bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-63. RE-IRRADIATION FOR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): THE SPANISH EXPERIENCE
Authors: Panizo Elena , Vazquez-Gomez Felisa , Perez-Somarriba Marta , Cruz Ofelia , Lopez-Ibor Blanca , Solano Palma , De las Heras Blanca Martinez- , Cortés-Hernandez Marta , Garcia-Ariza Miguel , Raynero-Mellado Roberto Carlos , Martinez-Merino Marta , De Lucio Ana , Tallón María , Garrido-Colino Carmen , Ortiz-Gonzalez Irene , Portugal Raquel , Baro Maria , Gonzalez-Sansegundo Carmen , Calvo Felipe , Lassaletta Alvaro 
Published: June 2024

Abstract

BACKGROUND
Despite advances in its biological understanding, current treatments for diffuse intrinsic pontine glioma (DIPG) have shown minimal impact on overall survival in this fatal disease. Radiotherapy (RT) is the only therapeutic intervention that has demonstrated efficacy in improving symptoms and prolonging progression-free survival. In addition, re-irradiation (rRT) is emerging as an alternative treatment for advanced disease, albeit palliative. This study presents the Spanish experience with re-irradiation in DIPG.

METHODS
We retrospectively reviewed demographic, clinical and RT data of patients with DIPG treated with rRT in Spain.

RESULTS
Between April 2015 and December 2023, 44 Pediatric patients with progressive DIPG underwent rRT in 16 Spanish institutions. Median time from diagnosis to progression was 10 months (range, 4.2-24.3). Median dose of rRT was 20 Gy (range, 18-40) in a median of 2 Gy fractions (range, 1.3-4). Twenty-one patients (47.7%) underwent additional treatments in addition to RT. Clinical and radiological improvements were observed in 77.3% and 60% of cases, respectively. Treatment was well tolerated with only 3 patients experiencing severe toxicity (one requiring a VP-shunt, and two finalizing rRT due to bronchoaspirations). Median overall survival was 15.1 months (range, 8.2-61.2), with a median time from rRT to death of 4.2 months (range, 0.6-10.3). Compared to patients who experienced earlier relapses, those who relapsed after 10 months exhibited superior overall survival (21.8 vs. 12.9 months; p &lt; 0.001%), and a longer interval from rRT to death (6.2 vs. 3.8 months; p = 0.058). There was no survival benefit in patients receiving additional treatments.

CONCLUSIONS
rRT effectively improves symptoms and prolongs survival in many progressive DIPG patients. However, the ideal candidates for rRT remain undefined. The retrospective nature of the study makes it difficult to assess the true impact of additional treatments. We encourage prospective research into the combination of rRT with other therapies.
DIPG-78. OSSEOUS METASTASIS IN DIFFUSE MIDLINE GLIOMA: A CASE REPORT AND REVIEW OF LITERATURE
Authors: Agarwal Vibhuti , Nagasubramanian Ramamoorthy , Maxwell Rochelle , Douglas-Lindsay Dorothea , Ramakrishna Naren , Hayes Laura , Chandra Tushar 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG), H3K 27M-altered are uniformly fatal CNS tumors with 2-year overall survival of less than 10%. Neuroaxis dissemination with disease progression is well known. However, osseous metastasis is a rare occurrence.

METHODS
We report a patient with localized DMG at diagnosis with subsequent craniospinal and osseous metastasis. We also performed an updated literature review on DMG with extra-neural metastasis (ENM).

RESULTS
At 11 years of age, the patient presented with progressively worsening headache and vomiting and was found to have a tumor within the right thalamus with mild mass effect on the right lateral ventricle without hydrocephalus. The patient underwent stereotactic tumor biopsy with pathology consistent with DMG, H3K 27-altered. Whole exome sequencing revealed alterations in H3-3A, TP53 and PTPN11. Treatment consisted of upfront focal radiation therapy with subsequent stabilization of the thalamic lesion. However, within 1.5 months of completing radiotherapy, the patient developed drop metastasis, intracranial leptomeningeal dissemination, and diffuse osseous metastasis within the spine, bilateral iliac wings, and ribs. The patient died from disease progression within 2 months of metastatic progression, 6 months from initial diagnosis. Review of literature yielded 11 cases of ENM in pediatric patients with DMG, H3K 27M-altered. Four patients had ENM at diagnosis. The remaining seven patients developed extra CNS metastasis within 1-6 months of diagnosis. Eight patients received upfront radiotherapy with variation in adjuvant chemotherapy. All patients died with median overall survival of 9 months (range, 0.5-24) from diagnosis and 6 months (range, 0.5-22) from ENM occurrence.

