bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-44. NCT03643549 PHASE IB/II TRIAL: EFFICACY, SAFETY, AND BIOLOGICAL MECHANISMS OF OBJECTIVE RESPONSES IN RECURRENT GBM PATIENTS WITH UNMETHYLATED MGMT PROMOTER TREATED WITH SEQUENTIAL BORTEZOMIB AND TEMOZOLOMIDE
Authors: Goplen Dorota , Rahman Mohummad Aminur , Brekke Jorunn , Kumar Surendra , Arnesen Victoria , Birkeland Even , Simonsen Anne , Waha Andreas , Marienhagen Kirstin , Oltedal Leif , Haasz Judit , Miletic Hrvoje , Selheim Frode , Solheim Tora Skeidsvoll , Brandal Petter , Lie Stein Atle , Chekenya Martha 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is amongst the deadliest malignancies in adults, but especially for patients with unmethylated MGMT promoter (uMGMT) who gain limited benefit from the standard treatment. We previously demonstrated that proteosome inhibitor bortezomib (BTZ), inhibited NFkB activation,depleted MGMT protein and sensitized uMGMT GBM cells to Temozolomide (TMZ). Thus, a phase I/II trial testing sequential combination BTZ+TMZ was launched to investigate safety and clinical benefit.

METHODS
Recurrent GBM patients with uMGMT promoter, progressing ≥12 weeks after radiotherapy, KPS≥70 and radiologically measurable lesions were enrolled. The trial was powered for n=63 patients compared with n=102 historical controls. Patients received BTZ 1.3mg/m² IV on days 1, 4, and 7 of each 4-week cycle, starting on day 3 with oral 200mg/m² TMZ for 5 days/week. Whole exome sequencing (WES) of tumor DNA was conducted to identify genetic changes and LC-MS/MS used to asses proteomic changes in plasma collected during treatment.

RESULTS
As of January 2024, 54 patients (median 55y (25-70); 38 males, 16 females) were treated. The median KPS 90 (range 70-100) and NANO score was 1 (range 0-7). QoL was preserved, with mild /moderate adverse events. Adjusted analyses showed overall survival (OS) of 16.2 months compared to 8.4 months for uMGMT control patients, HR0.48, 95%CI[1.057-2.74],P=0.028. Objective radiological responses stable disease or better were observed in 22% (12/54) patients. Survival from recruitment was 10.5 months for responders vs. 4.8 months for rest of cohort, P=0.054 HR2.55, 95%CI[0.984-5.94]. Preliminary data indicate 78% (7/9) of responders harboured amplified EGFR vs. 38% in rest-of-the patients. The responders differentially expressed proteins critical for cellular processes, including ADAMTSL4, NCAM1, AZGP1, MMP2, CD163, and IL6ST.

CONCLUSION
Sequential BTZ+TMZ therapy is safe, effective and showed clinical benefit. EGFR amplification may be a predictive biomarker for response through NFκB activation, that is targeted by BTZ thereby depleting MGMT protein and enhancing treatment efficacy. Sequential BTZ+TMZ treamtment may represent additional treatment option at recurrence.
CTNI-49. PRECISION MEDICINE CLINICAL TRIAL FOR ADULT PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Chen Jiaying , Solomon David A , Bush Nancy Ann Oberheim , Grabowsky Jennifer A , Kline Cassie , Kroetz Deanna L , Taylor Jennie W , Villanueva-Meyer Javier , Molinaro Annette M , de Groot John F , Butowski Nicholas A , Tedesco Meghan , Rabbitt Jane , Hervey-Jumper Shawn L , Aghi Manish , Berger Mitchel , Chang Edward F , Chang Susan M , Clarke Jennifer L 
Published: November 2024

