bluuebunny/crossref_metadata_2025_split huggingface dataset:
CP-11. BODY MASS INDEX INCREASE FOLLOWING CHILDHOOD CRANIOPHARYNGIOMA SURGERY IS MOST SEVERE IN THE FIRST THREE MONTHS; TIME TO ACT!
Authors: Hulsmann Sanne C , Hoving Eelco W , de Vos-Kerkhof Evelien , Janssens Geert O , Bakker Boudewijn , van Santen Hanneke M 
Published: June 2024

Abstract

BACKGROUND
Centralization of care for childhood craniopharyngioma (cCP) in the Netherlands (June 2018), including the involvement of a multidisciplinary team, has resulted in a decreased prevalence of hypothalamic obesity. Unfortunately, in certain patients, increasing body mass index standard deviation scores (BMI SDS) are still encountered after tumor resection. The aim of this analysis is to identify timing of BMI change, incidence/prevalence and predictive factors for BMI changes enabling early preventive strategies.

METHODS
A retrospective cohort study was performed of all newly diagnosed cCP patients since centralization of care in the Netherlands (June 2018). Data on anthropometrics, radiology, tumor treatment (surgery, radiotherapy, interferon and tocilizumab), hypothalamic-pituitary function, medication and visual function, were collected. Uni- and multivariate analyses were done with the ‘mean’ change in BMI SDS at 3, 6 and 12 months after resection as primary endpoint. Body mass index trends were assessed as secondary outcome.

RESULTS
Of 34 patients, median age 8.93 (range 0.79-17.36), mean ∆BMI SDS was most pronounced at 3 months (+1.09 SDS (SD 1.17), p&lt;0.01), followed by a further mean increase of +0.25 SDS from 3 to 6 months (SD 0.50, p=0.01). In 17 patients, BMI SDS increased with ≥1.0 SDS in the first 3 months after resection (50%). A Muller grade 2 at diagnosis was associated with ∆BMI SDS at 3 months. Children with the highest BMI at diagnosis had the highest BMI at three months, but not the highest ∆BMI SDS.

CONCLUSION
Changes in BMI SDS ≥1.0 are observed in half of cCP patients following surgical resection despite expert multidisciplinary care, with most pronounced BMI changes during the first 3 months. These observations are a plea for more early interventions to prevent (morbid) hypothalamic obesity.
CP-12. PHASE 0 AND FEASIBILITY SINGLE-INSTITUTION CLINICAL TRIAL OF INTRAVENOUS TOCILIZUMAB FOR ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Dorris Kathleen , Mettetal Ashley , Hemenway Molly , Winzent-Oonk Shelby , Dahl Nathan , Levy Jean Mulcahy , Prince Eric , McWilliams Jennifer , Jordan Kimberly R , Mirsky David , Hoffman Lindsey , Hankinson Todd 
Published: June 2024

Abstract

BACKGROUND
Adamantinomatous craniopharyngioma (ACP) is a devastating skull-base tumor believed to derive from epithelial remnants of the primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to the anterior pituitary gland. ACP lacks medical antitumor therapies. Current standard therapy with surgery and radiation is associated with poor quality of life. Clinical and preclinical data indicate that IL-6 blockade may contribute to ACP tumor control.

METHODS
Children aged 2–21 years with newly diagnosed or previously treated ACP with measurable disease are eligible for the Phase 0/feasibility single-institution clinical trial (NCT03970226) of intravenous (IV) tocilizumab at Children’s Hospital Colorado (Aurora, CO, USA). The phase 0 stratum is completed and involved a single IV tocilizumab dose prior to a standard-of-care surgical resection. The feasibility portion of the trial involves IV tocilizumab every two weeks for up to 13 28-day cycles. Tocilizumab is administered at the established weight-based pediatric dosage of 8 mg/kg for patients who weigh ≥30kg or 12 mg/kg for patients who weigh &lt;30kg.

RESULTS
Six patients (4 female; median age—10 years, range—6-15 years; 4 who had progressive disease after radiation prior to enrollment) have been treated on the feasibility stratum. The subjects have received a median of 6 cycles (range 0.5-13 cycles). The best response to date is minor response. One dose reduction for myelosuppression has been required. One patient discontinued therapy due to anaphylaxis related to tocilizumab on the first dose.