CONCLUSION
ENM in DMG, H3K 27-altered is uncommon. Mechanisms for development of ENM in DMG is unclear. Biopsy and molecular testing for both primary site and ENM should be considered to help elucidate biologic mechanisms of ENM and potentially guide management.
DIPG-79. METTL16 AS A THERAPEUTIC VULNERABILITY IN H3K27M MUTANT DMG CELLS
Authors: Chilukuri Akanksha , Pomaville Monica , Halbert Matthew , He Chaun , Agnihotri Sameer 
Published: June 2024

Abstract

BACKGROUND
Diffuse Midline Glioma (DMG) is a highly aggressive (CNS WHO Grade IV) pediatric brain tumor characterized by the histone mutation H3K27M, resulting in global hypomethylation of histones. H3K27M mutant cells are highly dependent on methionine and methionine Adenosyltransferase 2A (MAT2A), a central regulator of the methionine cycle, representing a key vulnerability in H3K27M gliomas. MAT2A is upregulated by methyltransferase-like protein 16 (METTL16), which deposits N6-methyladenosine (m6A) on a subset of RNA residues to regulate gene expression. MAT2A is a sensor of methyl group donor S-adenosylmethionine (SAM) that, when placed, increases MAT2A intron splicing to compensate for a decrease in MAT2A function.

METHODS
To investigate our hypothesis, H3K27M histone mutation knockout cell lines were established using CRISPR Cas9 (Jabado lab) in DIPG4 cells. shRNA-mediated knockdown was used to attenuate METTL16 expression in DIPG4 H3K27M cells, and growth was assessed via sulforhodamine B (SRB) assay.

RESULTS
In silico analysis of normal brain tissue compared to low-grade glioma and high-grade glioma demonstrated increased METTL16 at both the RNA and protein levels (p=&lt;0.0001). Therefore, we postulated that targeting METTL16 would affect H3K27M growth. Results showed increased cell death compared to control cells by day 4 (p=0.0034) and day 8 (p=&lt;0.0001). Furthermore, knockdown of METTL16 in DMG cells with H3K27M decreased m6A levels on poly (A) RNA (p=0.049).

CONCLUSIONS
Our study highlights the vulnerability of H3K27M mutant cells to METTL16 modulation, elucidating underlying molecular mechanisms and paving the way for innovative therapeutic strategies targeting this axis.
DIPG-84. PHASE 1 DOSE-ESCALATION STUDY OF ACT001 IN PEDIATRIC PATIENTS WITH ADVANCED BRAIN AND SOLID TUMORS SHOWS ACTIVITY IN DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Ziegler David S , Hassall Tim , Valvi Santosh , Cai Dongpo 
Published: June 2024

Abstract

BACKGROUND
ACT001, an oral parthenolide derivative targeting STAT3 and NF-κB pathways, has shown activity in preclinical models of DMG. We evaluated safety, toxicity and activity of ACT001 in this recently completed, first-in-child study of DMG and other relapsed/refractory brain and solid tumors.

METHODS
Eligible patients ≥ 1 and ≤ 21 years old were enrolled with dose escalation following a rolling 6 design and tumor lesions evaluated every 8 weeks per RANO/ RECIST criteria.

RESULTS
A total of 29 patients were enrolled across 5 cohorts, including 19 with DMG (13 with Diffuse Intrinsic Pontine Glioma (DIPG)). Median age was 11 years for the whole cohort and 7 years (3-17) for DMG patients. Safety was evaluated in escalating doses in 188, 533, 700, 875 and 1100 mg/m2,BID cohorts. No DLT nor grade 3 and above TRAE was identified. One SUSAR was noted for a grade 1 pain in extremity event. Peak ACT001 concentration for each dose cohort were estimated based on limited PK sampling time (cycle 1 day 1 at pre-dose, 2 and 4 hours post dose; cycle 1 day 15 and cycle 2 day 1 both at pre-dose). ACT001 peak concentration plateaued at the highest dose levels, fluctuating in the range of 6360, 5430 and 5980 mg/m2 for 700, 875 and 1100 mg/m2 cohorts respectively. The half-life was approximately 3 hours. 8/14 DMG patients treated at ≥ 700 mg/m2 exhibited objective response or stable disease (SD), including one patient with SD for 14 months, another patient with confirmed Partial Response who remained on study for 11-months before disease progression and five other patients with different degrees of tumor burden reduction.