Abstract
Salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median overall survival of 9 months (OS-9) and 6-month progression-free survival (PFS-6) of 10-25%. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. An initial 15-patient cohort evaluated the feasibility and safety of treating patients with rGBM with an individualized treatment regimen; we added a second 15-patient expansion cohort to improve the power of preliminary efficacy assessment. Patients underwent clinically indicated surgery with genomic profiling using the UCSF500 targeted DNA sequencing panel. Each personalized treatment regimen combined up to 4 FDA-approved drugs, including one cytotoxic agent, as determined by consensus discussion at an individualized molecular tumor board for each patient. Bevacizumab was not utilized in these combinations. The primary objective of the combined 30-patient cohort was efficacy of individualized treatment regimens by OS-9; secondary objectives included safety and additional efficacy measures including PFS-6. Median age was 53 years (range 32-71). Of 30 patients, 18 were male, 23 were enrolled at first recurrence, 29 had IDH-wildtype glioblastoma, 1 had IDH-mutant astrocytoma, and 10 had MGMT promoter methylation. A total of 12 FDA-approved drugs were used in 18 combinations; the most common regimen prescribed was lomustine, afatinib, and abemaciclib (7; 23%,); second-most common was temozolomide, olaparib, and afatinib (4; 13%). OS-9 of the combined cohort was 70% (95% CI 0.55 – 0.89) and PFS-6 was 27% (95% CI 0.15 – 0.48), with median OS of 11.6 months (95% CI 9.7 – 16.7) and median PFS of 3.7 months (95% CI 2.0 – 5.5).While overall efficacy was modest, implementation of individualized treatment regimens in a timely fashion was safe and feasible for patients with surgically resectable rGBM. Analysis is ongoing to assess whether specific genomic profiles or treatment regimens were particularly efficacious.
CTNI-54. RESPONSE BY RANO2.0 CRITERIA IN ONC201 (DORDAVIPRONE)-TREATED PATIENTS WITH RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Cloughesy Timothy , Allen Joshua E , Arrillaga-Romany Isabel , Barbaro Marissa , Batchelor Tracey T , Butowski Nicholas , Cluster Andrew , de Groot John , Graber Jerome , Haggiagi Aya M , Kilburn Lindsay B , Kurz Sylvia C , Melemed Allen S , Ramage Samuel C , Salacz Michael E , Shonka Nicole , Sumrall Ashley , Tarapore Rohinton , Taylor Lynne , Wen Patrick 
Published: November 2024

Abstract

PURPOSE
Response assessment in neuro-oncology (RANO) 2.0 is a recently established response assessment for glial tumors that is agnostic to WHO grade. This updated response assessment includes quantitative evaluation of enhancing and non-enhancing disease and recommendations to account for pseudoprogression. This analysis evaluated response to ONC201 by RANO2.0 in recurrent, H3K27M-mutant diffuse midline glioma (DMG), which was previously assessed by RANO-HGG/RANO-LGG (Arrillaga-Romany, JCO, 2024).

METHODS
Fifty patients with recurrent H3 K27M-mutant DMG were selected based on criteria designed with input from regulators to evaluate objective response to ONC201 monotherapy. Patients had contrast-enhancing, measurable, progressive disease, and were ≥90 days from radiation, with adequate washout from other anti-cancer therapies. Diffuse intrinsic pontine glioma, primary spinal tumors, leptomeningeal spread, or CSF-disseminating tumors were ineligible. Response was assessed using RANO2.0 criteria by two-party blinded independent central review.

RESULTS
Best response by RANO2.0 included one complete response (CR, 2.0%), nine partial responses (PR, 18.0%), and four minor responses (MR, 8.0%). Overall response rate (CR+PR+MR) by RANO2.0 criteria was 28.0% (n=14; 95%CI, 16-42). Disease control rate (CR+PR+MR+SD) was 40.0% (n=20; 26-55). Median duration of response was 10.4 months (95%CI, 7.4-15.4). Median time to response was 4.6 months (range, 1.6-15.9). 6- and 12-month progression free survival rates were 32.0% (95%CI, 19-47) and 27.0% (15-41), respectively. RANO2.0 response as a time-varying covariate was significantly associated with overall survival in a multivariate analysis considering baseline performance score, multiple enhancing target lesions, enhancing tumor size, and number of prior recurrences (HR [95%CI], 0.22 [0.08–0.58]; p=0.0023). Patients with an objective response by RANO2.0 were more likely to be alive at 12 (100%) and 24 (86%) months, have reduced corticosteroid usage, and have improved performance status. Responses occurred at a higher rate among patients with a higher performance score and fewer target lesions.

