Jessica , LaRiviere Michael , Maule Laura , Carrion Andrea W , Kline Cassie , Bruningk Sarah , Nazarian Javad , Waszak Sebastian M , Mueller Sabine 
Published: June 2024

Abstract

BACKGROUND
H3K27-altered diffuse midline gliomas (DMGs) have poor prognosis with no standard of care therapy beyond radiation (RT). While RT prologues survival, not all patients respond. Prior work has shown somatic TP53 mutations predict radiation resistance, and poorer outcomes. We report on a multi-center retrospective cohort study to identify molecular biomarkers of RT response in DMG patients.

METHODS
We performed retrospective chart reviews of patients with biopsy-proven H3K27M-altered DMG between 2013-2023 from six US medical centers and the DMG Center in Zurich. Patients with tumor genomic sequencing and completion of RT were eligible. Genomic alterations were evaluated for somatic mutations, fusions, and chromosomal instability. Cox proportional hazard models were used to evaluate associations between genomic alterations and survival. Multivariate analysis included all significant variables at P &lt;0.1 in initial analysis, including age at diagnosis, tumor location, TP53 and PIK3R1 alterations.

RESULTS
297 patients (135 female; median age 8.3years; range 0.2-71.4 years) were included. Median progression-free survival (PFS) and overall survival (OS) was 7.6months (95%-CI 6.9-8.6) and 14.0months (95%-CI 12.9-15.7). Univariate analysis identified TP53 or PIK3R1 status to be associated with shorter OS (TP53-mutant 12.5months vs. TP53-wildtype 17.5months; HR=1.5; 95%-CI (1.1-2.0), P=0.005); (PIK3R1-mutant 12.6months vs. PIK3R1-wildtype 14.5months; HR=1.9, 95%-CI (1.1-3.4), P=0.03). Multivariate analysis corroborated TP53 status association with shorter OS (HR=1.5; 95%-CI (1.2-2.0), P=0.003). Subgroup univariate analysis of pontine DMG patients showed reduced OS with TP53, NF1, or TERT mutations (TP53-mutant 11.9months vs. TP53-wildtype 15.2months; HR=1.6; 95%-CI (1.1-2.3), P=0.02); (NF1-mutant 8.4months vs. NF1-wildtype 13.6months; HR=2.3; 95%-CI (1.1-5.0), P=0.03); (TERT-mutant 8.5months vs. TERT-wildtype 13.6months; HR=2.5; 95%-CI (1.1-5.7), P=0.03). Subsequent multivariate analysis corroborated the association of TERT mutations with shorter OS in pontine DMG (HR=2.5; 95%-CI (1.05, 5.9), P=0.03).

CONCLUSIONS
This is one of the largest molecular characterized cohorts of H3K27M-altered DMG patients. DMGs with somatic TP53 or PIK3R1 mutations demonstrate inferior OS. Pontine DMG patients with somatic TP53, NF1 or TERT mutations demonstrate inferior OS.
DIPG-87. TARGETING GENE-REPRESSIVE EPIGENETIC REGULATION TO INDUCE INTERFERON SIGNALING IN DIFFUSE MIDLINE GLIOMA
Authors: Craig-Schwartz Jordyn , Tetens Ashley R , Lunsford Kayleigh , Liapodimitri Athanasia , Koldobskiy Michael A 
Published: June 2024

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brainstem tumor with no known effective treatment. DIPG is driven by the H3K27M mutant histone, which promotes epigenetic dysregulation, leading to loss of gene-repressive H3K27me3 marks, global DNA hypomethylation, and a distinct gene expression profile. DIPG cells retain histone methylation at histone H3 lysine 9 (H3K9me2/3), suggesting that the tumor may rely on these marks to repress unwanted expression. Our prior work has demonstrated that treatment with the DNA hypomethylating agent decitabine (DAC) elicits expression of cancer-specific antigens and immune activation, including activation of interferon signaling, but modulating gene-repressive H3K9 methylation in DIPG has not been extensively investigated.