CONCLUSION
Systemic delivery of tocilizumab at the established pediatric dosage is promising for treatment of ACP based on preclinical work and its demonstrated penetration into cystic and solid portions of ACP tumors. The therapy to date has been well tolerated overall. Further study is underway through a CONNECT consortium international Phase II trial (NCT05233397) to explore clinical efficacy.
DIPG-06. FUNCTIONAL MULTI-OMIC PROFILING OF THE LANDSCAPE OF DIFFUSE MIDLINE GLIOMAS TO IDENTIFY THERAPEUTIC VULNERABILITIES
Authors: Findlay Izac J , Staudt Dilana , Duchatel Ryan J , Jackson Evangeline R , Kearny Padraic , Persson Mika L , McEwen Holly , Smith Nathan D , Vitanza Nicholas A , Cain Jason E , Waszak Sebastian M , Hansen Mitchell , Alvaro Frank , Dun Matthew D 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG) is a devastating pediatric high-grade glioma (pHGG) located along the midline structures of the brain and spine. Palliative radiotherapy is the only approved treatment outside of clinical trials, with patients given 9–11-months survival post-diagnosis. Over the last 10-years, it has become common for patients to be prescribed precision therapies targeting genetic alterations, however largely, DMG harbor genetic alterations that are untargetable.

METHODS
To improve DMG patient outcomes, we are performing multi-omic analysis on 210 DMG, normal controls and other pHGG samples to functionally characterize the genomic landscape of these tumors and understand the protein-controlled functional consequences of recurring somatic alterations.

RESULTS
Genomic sequencing has been performed on 40/210 pHGG samples, identifying 290 unique mutations and several recurrent chromosomal alterations. Additionally, proteomic/phosphoproteomic profiling identified both unique and similar features of post-translational landscapes across genotypes. Examining H3.3K27M DMG cell-lines, SU-DIPG-XIII and UON-VIBE5, genomic sequencing identified 11 and 6 mutations respectively, however, only UON-VIBE5 possessed a genomically-predicted target, a PDGFRA-D842V mutation, potentially targetable by Avapritinib. Conversely, investigation of proteomes/phosphoproteomes revealed several potential therapeutic vulnerabilities. SU-DIPG-XIII possessed high enrichment of HDAC/BRD and CDK pathways and UON-VIBE5, ATM-centric pathways. In vitro proliferation assays of Avapritinib treated UON-VIBE5 failed to elicit a response at clinically relevant doses, while all proteomically-predicted therapies (HDAC – Fimepinostat, BRD – JQ1, CDK – Ribociclib and ATM – WSD-0628) successfully influenced tumor cell growth whilst leaving microglia controls cells unaffected. Avapritinib and WSD-0628 (CNS-active ATM inhibitor) drug predictions were further validated in the RA055 DMG model, which possesses similar genomic and proteomic features to UON-VIBE5. Avapritinib alone failed to influence tumor growth, while WSD-0628 notably reduced cell proliferation. The combination of these drugs, however, synergistically inhibited RA055 proliferation.

CONCLUSIONS
These findings thus provide preliminary evidence supporting the need to take a multi-omic approach in treating DMGs.
DIPG-10. SUBCLONAL POPULATIONS OF DIFFUSE MIDLINE GLIOMA CELLS PROMOTE TUMORIGENESIS THROUGH AP-1 TRANSCRIPTION FACTOR DYSREGULATION
Authors: Kessler Ketty , Grabovska Yura , Carvalho Diana , Burford Anna , Temelso Sara , Tari Haider , Molinari Valeria , Crampsie Shauna , Yu Lu , Choudhary Jyoti , Proszek Paula , Hubank Mike , Mackay Alan , Jones Chris 
Published: June 2024

Abstract

BACKGROUND
Paediatric-type diffuse high-grade glioma (PDHGG) are brain tumours occurring largely in children, classified into distinct subgroups based upon their location and defining molecular alterations, with very poor clinical outcomes. The presence of a wide diversity of genotypically- and phenotypically-distinct subclones within individual tumours provides a substantial barrier to developing effective treatments.

METHODS
To understand their role, and how this may be exploited therapeutically, we established 218 subclones in vitro from 8 patient-derived PDHGG different cell lines, and characterised them using single-cell and bulk multi-omic approaches linked to high-content phenotypic screening.