CONCLUSIONS
RANO2.0 assessment of ONC201-treated patients suggests durable and clinically meaningful efficacy in recurrent H3K27M-mutant DMG.
CTNI-67. AI BASED PREDICTION OF CLINICAL TTFIELDS RESPONSE IN GLIOBLASTOMA PATIENTS (RETROSPECTIVE ANALYSIS)
Authors: Kebir Sied , Wilms Sarah , Wenger Katharina , Kessler Almuth F , Pröscholdt Martin , Harapan Biyan N , Quach Stefanie , Hottinger Andreas F , Suchorska Bogdana , Schmidt Teresa , Oster Christoph , Sure Ulrich , Kleinschnitz Christoph , Scheffler Björn , Glas Martin 
Published: November 2024

Abstract

RESEARCH QUESTION
Accurate and individualized prediction of response to therapies is central to precision medicine and a major goal in neuro-oncology. An extension of overall survival (OS) and progression-free survival (PFS) was observed in patients treated with tumor treating fields (TTFields) plus maintenance temozolomide compared to those treated with maintenance temozolomide alone and TTFields have become an integral part of the treatment of glioblastoma. To identify patients who benefit most from TTFields, we aim to implement a state-of-the-art machine learning approach to create a model capable of identifying responding patients early in treatment.

METHODOLOGY
In this retrospective analysis, patients with IDH-wildtype glioblastoma treated with TTFields, in addition to RT and temozolomide, as first-line therapy are included. Clinical data and MRI raw data (in DICOM format) are collected. The preprocessing of the MRI data includes reorientation, bias field correction, registration, segmentation, and intensity normalization. This is followed by the extraction of a Radiomics signature. The latter, along with the clinical data, is trained using various machine learning models. The model validation occurs on an independent test cohort. Data collection from various neuro-oncological centers across Europe is ongoing.

RESULTS
So far, data from 134 TTFields patients and 131 control patients have been collected. Initial results, providing detailed insights into the model architecture and performance, will be presented at the time of the SNO meeting.

CONCLUSION
This study has the potential to optimize the treatment of glioblastoma patients by using machine learning to allow the early identification of patients that respond to first line therapy.
CTNI-72. VAL-083 IN PATIENTS WITH RECURRENT GLIOBLASTOMA TREATED UNDER EXPANDED ACCESS PROGRAM
Authors: Kamiya-Matsuoka Carlos , Weathers Shaio-Pei , Harrison Rebecca , Majd Nazanin , Aaroe Ashley , Knight Stephanie , Hanna Teresa , Patel Chirag , Langlands john , Brown Dennis , Puduvalli Vinay 
Published: November 2024

Abstract

BACKGROUND
Current standard-of-care for glioblastoma (GBM) includes surgery followed by chemoradiation with temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience disease progression despite upfront standard-of-care treatment, with a median overall survival of 3-9 months after first recurrence. There are limited treatment options at the time of disease progression, apart from participation in clinical trials. VAL-083 is a bi-functional DNA damaging agent that induces inter-strand DNA cross-links at N7-guanine in a manner independent of O6-methylguanine-DNA-methyltransferase (MGMT).

METHODS
Under an Expanded Access program (NCT03138629), we used VAL-083 to treat 30 patients with recurrent GBM who were not eligible to participate in clinical trials. Here we report safety and efficacy results.

RESULTS
Four patients (13.3%) with leptomeningeal disease were excluded from efficacy evaluation. All patients received chemoradiation with TMZ. Twelve (12/26; 46.2%) patients had ≥2 recurrences and 9/26 (34.6%) had prior lomustine. All tumors had ≥1 mutation, with 14/26 (53.8%) having ≥5 mutations; one patient had a hypermutator phenotype. The most common mutations were TERT (57.7%), PTEN (38.5%), TP53 (26.9%), and NF1 (26.9%). All patients started treatment with VAL-083 at 30 mg/m2/day administered on 3 consecutive days every 21 days. Eight (8/26; 30.8%) patients received bevacizumab concurrently with VAL-083. Eight (8/26; 30.8%) patients had a VAL-083 dose reduction. Patients received a median of 3.0 (5-95pth 1-10) VAL-083 treatment cycles. Median progression free survival (mPFS) and median overall survival (mOS) from last disease progression was 5.1 (95%CI: 2.7-7.2) and 9.8 (95%CI: 5.3-16.4) months, respectively. VAL-083 was well-tolerated and the most frequent adverse events were consistent with prior experience, i.e., thrombocytopenia and neutropenia.