METHODS
We treated four primary patient-derived DIPG neurosphere cell lines with BIX01294 and UNC0642, inhibitors of H3K9 methyltransferases G9a/GLP, and analyzed gene expression changes by RNA-sequencing and Western blot. We assessed the effect of combination treatments on these four cell lines with both DAC and either BIX01294 or UNC0642 and evaluated impact on gene expression, innate immune signaling, and interferon pathway activation.

RESULTS
We found that treatment with either of the G9a/GLP inhibitors resulted in the upregulation of genes involved in immune signaling. Given the similarities in the immune signaling response elicited from treatment with DAC and the G9a/GLP inhibitors, we evaluated the effect of combination treatments with both DAC and either BIX01294 or UNC0642. These combinations resulted in an increased induction of genes involved in immune signaling, including STING.

CONCLUSIONS
Pharmacologic inhibition of DNA methylation and histone H3K9 methylation elicits immune activation in DIPG cells. Upregulation of interferon and STING signaling with this combination treatment may be significant in enhancing the immunogenicity of DIPG cells to allow effective immunotherapy.
DIPG-93. OVERALL EXPERIENCE OF TWO PHASE I CLINICAL TRIALS WITH FOCUSED ULTRASOUND-MEDIATED BLOOD BRAIN BARRIER OPENING IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH PROGRESSIVE DIPG/DMG USING A NEURONAVIGATION-BASED DEVICE
Authors: Szalontay Luca , Fino Jessica , Berg Xander , Lipina Jennifer , Gallitto Matthew , De Santos Genesis Los , Yoh Nina , Gartrell Robyn , Pavisic Jovana , Garvin James , Lignelli Angela , Gomes William , Feldstein Neil , Konofagou Elisa E , Zacharoulis Stergios , Wu Cheng-Chia 
Published: June 2024

Abstract

OBJECTIVES
DIPG/DMG is a fatal brain tumor developing in delicate areas of the brain with a median overall survival of 1 year. The dismal outcome is partly due to the blood-brain barrier (BBB) which poses a major challenge to delivering effective therapeutic agents. Over the past 4 years we opened two Phase I clinical trials using Delsona focused ultrasound (FUS) device developed at Columbia University to treat pediatric and AYA patients with relapsed DMG. In the first study, we delivered FUS with concomitant panobinostat and during the second study we gave oral etoposide. Here we present our experience of delivering neuronavigation based FUS for pediatric patients with progressive DMG.

METHODS
Pediatric and AYA patients with biopsy proven DIPG/DMG at disease progression were enrolled (FUS with oral panobinostat: NCT04804709 and FUS with oral etoposide: NCT05762419). Patients were allowed to have prior therapies, including radiation and reirradiation. FUS was delivered over the course of six or four cycles respectively. MRI was performed to validate BBB-opening and closure.

RESULTS
During the FUS-panobinostat study, we treated 3 patients. The study was closed prematurely when panobinostat was taken off the US market. In the FUS-etoposide study, we have already treated 2 patients (the study is currently open). For the two trials combined, we delivered over twenty-five FUS treatments. Four of the five patients treated had achieved BBB-opening. Two patients in the FUS and panobinostat study showed improvement in their neurological symptoms. The average time for FUS-delivery was approximately 47 minutes. All treatments were performed in the outpatient settings in the Department of Radiation Oncology. Side effects from FUS was limited to one grade 1 dermatological toxicity.

CONCLUSION
FUS-mediated BBB-opening delivered as an outpatient procedure is feasible, to date, in children with relapsed DIPG/DMG. Further studies are needed to assess for efficacy.
DIPG-94. PROTEOMIC AND BIOINFORMATICS ANALYSIS OF THE SURFACEOME AND EXTRACELLULAR MATRIX OF DIFFUSE MIDLINE GLIOMAS
Authors: Thomas Bryce 
Published: June 2024

Abstract

INTRODUCTION
Diffuse midline glioma (DMG) is a universally fatal pediatric brain cancer with a median overall survival of 9-11-months. The extracellular matrix (ECM) plays a significant role in regulating bidirectional communication between glioma cells and the niches of the tumor immune microenvironment (TIME); influencing expression of immunosuppressive cytokines and regulating immune cell infiltrations, all of which contribute to poor outcomes. DMG immunosuppression remains poorly understood but has implications for emerging immunotherapies such as CAR T cells. Using a sucrose gradient plasma membrane purification method coupled with quantitative high-resolution proteomics we have discovered a novel cancer-associated protein termed ‘Protein-J 4 (PJ-4)’. PJ-4 is an important component of the DMG-ECM that we believe contributes to immunosuppression.