CONCLUSION
ACT001 was well tolerated and showed preliminary evidence of anti-tumor activity in DMG/DIPG patients dosed at the highest dose levels. A Phase 2 trial is planned using 875 mg/m2 as the RP2D.
TRLS-01. INTRAVENTRICULAR B7-H3 CAR T CELLS FOR DIFFUSE INTRINSIC PONTINE GLIOMA: SAFETY AND EFFICACY REPORT FROM THE COMPLETED PHASE 1 TRIAL BRAINCHILD-03
Authors: Vitanza Nicholas A , Ronsley Rebecca , Huang Wenjuan , Seidel Kristy , Thomsen Alison , Gust Juliane , Hauptman Jason , Choe Michlle , Crotty Erin , Leary Sarah , Gustafson Joshua A , Gardner Rebecca A , Pattabhi Sowmya , Wendler Jason , Ho On , Annesley Colleen , Park Julie R , Jensen Michael C 
Published: June 2024

Abstract

BACKGROUND
BrainChild-03 is a first-in-human clinical trial that completed the phase 1 component of repeatedly dosed intraventricular B7-H3 CAR T cells to children with diffuse intrinsic pontine glioma (DIPG) without lymphodepleting chemotherapy.

METHODS
We report on BrainChild-03 Arm C, patients with DIPG receiving up to 10x10^7 B7-H3CAR T cells/dose. Primary endpoints were feasibility and safety. Secondary endpoints were disease response and correlatives of CAR T activity.

RESULTS
23 patients enrolled. All had successful CAR T manufacturing. 21 patients were treated; 17 received sufficient doses for safety evaluation (4 doses/8 weeks) without a dose limiting toxicity (DLT). 4 other treated patients include: 1 patient DLT (pontine hemorrhage 8 days post-initial dose) and 3 unevaluable patients (2 discontinued protocol therapy for rapid progression; 1 did not meet eligibility to begin treatment). Overall, patients received 224 doses (median: 7, range: 1-60). Common adverse events included headache, nausea/vomiting, and fever. Of 21 treated patients, 11 enrolled after progression and survived 9.7 months (range: 6-16.9) after initial CAR T cell infusion. Of the 10 patients enrolled prior to progression, the overall survival is 16.9 months (range: 7.6-40.5) with 5/10 patients still alive. Three patients are alive 3 years from diagnosis, including 2 patients still on protocol therapy. Patients were not allowed to receive other anti-tumor agents, radiation, or surgical debulking while on protocol therapy. Circulating CSF CAR T cells were identified in 18/21 (85.7%) of patients and elevations in chemokine/cytokines associated with T cell activation and migration, including CXCL10 and IFNy.

CONCLUSIONS
Repeated intraventricular B7-H3 CAR T cell dosing is feasible and tolerable for children with DIPG, even after progression, with evidence of local immune activation. Early signals of survival extension underscore the potential for clinical benefit and the consideration to advance to phase 2 multi-site clinical trials.
TRLS-15. “TAZNI”: A PHASE I/II COMBINATION TRIAL OF TAZEMETOSTAT WITH NIVOLUMAB AND IPILIMUMAB FOR CHILDREN WITH INI1-NEGATIVE OR SMARCA4-DEFICIENT TUMORS (NCT05407441)
Authors: Yi Joanna S , Czaplinski Jeffrey , Bhushan Ketki , Forrest Suzanne J , Shukla Neerav , Mack Stephen , Hong Andrew , Strachan Marylynne , Dubois Steven G , London Wendy B , Chi Susan N 
Published: June 2024

Abstract

BACKGROUND
Recent pediatric trials with EZH2 inhibitor tazemetostat monotherapy have demonstrated efficacy and disease stabilization in children with relapsed INI1/SMARCA4-deficient tumors: overall response rate (ORR) 14% in all patients (dose expansion cohort), and 24%, 33% and 22% response rates in ATRT, chordoma and epithelioid sarcoma, respectively (NCT02601937); and prolonged disease stabilization &gt;6 months (NCT03213665). Leveraging the role of EZH2 in tumor immunity and increased immune signaling by tazemetostat, we hypothesized that combining this EZH2 inhibitor with checkpoint inhibitors may benefit pediatric patients with these rare cancers.