CONCLUSIONS
Use of VAL-083 continues to show benefit in the treatment of GBM patients who have had multiple recurrences and have limited therapeutic options.
CTNI-82. BELZUTIFAN TREATMENT OF VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA
Authors: Thomsen Anna , Valerius Allison , Uhm Joon , Ruff Michael , Baykal Duru , Caron Samantha , White Jessica , Webb Mason , Pichurin Pavel , Neth Bryan , Sener Ugur 
Published: November 2024

Abstract
Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.
DNAR-01. THERAPEUTIC APPLICATIONS OF MESENCHYMAL STEM CELL LOADED WITH GOLD NANOPARTICLES FOR REGENERATIVE MEDICINE
Authors: Cheng Wen-Yu , Yang Meng-Yin , Yeh Chun-An , Yang Yi-Chin , Shen Chiung-Chyi , Hung Huey-Shan 
Published: November 2024

Abstract
In the present study, the various concentrations of AuNP (1.25, 2.5, 5, 10 ppm) were prepared to investigate the biocompatibility, biological performances and cell uptake efficiency via Wharton’s jelly mesenchymal stem cells and rat model. The pure AuNP, AuNP combined with Col (AuNP-Col) and FITC conjugated AuNP-Col (AuNP-Col-FITC) were characterized by Ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR) and Dynamic Light Scattering (DLS) assays. For in vitro examinations, we explored whether the Wharton’s jelly MSCs had better viability, higher CXCR4 expression, greater migration distance and lower apoptotic-related proteins expression with AuNP 1.25 and 2.5 ppm treatments. Furthermore, we considered whether the treatments of 1.25 and 2.5 ppm AuNP could induce the CXCR4 knocked down Wharton’s jelly MSCs to express CXCR4 and reduce the expression level of apoptotic proteins. We also treated the Wharton’s jelly MSCs with AuNP-Col to investigate the intracellular uptake mechanisms. The evidence demonstrated the cells uptake AuNP-Col through clathrin-mediated endocytosis and the vacuolar-type H+-ATPase pathway with good stability inside the cells to avoid lysosomal degradation as well as better uptake efficiency. Additionally, the results from in vivo examinations elucidated the 2.5 ppm of AuNP attenuated foreign body responses and had better retention efficacy with tissue integrity in animal model. In conclusion, the evidence demonstrates that AuNP shows promise as a biosafe nanodrug delivery system for development of regenerative medicine coupled with Wharton’s jelly MSCs.
DNAR-08. THY1 MEDIATES TREATMENT RESISTANCE IN GLIOBLASTOMA THROUGH RAPID REPAIR OF DNA DAMAGE
Authors: Basha Syed Safiulla , Tripathy Arushi , Ravikumar Visweswaran , Awadia Sahezeel , Palavalasa Sravya , Huang Dah-Luen , Rao Arvind , Wahl Daniel R , Rehemtulla Alnawaz , Al-Holou Wajd N 
Published: November 2024

Abstract
Glioblastoma (GBM) is a uniformly lethal primary intracranial neoplasm that inevitably recurs despite treatment by DNA damaging agents radiation (RT) and temozolomide (TMZ). Recurrence may be driven by inherently resistant glioma stem-like cells (GSCs). GSCs have been shown to have constitutive upregulation of DNA damage response (DDR) pathways, resulting from elevated DNA replication stress. This baseline elevated DDR has consequently been shown to confer inherent resistance to DNA damaging agents, TMZ/RT. However, factors mediating elevated replication stress and upregulated DDR in GSCs are poorly defined. Previously, we identified the cell-surface protein, THY1, as a mediator of GSC phenotype and treatment resistance in GBM. To determine mechanisms mediating treatment resistance in THY1+ cells, we engineered patient-derived neurosphere and organoid models, to either overexpress or silence THY1 expression. These models were treated with RT and collected at various time points to measure DNA repair efficiency by assessing the formation and resolution of yH2AX foci and ATM/ATR activation. In parallel, patient-derived GBM tissue from over 20 patients was analyzed using single cell RNA sequencing and spatial transcriptomics to assess pathways associated with THY1 expression. Interestingly, spatial transcriptomics and single cell RNA sequencing data demonstrates significant upregulation of GSC pathways, as well as constitutive upregulation of DDR pathways (p&lt;2e-16) in THY1-high cells. Exploiting our patient-derived lines we determined that DNA repair activation was upregulated at baseline, measured using yH2AX foci and immunoblotting. We then measured DDR in response to radiation and found that high THY1 expression mediated rapid repair of DNA. Overall, we demonstrate that THY1 mediates therapy resistance by constitutively upregulating DDR, likely by upregulating DNA replication stress. We are now working to determine the mechanisms mediating the GSC phenotype and DNA replication stress in THY1 cells in hopes of future translation.
DNAR-15. GROUP 3 MEDULLOBLASTOMAS EXPLOIT A TRANSIENT MECHANISM OF TELOMERE REPAIR MEDIATED BY ZSCAN4 WHICH IS TARGETABLE FOR THERAPEUTIC BENEFIT WITH BRAIN-PENETRANT DRUGS
Authors: Jung Jangham , Yu Bohyeon , Diaz Aaron 
Published: November 2024