METHODS
Expression of PJ-4 was validated by Immunoblotting, flow cytometry and immunofluorescences microscopy. CRISPR/dCas9 gene deletion and amplification of PJ-4 and its transcription factor are current being established using DMG patient-derived cell lines, and syngeneic DIPG models to help elucidate the biological significance of PJ-4 expression.

RESULTS
Immunofluorescences microscopy showed PJ-4’s translocation from the Golgi apparatus to the cell membrane is dependent neurosphere formation, hence the formation of an ECM. Further, PJ-4 demonstrated high affinity with pro-TGF-β and may serve to regulate its bioavailability in the TIME, suggestive of an immunomodulatory role. Immunohistochemistry analysis of our PJ-4, TGF-β and CD45 is currently underway using a constructed tissue microarray of healthy brain tissue samples and over 30 pediatric brain cancers to determine tumor specificity and correlation with immune cell infiltration.

CONCLUSIONS
Resistance to conventional therapies and a poor understanding of the TIME and ECM remains a significant challenge to the development of effective DMG therapies. The identification of PJ-4 as a cancer-associated constituent of the DMG-ECM may help us to develop strategies to that increase DMG response to standard-of-care radiation therapy, novel target agents and immunotherapies.
DEI-04. RACE AND ETHNICITY DIFFERENCES IN TREATMENT-LIMITING TOXICITIES IN PATIENTS TREATED WITH MEK INHIBITORS
Authors: Siegel Benjamin I , Kim AeRang , Bornhorst Miriam A 
Published: June 2024

Abstract

BACKGROUND
MEK inhibitor (MEKi) therapies are used to treat pediatric low grade glioma (pLGG) and plexiform neurofibroma (PN). The toxicity profile reported in clinical trials have been favorable, but samples have been demographically homogeneous. In this study, we evaluate differences in treatment-limiting toxicities by race and ethnicity.

METHODS
This is a single-institution, retrospective study of patients treated with MEKi on the Sprint (NIH plexiform) trial or off-study for pLGG or PN from 2014 to 2023. Patient data was abstracted from clinical records. Treatment-limiting toxicity was defined as temporary hold, dose reduction, or discontinuation due to toxicity.

RESULTS
Fifty-eight evaluable patients received MEKi for PN (N=40) or pLGG (N=18), 5 of whom received multiple agents. Selumetinib was used in 44 cases, trametinib in 16, and binimetinib in 3. Median age was 11.0 years (IQR 7.7-14.5) and 37(64%) were male. Twenty-nine (50%) patients identified as White, 15(26%) Black, 6(10%) Asian, 4 (7%) Hispanic, and 4(7%) other/declined. Treatment-limiting toxicity occurred in 27(47%). Each demographic group had a similar rate of treatment-limiting toxicities; 52%(n=15) of White, 40%(n=6) of Black, 66%(n=4) of Asian patients, and 50%(n=2) of Hispanic patients. The most prevalent treatment-limiting toxicity was skin-related (N=10; 6 White, 1 Black, 2 Asian, 1 Hispanic) and included rash, paronychia, and impetigo. Other recurring toxicities were gastrointestinal (N=6, 5 White, 1 Black), edema (N=4, 1 White, 1 Black, 1 Asian, 1 Hispanic), cardiac (N=2, 1 White, 1 Black), and weight gain/loss (N=4, 2 White, 2 Asian).

