bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-69. REAL-TIME DRUG SCREENING AND GENOMIC TESTING TO DETERMINE INDIVIDUALIZED TREATMENT PLANS IN CHILDREN AND YOUNG ADULTS WITH RELAPSED MEDULLOBLASTOMA: PRELIMINARY REPORT OF PNOC027
Authors: Shatara Margaret , Paul Megan R , Boyle-Lang Janel , Meyer Ashley , Raber Shannon , Yeh-Nayre Lanipua , Jalkanen Aimee , Kilburn Lindsay , Packer Roger , Elster Jennifer , Reddy Alyssa T , Koschmann Carl , Kraya Adam , Resnick Adam , Prados Michael , Kline Cassie , Mueller Sabine , Wechsler-Reya Robert J , Rubin Joshua B 
Published: November 2023

Abstract
While current upfront multi-modal treatment for medulloblastoma is effective in many cases, for patients who relapse or don’t respond to initial therapy, effective treatment options are limited and novel therapeutic approaches are needed. The Pacific Pediatric Neuro-Oncology Consortium (PNOC) PNOC027 clinical trial investigates a precision medicine approach that combines real-time drug screening with whole exome and RNA sequencing of fresh tumor tissue to inform individualized treatment recommendations for children and young adults with relapsed medulloblastoma. The primary endpoint is to determine the feasibility of incorporating real time drug screening with DNA/RNA sequencing of tumor to develop a treatment regimen of up to 4-drug of FDA approved agents within 21 business days of tumor acquisition. To this end, freshly isolated cells from relapsed medulloblastoma tumor tissue undergo high-throughput drug screening using a platform of 232 clinically available compounds in parallel with multi-omic genomic analyses to predict individualized tumor response to treatment. Drug responses are assessed after 72 hours of drug exposure and the results yield drug prioritizations based on cytotoxicity and predicted blood-brain barrier permeability. Drugs from different classes are selected based on results from drug screening and molecular analyses combined with patient age, prior treatments, and other medical conditions. Four patients have been enrolled to date and viable tissue samples have been successfully collected and analyzed with treatment recommendations rendered within 21 business days for all patients. The five drug classes with the highest in vitro responses on the drug screen are HDAC inhibitors, proteosome inhibitors, anthracyclines, DNA crosslinkers and kinase inhibitors. PNOC027 demonstrates preliminary feasibility of real-time drug screening combined with DNA/RNA sequencing to inform targeted therapy selection for patients with relapsed medulloblastoma in clinically relevant timeframes. The trial is informing an expanded precision-based approach for relapsed medulloblastoma and the impact of genetic and epigenetic alterations on treatment response.
CTNI-71. BELZUTIFAN FOR VON HIPPEL-LINDAU DISEASE-RELATED CENTRAL NERVOUS SYSTEM (CNS) HEMANGIOBLASTOMAS: SUBGROUP OF PHASE 2 LITESPARK-004 STUDY
Authors: Iliopoulos Othon , Iversen Ane B , Narayan Vivek , Maughan Benjamin L , Beckermann Kathryn E , Oudard Stephane , Else Tobias , Maranchie Jodi K , Fu Wei , Perini Rodolfo F , Liu Yanfang , Linehan W Marston , Srinivasan Srinivasan , Jonasch Eric 
Published: November 2023

Abstract
The HIF-2α inhibitor belzutifan is approved for von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), CNS hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery based on results of the phase 2 LITESPARK-004 study (NCT03401788). Updated results in patients with CNS hemangioblastomas are presented. Adults with VHL disease based on germline VHL alteration, ≥ 1 measurable RCC tumor, and no prior systemic anticancer therapy received oral belzutifan 120 mg once daily. End points included ORR, DOR, and PFS per RECIST v1.1 and safety. CNS hemangioblastomas were assessed using 2 approaches: (1) measurable (≥ 1 cm) and/or nonmeasurable lesions at baseline based on total size of solid and associated cystic components, if present, and (2) only measurable solid lesions at baseline. Of 61 patients, 50 (82%) had ≥ 1 CNS hemangioblastoma evaluable at baseline; 19/50 (38%) underwent ≥ 1 CNS-related procedure ≤ 3 years before starting belzutifan. Median follow-up was 38.0 months (range, 36.1-46.1). ORR was 44%. Median DOR was not reached (NR; range, 3.7+ to 38.7+ months). DCR was 90%. Median PFS was NR (95% CI, 38 months-NR). 25/50 (50%) had ≥ 1 measurable, solid-only CNS hemangioblastoma. For these patients, ORR was 76%. Median DOR was NR (range, 3.7+ to 38.7+ months). DCR was 96%. Median PFS was NR (95% CI, 36 months-NR). 2/50 patients (4%) underwent 3 procedures for CNS hemangioblastomas after starting treatment with belzutifan. Two patients (3%) discontinued treatment due to treatment-related AEs (grade 2 intracranial hemorrhage and grade 1 dizziness). RESULTS: showed consistent and durable antitumor activity in patients with CNS hemangioblastomas. Belzutifan induced shrinkage of CNS hemangioblastomas with or without the presence of associated cysts. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved.
CTNI-77. POST-PROGRESSION TREATMENT AFTER VAL-083 WITH RADIATION IN NEWLY DIAGNOSED GBM MGMT UNMETHYLATED PATIENTS
Authors: Guo Cheng-chen , Yang Qun-ying , Xi Shao-yan , Liao Yi-Xiang , Li De-pei , Jiang Xiao-bing , Chen Yin-sheng , Ke Chao , Sai Ke , Schwartz Richard , Langlands John , Brown Dennis , Chen Zhongping 
Published: November 2023