Abstract
All cancers need some mechanism of telomere repair. However, it is unknown how Group 3 (G3) medulloblastomas (MB) repair their telomeres, even though MB is the most common malignant brain tumor in kids and G3 is its most aggressive subtype. With rare exceptions, G3 MBs lack telomerase gain-of-function alterations or evidence of constitutive alternative-lengthening-of-telomeres pathway activation. We profiled tumors from N=38 MB patients from UCSF via single-nucleus RNA sequencing; 13 cases were also subjected to single-cell assay for transposase-accessible chromatin by sequencing, and 4 were subjected to single-cell cleavage under targets and tagmentation for H3K27ac. These data identified a network of gene enhancers that were specifically active in rhombic-lip progenitor-like MB cells, the putative G3 MB cell of origin. This program was driven by zinc finger and SCAN domain containing 4 (ZSCAN4), a gene reported to drive transient telomere repair during zygotic genome activation in early embryos. CRISPR inhibition of ZSCAN4 led to significant telomere shortening, telomeric DNA damage, telomere fusions, decreased proliferation, and increased survival of orthotopic xenografts. Conversely, ZSCAN4 over-expression induced significant telomere elongation, increased proliferation, and decreased survival in vivo. Analysis of endogenous-reporter cells indicated that ZSCAN4 is transiently expressed in response to telomere shortening and increases global histone acetylation by inducing chromatin-remodeling factors. Rebastinib targeted ZSCAN4, histone acetylation, and telomere repair, was brain penetrant, and significantly enhanced orthotopic-xenograft survival with no toxicity. Acetyltransferase inhibitor CPI-1612 was brain penetrant and extended xenograft survival with no toxicity. Our data support the hypothesis that G3 MBs exploit a transient mechanism of telomere repair mediated by ZSCAN4. Targeting ZSCAN4 or downstream histone acetylation is therapeutically viable. Pan-cancer whole-genome sequencing data showed that MBs have lower telomeric content than most other cancers. Thus, MBs may be particularly vulnerable to therapeutic strategies that inhibit telomere repair.
DDEL-01. ENGINEERING MRNA THERAPIES FOR BRAIN TUMORS
Authors: Yerneni Saigopalakrishna , Azambuja Juliana Hofstatter , Strelkova-Petersen Daria , Gallagher Brendan , Kim Julie Shin , Chaudhary Namit , Zhao Yongxin , Lucas Peter , McAllister-Lucas Linda , Pardi Norbert , Weissman Drew , Whitehead Kathryn 
Published: November 2024

Abstract
Safe delivery of mRNA to the brain will revolutionize the treatment of brain tumors. While lipid nanoparticles (LNPs) are clinically most advanced non-viral delivery vehicles for therapeutic mRNA, LNP-mediated mRNA delivery to the brain remains challenging. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain cells without undue toxicity. We engineered LNPs consisting of four components similar to the formulation used in the mRNA COVID-19 vaccines (Moderna and Pfizer-BioNTech): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. We screened ten classes of helper lipids based on lipids enriched in extracellular vesicles to engineer biomimetic LNPs and tested their GFP mRNA delivery efficacy in SIM-A9 mouse microglia cell line. Several unique LNP formulations with potent delivery efficacy (&gt;90% cells transfected) and stable GFP expression kinetics (5 days) were identified. LNP formulations with high transfection efficacy were then tested in vivo for luciferase mRNA delivery via intrathecal injection in C57BL/6 mice. Luciferase expression in vivo confirmed widespread mRNA delivery in the brain. We then tested Cre recombinase mRNA delivery in Ai9 mouse to identify LNP-targeted cells via flow cytometry and histology. Flow cytometry and expansion microscopy confirmed Cre recombinase mRNA delivery to a variety of brain cells, including microglia (75-90%), neurons (31-40%), neural stem cells (39-62%), oligodendrocytes (70-90%), and astrocytes (44-76%). LNPs were further evaluated for Cas9 mRNA and CD81 sgRNA delivery in C57BL/6 mouse brains to assess brain-targeted gene editing. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~40% of cells in the mouse brain. In summary, we engineered extracellular vesicle-based LNP library that can deliver RNA therapeutics to a variety of brain cells in vivo. With further development, this technology could potentially enable genetic and epigenetic therapies targeting drivers of brain tumors.