RESULTS
Highly migratory subpopulations of diffuse midline glioma (DMG) cells were isolated, whereby RNAseq and proteomics identified a specific metaprogram associated with migration, enriched in AP-1 target genes, and common across a series of DMG patient-derived cells. Data integration of scRNAseq/scATACseq showed an opening of the chromatin at loci such as the early development transcription factors FOS and JUN (AP-1 targets) associated with their overexpression in highly migratory cells. Co-culturing these subclones with less motile patient-matched counterparts conferred an enhanced migratory capacity in these cells, so we sought to abrogate this via high-throughput screening of over 900 compounds aimed at selectively targeting DMG subclones grown in co-culture. Inter-clonal interactions were disrupted by a diverse set of compound classes including previously identified secreted protein inhibitors (MMP2/9i). Moreover, hits were seen with numerous neuroactive drugs inhibiting a series of neural receptors, ion channels, and transporters shown to be highly expressed in subpopulations of DMG cells, and linked to a common mechanism of action via AP-1.

CONCLUSIONS
Clinically available neuroactive drugs may therefore represent a novel therapeutic approach in targeting highly migratory cells within DMG, which undergo chromatin remodelling to confer a pro-tumorigenic programme via upregulation of AP-1 targets.
DIPG-18. MULTIMODALITY VISUALIZATION OF A PRECLINICAL MODEL OF DIFFUSE MIDLINE GLIOMA DEMONSTRATES CLEAR TREATMENT EFFECT AFTER RNA NANOPARTICLE THERAPY
Authors: Moor Rachel , Weidert Frances , von Roemeling Christina , Robles Jonathan Chardon , Merritt Matthew , Rushin Anna , Sharma Guarav , McGuiness James , Thomas Nagheme , DeVries Anna , Qdaisat Sadeem , Zhang Dingpeng , Rahman Maryam , Ogando-Rivas Elizabeth , Castillo Paul , Ghiaseddin Ashley , Carrera-Justiz Sheila , Mitchell Duane , Mendez-Gomez Hector , Silver Natalie , Ligon John , Sayour Elias 
Published: June 2024

Abstract

BACKGROUND
Diffuse Midline Glioma (DMG) is an inoperable pediatric brain tumor with insufficient treatment options. Our group has developed a novel treatment modality for this disease and others, using mRNA vaccines consisting of tumor derived antigens in a unique lipid-nanoparticle (NP).

METHODS
We have treated mice, canines, and human patients with primary brain tumors to define local immunotherapuetic treatment response. We treated our neonatally implanted DMG model with NPs generated from total-tumor mRNA beginning day 31 and used MRI, MR spectroscopy, suprerspectral imaging, and immunofluorescence to visualize and quantify treatment effects.

RESULTS
In canine glioma patients enrolled in clinical trial, we visualized radiographically enlarging tumors of animals that ultimately became long-term survivors, supporting the concept of a process by which lesion size increases in the absence of true disease progression. In our clinical trials investigating NPs as a treatment for human and canine glioma, we found features of both reactive gliosis and traditional pseudoprogression (immune infiltration), suggesting a new radiographic diagnosis, thus named paraprogression. In mice bearing DMG, NP therapy led to long-term survivors, despite the development of hydrocephalus. We were able to visualize treatment response during the course of NP therapy using MRI.

CONCLUSIONS
These results are rapidly translatable to aid clinical decision making in patients with brain tumors treated with immunotherapy. Future studies will aim to mitigate effect of paraprogression without compromising benefit of NP therapy.
DIPG-22. A NOVEL ROLE FOR ACVR1/ALK2 IN REGULATING CHOLESTEROL BIOSYNTHESIS PROVIDES A NEW COMBINATORIAL THERAPEUTIC APPROACH FOR PATIENTS WITH DMG
Authors: Rogers Rebecca , Grabovaska Yura , Mackay Alan , Carvalho Diana , Dobinson Claire , Pereira Rita , Sejdiu Drenusha , Burford Anna , Molinari Valeria , Ruddle Ruth , Raynaud Florence , Chew Nicole , Tsui Vanessa , Sun Claire , Firestein Ron , Jones Chris 
Published: June 2024

Abstract

BACKGROUND
The discovery of somatic mutations in ACVR1, which encodes the serine/threonine kinase ALK2, in 20-25% of diffuse midline glioma H3K27-altered (DMG-H3K27) patients has led to the development of numerous chemotypes of ALK2 inhibitor (ALK2i). However, in models of ACVR1-mutant DMG-H3K27 the efficacy of single-agent ALK2i’s has been modest and new combinatorial treatment approaches are desperately needed.

METHODS
We performed unbiased combinatorial genetic and drug screens in patient-derived ACVR1-mutant DMG-H3K27 cells in vitro, using multiple chemotypes of ALK2i. We also generated in vitro transcriptomic, proteomic and metabolomic profiles of three ACVR1-mutant DMG-H3K27 models following ALK2i treatment.