CONCLUSIONS
Frequencies of treatment-limiting toxicities were similar across race and ethnicity. Dermatologic and gastrointestinal toxicity were more commonly seen in White patients relative to other adverse events. Findings should be interpreted with caution due to sample size, but support future efforts to understand demographic differences in MEKi toxicity.
DEI-05. ASSESSING HOUSEHOLD MATERIAL HARDSHIP IN CHILDREN WITH CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Coven Scott L , Tran Yvette H , Park Seho , Mendonça Eneida A 
Published: June 2024

Abstract

BACKGROUND
Household material hardship (HMH) is defined as unmet basic needs including food, heat, housing, or transportation. Researchers have documented higher rates of poor nutrition, injury, infectious disease, and hospitalization in healthy children living in families with household material hardship. Furthermore, targeted interventions exist to modify these health outcomes. However, little is known regarding the relationship between social determinants of health and their impact on overall and quality of survival for children with brain or spinal cord tumors. The current available information is based upon retrospective and secondary data sources, often limited to basic socioeconomic factors such as race and ethnicity. The objective was to describe the change in household material hardship through patient reported outcome measures from baseline to six-months and explore the association between social determinants of health, including prospective household material hardship data, and clinical outcomes among children with brain and spinal cord tumors.

METHODS
We aimed to enroll 150 patients with a brain or spinal cord tumors who were followed by the Pediatric Neuro-Oncology Program at Riley Hospital for Children at IU Health. These participants were approached during their routinely scheduled clinic visits by a member of the study team. Written or verbal consent/assent was obtained, and their data was transcribed into a REDCap™ database.

RESULTS
To date, we have enrolled 118 children onto this study, with 35/76 participants completing their six-month follow-up survey. In line with Kira Bona’s previous work, we have found that around 30% acknowledged one positive domain of household material hardship. Additionally, we have found that almost 40% of our cohort fall below the 200% Federal Poverty Level, which is often considered a cutpoint for lower socioeconomic status.

CONCLUSIONS
We have shown that collecting prospective patient reported sociodemographic information is feasible in a busy clinical setting.
TRLS-10. CLINICAL TRIAL IN PROGRESS - CONNECT2007: PHASE I/II STUDY OF LUTATHERA IN PATIENTS WITH RECURRENT AND/OR PROGRESSIVE HIGH-GRADE CENTRAL NERVOUS SYSTEM (CNS) TUMORS AND MENINGIOMAS THAT DEMONSTRATE UPTAKE ON DOTATATE PET
Authors: Lazow Margot A , Trout Andrew T , Szabo Sara , Fuller Christine , Bobbey Adam , White William , Stanek Joseph , Brady Samuel , Mardis Elaine , Palmer Joshua , Rodriguez Diana P , Reuss Jaime , Brandt Cierra M , Acree Joanna , Harr Anna , Mikael Leonie , Fouladi Maryam , Salloum Ralph 
Published: June 2024

Abstract

BACKGROUND
Somatostatin type-2A receptors (SST2A) regulate cell growth through complex downstream modulation of proliferation and apoptosis signaling, thereby representing a potential therapeutic target. Lutetium (177Lu-DOTATATE), a radionuclide therapy which binds SST2A and delivers local radiation via beta particle emission, gained FDA approval for gastroenteropancreatic neuroendocrine tumors, a disease characterized by SST2A expression. Potential expansion of Lutathera into pediatric neuro-oncology is supported by evidence that medulloblastoma, other embryonal tumors, and meningiomas consistently express membranous SST2A, exhibit corresponding uptake on SST2A-radiolabeled nuclear imaging (DOTATATE PET), and have demonstrated radiographic response to SST2A-targeted therapy, suggesting sufficient CNS penetration to achieve therapeutic benefit.