METHODS
“TAZNI” is a phase 1/2, multi-center trial of tazemetostat, nivolumab and ipilimumab for children with INI1/ SMARCA4-deficient tumors, administered either after standard upfront therapy or in the relapsed setting. All patients will receive standard nivolumab and ipilimumab doses/dosing schedule, with continuous tazemetostat dosing determined by disease strata: Stratum A- subjects with ATRT; Stratum B- all other (non-ATRT) tumors. Each stratum is subdivided by disease status: A1/B1- refractory disease; A2/B2- relapsed disease; and A3/B3- no evidence of disease. Part 1 of the study consists of two concurrent “rolling six” phase 1 studies to identify the recommended phase 2 dose (RP2D) by disease stratum. Two dose levels are planned, with one dose de-escalation. Part 2 will consist of two phase 2 studies to estimate the ORRs in substrata A1 and A2, in a Simon’s 2-stage design at the RP2D. All other substrata will have descriptive analyses. Patients may receive up to 26 cycles of therapy. Key inclusion/exclusion criteria include INI1 or SMARCA4 loss (by immunohistochemistry or molecular confirmation); age 6 mo - 21 yo; no prior immunotherapy; limited corticosteroid usage; and no concern for hematologic malignancy. This trial is currently ongoing and open to accrual. To date, four patients have enrolled and additional sites across the US are anticipated to open for enrollment (NCT05407441).
TRLS-17. INTERIM CLINICAL, PHARMACOKINETIC, AND TECHNICAL REPORT OF A PHASE 2 STUDY OF SONODYNAMIC THERAPY (SDT) USING SONALA-001 TOGETHER WITH MR-GUIDED LOW-INTENSITY FOCUSED ULTRASOUND (MRGFUS) IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Syed Hasan R , Packer Roger J , Fonseca Adriana , Keating Robert F , Mueller Sabine , Narsinh Kazim , Ho Winson , Niazi Toba , Fenn Peter , Clanton Ryan , Henry Lenora , Potter Wyatt , Andresen Corina , Marcus Stuart , Benaim Ely , Kilburn Lindsay 
Published: June 2024

Abstract

BACKGROUND
Children with DIPG have limited treatment options and poor prognosis with median survival of 9-12 months. Preclinical studies reveal that sonodynamic therapy (SDT) via MR-guided focused ultrasound (MRgFUS) activates SONALA-001 (ALA) metabolite, protoporphyrin IX (PpIX), inducing tumor cell death and extending survival in glioma models.

METHODS
We present preliminary data from an ongoing first-in-child drug-device trial (NCT05123534) of SONALA-001 SDT in children with DIPG aged ≥ 5 years post-radiation therapy. The trial evaluates the safety of ALA-SDT, preliminary efficacy and pharmacokinetics (PK) of SONALA-001 at 5mg/kg administered 6-12 hours before SDT and establishes the RP2D. Each cohort involves three subjects: the first receiving half-pons treatment 30-days apart; the others receiving entire pons treatment. Single-treatment approach was amended to allow up to 12 monthly-treatments.

RESULTS
Six patients (4M:2F, 5-12 years) in 2 cohorts received 22 SDT-treatments between August 2022 and February 2023. Sonication duration averaged 147 minutes. Five of 6 patients received repeated treatments. All were discharged post-procedure day 1 with no DLTs or related AE grade ≥ 3. For SONALA-001, the Cmax occurred at end of infusion, followed by rapid clearance (15.7 mL/min/kg); plasma half-life of &lt; 1 hour, indicating rapid distribution. The PpIX-Cmax occurred 4-6 hours post-dose, declining with a longer mean half-life than SONALA-001 of 6 hours. Both Cmax and AUCall demonstrate circulating-PpIX and systemic exposure were significantly lower than for SONALA-001. Two of 6 patients achieved a partial response per RAPNO central-review, and 2 continue in the study treatment for 11 and 15 months, respectively.