RESULTS
The top ALK2i sensitising CRISPR hits (vehicle vs. ALK2i) were analysed using gene set enrichment analysis (GSEA) which revealed specific genetic dependencies in cholesterol synthesis/regulation following both M4K2009 and TP-0184 treatment. The top CRISPR hits included multiple key nodes of cholesterol biosynthesis such as HMGCR (HMG-CoA&gt;mevalonate), LSS (squalene-2-2-epoxide&gt;lanosterol) and DHCR24 (lanosterol&gt;cholesterol). These hits were pharmacologically mirrored in the top hits identified from the drug screen, including drugs that either directly or indirectly target cholesterol synthesis. Integration of the multi-omic data revealed a raft of changes associated with cholesterol biosynthesis/efflux. The expression of HMGCR/HMGCS1 (cholesterol synthesis) and LXR/ABCA1 (cholesterol export) were down and upregulated, respectively, with metabolomic data showing a reduction in cholesterol and it’s derivative 4-cholesten-3-one and an increase in desmosterol, an immediate precursor to cholesterol synthesis. Highly synergistic interactions were observed between multiple ALK2i and a panel of pharmacological agents targeting the cholesterol synthesis/efflux pathway, including routinely used drugs such as simvastatin and lovastatin, clinically well-tolerated and with good CNS penetrance in immuno-compromised and immune-competent mouse models, in whom in vivo combination studies are ongoing.

CONCLUSIONS
These data provide evidence for a previously unappreciated link between ALK2 signalling and metabolism, and identify readily translatable combination partners for ALK2i in the clinic.
DIPG-24. COMBINED EPIGENETIC THERAPY WITH FACT AND BET INHIBITORS REMODELS CHROMATIN AND DISRUPTS ONCOGENIC TRANSCRIPTION IN DIFFUSE MIDLINE GLIOMA
Authors: Holliday Holly , Khan Aaminah , Jayatilleke Nisitha , Mayoh Chelsea , Ross Samuel E , Guo Xinyi , Sanguino Yolanda Colino , Gopalakrishnan Anjana , Ehteda Anahid , Tsoli Maria , Ziegler David S 
Published: June 2024

Abstract

BACKGROUND
Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be a key therapeutic strategy against this aggressive cancer. One such target is the Facilitates Chromatin Transcription (FACT) histone chaperone. FACT is targeted by the curaxin compound CBL0137 which is currently in Phase I/II Children’s Oncology Group clinical trial as a single agent for pediatric cancer patients (NCT04870944).

METHODS
We applied a multi-omics approach by integrating epigenetic profiling with transcriptomics (CUT&RUN, ATAC-seq and RNA-seq) to interrogate the role of FACT in DMG. We then employed in vitro cytotoxicity assays and in vivo orthotopic patient-derived xenograft (PDX) pre-clinical models to test a novel, mechanistic-anchored epigenetic combination therapy.

RESULTS
We found FACT to be enriched at developmental gene promoters, coinciding with regions of open chromatin and binding motifs of core DMG regulatory transcription factors (OLIG2, TCF12, and SNAI1). FACT interacted and co-localized with the Bromodomain and Extra-Terminal Domain (BET) protein BRD4 at active promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG. Investigating the combination of CBL0137 with two BET inhibitors (JQ1 and trotabresib) revealed potent cytotoxicity in vitro, particularly against H3K27M-mutant cells. Furthermore, this approach was recapitulated in vivo, significantly extending the survival of three independent orthotopic PDX models of DMG. Mechanistically, CBL0137 decreased chromatin accessibility, synergising with BET inhibition to disrupt transcription, leading to transcriptional silencing of several key oncogenes (MYC, PDGFRA and MDM4) as well as causing alterations to the splicing landscape.

CONCLUSIONS
This study highlights the therapeutic promise of simultaneously targeting FACT and BRD4 in DMG, and provides the rationale for a combination clinical trial, currently in development.
DIPG-26. H3.3K27M ENHANCES SENSITIVITY TO ATR INHIBITION IN PEDIATRIC GLIOMA
Authors: Wang Heng , Kaplan Jakub P , Chowdhury Dipanjan , Pal Sharmistha , Haas-Kogan Daphne 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG) is an aggressive, uniformly fatal childhood brain tumor. Radiation remains the standard of care but provides limited survival benefit. The most prevalent driver mutation in DMG is lysine to methionine mutation at position 27 (K27M) of histone H3.3, resulting in global loss of H3K27 trimethylation and remodeled chromatin, thus promoting DMG tumorigenesis. We have previously shown that inhibition of de novo pyrimidine synthesis induces replication stress that enhances DMG dependency on ATR. In this study, we sought to explore the contribution of H3K27M to basal replication stress in DMGs and vulnerability to ATR inhibition.