METHODS
CONNECT2007 (NCT05278208) is an international, multicenter phase I/II study investigating safety and efficacy of Lutathera in children and adults with SST2A-expressing CNS tumors. Patients with recurrent/progressive high-grade CNS tumors and meningiomas can undergo screening, consisting of DOTATATE PET imaging for functional confirmation of SST2A expression, requiring adequate uptake (Krenning score ≥2) by central review. The phase I cohort will enroll patients aged 4-&lt;12 years to determine the pediatric recommended phase II dose (RP2D) following a Rolling Six design, with three potential dose levels, starting at the adult RP2D (200mCi), scaled by body surface area. The phase II cohort will enroll patients aged ≥12 years to assess anti-tumor activity through evaluation of 6-month progression-free survival in medulloblastoma/embryonal tumors (descriptive in other histologies). Lutathera is administered intravenously, with concurrent amino acids for nephroprotection, dosed every 8 weeks for up to 4 cycles. Longitudinal correlative studies include 1) evaluating prevalence, heterogeneity, and clinical, histologic molecular, and radiographic predictors of SST2A expression, 2) characterizing radiation dosimetry of Lutathera in organs at risk of toxicity and within CNS to assess tumor penetration, and 3) identifying imaging and molecular biomarkers of response. Enrollment began in January 2023; both cohorts remain open to accrual.
TRLS-13. MULTI-OMICS AND FUNCTIONAL PRECISION MEDICINE FOR NEWLY DIAGNOSED AND RECURRENT PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Crawford John R , Lo Yan Yuen , Pagadala Meghana S , Chapman Owen S , Sridhar Sunita , Juarez Edwin F , Tzaridis Theophilos , Chau Lianne Q , Wang Jun , Eisemann Tanja , Masihi Meher Beigi , Chambers Kendall R , Dixit Deobrat , Koubourli Daphne , Larson Jon D , Guidugli Lucia , Hammer Monia , Wong Terence , Abdullaev Zied , Quezado Martha , Martins Timothy J , Reich Michael , Sears Timothy , Hobbs Charlotte , Kingsmore Stephen F , Levy Michael L , Gonda David , Malicki Denise M , Snuderl Matija , Becker Pamela S , Tamayo Pablo , Elster Jennifer D , Aldape Kenneth , Carter Hannah , Paul Megan R , Mesirov Jill P , Chavez Lukas , Wechsler-Reya Robert J 
Published: June 2024

Abstract

BACKGROUND
Comprehensive molecular characterization of pediatric brain tumors has led to a more refined diagnosis. However, the feasibility of performing multi-omic and functional precision medicine approaches using ex-vivo drug screening in the clinical setting is unknown.

METHODS
Patients with newly diagnosed or recurrent central nervous system tumors were enrolled in a feasibility study of multi-omic analysis including whole genome trio germline sequencing, tumor whole exome/RNA sequencing, RNA-based DiSCoVER analysis, methylation profiling, immunogenic potential analysis, and ex-vivo drug screening utilizing a customized panel of 175 FDA approved/investigational drugs. Findings were presented at a multidisciplinary molecular neuro-oncology tumor board.

RESULTS
Eighteen patients (9 female; average age 9.4 years; 12 newly diagnosed, 6 with recurrent disease; 5 high grade gliomas, 4 ependymomas, 4 embryonal tumors, 3 low grade gliomas, 2 others) were enrolled between 2020-2022. Whole genome germline testing (N=18) was normal in half of patients (pathogenic germline mutations in 3 patients, variants of unknown significance in 6 patients). Ex-vivo drug screening results (N=14) varied among patients, however sub-micromolar efficacy was commonly observed for proteosome inhibitors, HDAC inhibitors, and topoisomerase II inhibitors. Average time from surgery to receipt of finalized results varied across platforms (drug screening 5.7 days, whole exome/RNA sequencing 14.8 days, whole genome germline 10.6 days, methylation 21 days). Fifteen patients had a modification in diagnosis and 4 patients had a change in tumor classification. Multi-omic and functional precision medicine results alone or in combination led to changes in management in 50% of patients (Tumor Molecular Sequencing 6/18, Ex-Vivo Drug Screening 4/14, RNA DiSCoVER Analysis 2/15, Methylation 1/14).

CONCLUSION
Our studies demonstrate the feasibility of timely ex-vivo drug screening and multi-omic analysis and show that these data may lead to changes in patient diagnosis/management. These findings are the basis of an ongoing trial for recurrent medulloblastoma (NCT05057702).