CONCLUSION
SDT is an innovative and to-date well-tolerated strategy for children with DIPG post-initial radiotherapy. Sonications did not result in any adverse procedural effects. SONALA-001 exhibits rapid distribution and clearance, while PpIX PK align with metabolite formation. After dose escalation completion, dose-expansion at R2PD will offer insights into safety, PK, and efficacy.
ETMR-18. ADVANCING ETMR RESEARCH: NOVELIN VITRO ANDIN VIVO PRECLINICAL MODELS FOR DEVELOPING MORE EFFECTIVE TREATMENTS
Authors: Roosen Mieke , Krausert Sonja , Stathi Phylicia , Mack Norman , Schwalm Benjamin , Oehme Ina , Peterziel Heike , Meulenbroeks Chris , Kranendonk Mariëtte E G , Plasschaert Sabine L A , Hoving Eelco , Pfister Stefan M , Bunt Jens , van Tilburg Cornelis M , Witt Olaf , Kool Marcel 
Published: June 2024

Abstract

BACKGROUND
Embryonal Tumor with Multilayered Rosettes (ETMR) is a rare and aggressive tumor that occurs mainly in infants under three years of age. Genetically, ETMRs are characterized by amplification and fusion of a microRNA cluster on chromosome 19 (C19MC) with TTYH1, present in ~90% of the tumors. ETMR patients still have a poor prognosis without any recent advances in treatment. A major limitation to develop more effective treatment strategies is the lack of sufficient preclinical models.

METHODS
Establishment of ETMR patient-derived xenograft (PDX) models and tumoroid lines, molecular characterization, high throughput in vitro drug screens, targeted drug treatments in vitro and in vivo.

RESULTS
We have established four new tumoroid and five new PDX ETMR models. These models faithfully recapitulate ETMR patients’ tumors based on their histological, transcriptomic, and methylome signatures. The in vitro models were derived from two patients and two PDX models and included three C19MC-amplified cell lines, of which two were a primary-relapse pair, and one a primary C19MC non-amplified model. In vivo we established the same models as PDX models subcutaneously plus an additional C19MC-amplified relapse model. High-throughput drug screening assays, using drug libraries with 225 clinically approved drugs and other small molecules, were conducted across the panel of in vitro models. Potential therapeutic candidates with promising activity in ETMR tumoroid lines identified from these screens include FGFR, XPO1, MTOR, MDM2 and topoisomerase inhibitors.

CONCLUSIONS
The establishment of novel preclinical models represents a significant advancement in ETMR research, offering a platform that captures the molecular complexity of the disease. The identification of several inhibitors shows the potential of these models for drug discovery and preclinical testing. Ongoing in vitro and in vivo experiments with these drugs and combinations aim to further validate their activity, moving towards the development of more effective therapies for ETMR patients.
ETMR-23. CNS SARCOMAS WITHCIC- ORATXN1-ALTERATIONS — A META-ANALYSIS OF CLINICAL AND MOLECULAR FEATURES IN A LARGE SERIES OF PATIENTS
Authors: Geisemeyer Neal , Federico Aniello , Sill Martin , Rosenblum Marc , Bale Tejus , Mauermann Monika , Schrimpf Daniel , Johann Pascal , Pickles Jessica , Aldape Kenneth , Tauziède-Espariat Arnault , Hasselblatt Martin , Sturm Dominik , Tietze Anna , von Deimling Andreas , Sievers Philipp , Sahm Felix , Gojo Johannes , von Hoff Katja , Pfister Stefan M , Kool Marcel 
Published: June 2024

Abstract

BACKGROUND
In 2021, the 5th WHO classification of central nervous system (CNS) tumors acknowledged CNS sarcomas with CIC alterations as a distinct tumor type, which may also expand to non-CIC alterations including ATXN1. To tackle the lack of treatment protocols for these highly aggressive tumors, we conducted a meta-analysis to provide an overview of clinical and molecular characteristics, define clinically relevant subtypes, and ultimately advise on treatment guidelines.