METHODS
To investigate ATR sensitivity of DMG, we employed ART0380, a potent and selective ATR inhibitor currently in Phase 2 clinical trials in adults. Using isogenic models and a panel of patient tumor-derived DMG cell lines we perform viability assays, immunoblotting, microscopy and flow cytometry-based assays to determine various endpoints/measures of ATR inhibition in DMGs.

RESULTS
Our data show that H3K27M histone oncoproteins enhance dependency on ATR and ATR inhibition synergizes with radiation to induce DMG cell death. After ART0380 treatment, H3K27M oncoproteins result in greater induction in apoptosis and accumulation of DNA damage (as measured by g-H2AX) compared with their histone H3 wild-type isogenic counterparts. Inhibition of ATR by ART0380 is confirmed by effects on phosphorylation of bona fide ATR targets-CHK1 and RPA. To gain mechanistic insights into how H3K27M modulates dependency on ATR, we have evaluated accumulation of chromatin-bound RPA, R-loops, and frequency of transcription and replication collisions (TRC) in isogenic cells.

CONCLUSIONS
Our data indicate a heightened sensitivity of H3K27M mutated DMG to ATR inhibition thus identifying a therapeutic window for DMG treatment with ATR inhibitor as monotherapy or in combination with radiotherapy.
DIPG-32. NEOANTIGEN HEAT SHOCK PROTEIN VACCINE, RHSC-DIPGVAX, IS ASSOCIATED WITH INCREASED VACCINE-INDUCED B CELLS AND BCR/TCR REPERTOIRE DIVERSITY IN PEDIATRIC PATIENTS WITH DIFFUSE MIDLINE GLIOMAS
Authors: Boland Lauren K , Wang Si , Fourati Slim , DeLay Suzi , Chia Tzu-Yi , Billingham Leah , Katz Joshua , Wei Chao , Geng Yuheng , Sipila Patrick , Narendran Aru , Chi Susan , Sato Mariko , Lee-Chang Caty , Miska Jason M , Plant-Fox Ashley S 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline gliomas (DMG/DIPG) remain a devastating class of tumors with limited treatment options. Cancer vaccines educate the immune system to tumor neoantigens to facilitate immune-mediated tumor destruction. DMGs have high-frequency, co-occurring neoantigens and are therefore a relevant target for activation of anti-tumor immunity via vaccine. To this end, we have initiated a clinical trial (NCT04943848) to determine if a neoantigen peptide-based vaccine with recombinant human heat-shock constitutive protein 70 and QS-21 adjuvant can promote anti-tumor immunity against DMG/DIPG. NCT04943848 is ongoing and now enrolling subsequent arms with rHSC-DIPGVax plus checkpoint blockade.

METHODS
Whole blood was collected before the first vaccine cycle (C1D1). Vaccine doses were administered every 2 weeks and blood was collected prior to the third or fifth vaccine cycle (C3D1 & C5D1). Peripheral blood mononuclear cells (PBMCs) were isolated and stored at -160°C. PBMCs from each patient, pre- and post-vaccine, were stained with human T-cell, myeloid, and B-cell antibody panels before spectral flow cytometry, single-cell RNA sequencing, and genomic DNA isolation for T- and B-cell receptor (TCR/BCR) sequencing. Spectral flow cytometry data was analyzed via FlowJo v10. TCR/BCR sequencing was processed via MiXCR and Immunarch.

RESULTS
Following vaccination, there were higher percentages of two mature CD20+CD19+IgM+ B cell populations, including a 4-1BBL+CD86+ population previously shown to induce robust CD8+ T-cell activation in adults with glioblastoma. Interestingly, given the recent discovery of TIM3’s importance in DIPG, we also identified TIM3-expressing CD4+ and CD8+ T cell populations. Finally, TCR/BCR sequencing demonstrated increased receptor repertoire diversity after vaccination, which is indicative of the vaccine shaping adaptive immunity.

CONCLUSIONS
Peripheral immune populations and TCR/BCR sequences change during vaccination with rHSC-DIPGVax. Ongoing analyses will determine the specificity of the patient immune response to vaccine antigens and correlate changes in immune populations to clinical course.