METHODS
We collected molecular and clinical data for &gt;200 patients with CIC- or ATXN1-altered CNS sarcomas by screening our in-house DNA methylation database (581 potential patients initially identified), publication databases (50 patients), and contacting centers worldwide (60 patients). Tumor tissue (FFPE and fresh frozen) for further molecular characterization was obtained from a subset of patients. DNA methylation-based clustering analyses (t-SNE, UMAP, consensus partitioning) were performed, integrating gene fusion details (RNAseq, FISH), copy-number variations, and clinical patient data to identify associations between (epi-)genetic and clinical parameters.

RESULTS
Most prominent fusion partners for CIC (n=47) and ATXN1 (n=9) were NUTM1 (n=18), LEUTX (n=17) and DUX4 (n=15). Clustering analyses of DNA methylation patterns indicated several epigenetic subtypes associated with different fusion types. Potential clinical implications are still under evaluation. Age distribution of patients at diagnosis in this cohort ranged from two months to 71 years (median=7.5 years). We observed no gender bias. Survival analyses are currently being performed, first results on survival and follow-up studies will be shown at the symposium.

CONCLUSION
We show first-of-its-kind data describing a large cohort of CNS sarcomas with CIC or ATXN1 alterations, outlining molecular and clinical characteristics, which may facilitate the development of guidelines for optimal treatment of these tumors based on retrospective response data. New molecular insights may also open up an avenue for targeted therapeutic approaches.
EPEN-04. OVERWHELMING ZFTA-RELA NUCLEAR LOCALIZATION AS A THERAPEUTIC STRATEGY AGAINST EPENDYMOMA
Authors: Arabzade Amir , Ippagunta Siri , Kardian Alisha , Emanus Erik , Varadharajan Srinidhi , Shirnecki Hazheen , Venere Monica , Kriwacki Richard , Deneen Benjamin , Mack Stephen C , Bertrand Kelsey C 
Published: June 2024

Abstract

BACKGROUND
Pediatric ependymoma is a malignant brain tumor without targeted therapies. The 10-year survival is close to 50%, as this relentless tumor often relapses years following initial diagnosis. Over two thirds of supratentorial ependymomas harbor a gene fusion between ZFTA and RELA (ZFTA-RELA). Despite evidence that ZFTA-RELA drives tumorigenicity, mechanistic details remain elusive, hindering efforts to uncover therapeutic vulnerabilities. Since direct targeting of ZFTA-RELA is not currently possible, we hypothesized that ZFTA-RELA fusion binding partners would represent vulnerabilities amenable to therapeutic targeting.

METHODS
We investigated the biochemical basis of ZFTA-RELA, with the goal of identifying key members of the protein interaction landscape. This was performed in our in utero electroporation mouse model of ZFTA-RELA ependymoma. A series of sucrose gradient and immuno-precipitation experiments were performed, coupled with mass spectrometry. ZFTA-RELA interaction proteins were functionalized using focused CRIPSR-Cas9 library screens in cell cultures. Critically, these revealed novel dependencies and druggable targets, with XPO1 emerging as a lead candidate. In vitro and in vivo studies were conducted to evaluate targeting XPO1 in ZFTA-RELA ependymoma.

RESULTS
ZFTA-RELA regulates XPO1 gene transcription, and elevated gene expression is associated with poor survival in these patients. While expression of ZFTA-RELA is necessary for oncogenic transcription, extremely elevated nuclear localization is associated with reduced growth. This suggests a ‘goldilocks’ model in which XPO1 titrates precise levels of nuclear ZFTA-RELA protein. We reveal that a potential therapeutic vulnerability emerges through modulation of ZFTA-RELA nuclear localization. Supporting this, chemical inhibition of XPO1 using Selinexor, has a direct effect on ZFTA-RELA cellular localization patterns. Critically, in patient derived orthotopic xenograft models, XPO1 inhibition exerts anti-tumor effects both in vitro and in vivo.

CONCLUSION
Our findings reveal a novel therapeutic strategy in ependymoma, and provide the mechanistic and pre-clinical data needed to develop a clinical trial for patients with ZFTA-RELA ependymoma.