Abstract
VAL-083 is a novel DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and thus differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT-unmethylated GBM. Stage 1 was a dose-escalation to confirm the dose of VAL-083 in this setting; VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083.
CTNI-79. PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE ANTI-NERVE GROWTH FACTOR (NGF) ANTIBODY TANEZUMAB IN SUBJECTS WITH MODERATE TO SEVERE PAIN DUE TO SCHWANNOMATOSIS
Authors: Plotkin Scott R , Da Jennifer , Silverman Danielle , Merker Vanessa , Ly Ina , Muzikansky Alona , Parsons Michael , Wolters Pamela , Xu Lei , Brown Mark , Styren Scot , Haghpassand Mehrdad , Jordan Justin T 
Published: November 2023

Abstract

INTRODUCTION
Schwannomatosis (SWN) is a rare neurogenetic condition (prevalence 1:125,000) characterized by multiple schwannomas and severe chronic pain. Increased expression of nerve growth factor (NGF) has been identified in painful schwannomas.

METHODS
We conducted a single-institution, phase 2, randomized, double-blind, placebo-controlled trial of tanezumab, an anti-NGF antibody. Eligibility criteria included age ≥ 18; moderate-to-severe SWN-related pain; ability to discontinue NSAIDs; and absence of osteoarthritis. Participants were treated with tanezumab 10 mg SQ or placebo (double-blind treatment) followed by tanezumab 10 mg SQ (single-arm treatment). The primary endpoint was change in NRS-11 scores between days 1 and 57 (double-blind). Secondary endpoints included change in PROMIS-Pain Interference (PI) T-scores.

RESULTS
Nine subjects were enrolled (median age 44 years, 7 females). At baseline, mean NRS-11 score was 7.6 (SD 2.1) and mean PROMIS-PI T-score was 63.2 (SD 6.6). During double-blind treatment, four participants were randomized to receive tanezumab (early group) and five were randomized to placebo (delayed group). For the early group, the mean change in NRS-11 score was -2.5 (SD 4.5) after initial tanezumab and 0 (SD 0) with continued treatment. For the delayed group, the mean change in NRS-11 score was -0.4 (SD 2.1) with placebo and -1.4 (SD 1.9) after tanezumab. For the early group, the mean change in PROMIS-PI T-score was -6.2 (SD 10.9) after initial tanezumab and -0.4 (SD 2.0) with continued treatment. For the delayed group, the mean change in PROMIS-PI T-score was 1.1 (SD 2.9) after placebo and -3.3 (SD 4.1) after tanezumab. Discussion: For SWN patients with moderate-to-severe pain, addition of tanezumab was associated with decreases in pain intensity and pain interference. Although these changes reflect clinically meaningful differences per published literature, they were not statistically significant. This study was underpowered due to poor accrual and a larger study in this patient population is warranted.
DNAR-05. EXCEPTIONAL RESPONDERS TO BASE EXCISION REPAIR (BER) INHIBITION FOR RECURRENT GLIOBLASTOMA DISPLAY ENRICHMENT FOR DNA DAMAGE RESPONSE PATHWAYS: RNA SEQUENCING ANALYSIS FROM A MULTICENTER TRIAL
Authors: Ozair Ahmad , Drappatz Jan , Ye Xiaobu , Berens Michael , Peng Sen , Rath Sanhita , Dhruv Harshil , Walbert Tobias , Holdhoff Matthias , Lesser Glenn , Cloughesy Timothy , Sloan Andrew , Couce Marta , Peereboom David , Nabors Burt , Wen Patrick , Rogers Lisa , Grossman Stuart , Ahluwalia Manmeet 
Published: November 2023

Abstract

INTRODUCTION
Therapies for glioblastoma recurrence after surgery and chemoradiation are warranted. TRC102 (methoxyamine), a small molecule DNA base-excision repair (BER) inhibitor, reverses temozolomide (TMZ) resistance in preclinical glioma models. We had investigated efficacy of TRC102+TMZ for recurrent glioblastoma (rGBM) through a multicenter trial. This work sought to report translational findings from RNA sequencing performed on patients with available tumor tissue. METHOD: A two-arm, two-stage, non-randomized, Phase II trial of TRC102+TMZ for adults with rGBM named BERT was conducted. Arm 1 included bevacizumab-naive patients at first recurrence, with primary aim of estimating response rates using RANO criteria. If sufficient activity was identified, arm 2 was planned in bevacizumab-refractory patients. Secondary aims were to determine overall survival (OS), progression-free survival (PFS), 6-month PFS, and toxicity. Exploratory aims were correlating clinical outcomes with MPG expression and MGMT methylation. Differential gene expression profiling was analyzed using DESeq2 GSVA (RRID:SCR_015687) and transformed into enrichment scores for 'hallmark of DNA repair' pathways from Molecular Signatures Database (MSigDB, RRID:SCR_016863) to assign mechanistic signatures of therapeutic vulnerability.

RESULTS
Arm 1 enrolled 19 patients with median of two treatment cycles, but objective responses were not observed. Hence, arm 2 did not open. Median OS was 11.1 months (95%CI 8.2-17.9). Median PFS was 1.9 months (95%CI 1.8-3.7). MGMT promoter was unmethylated in 14/19 patients, and MPG expression was present in 8/14 cases with available tumor tissue. MGMT methylation and MPG non-expression were associated with better OS and PFS. However, two ‘exceptional responders’ had PFS ≥11 months, with MGMT methylated and MPG expressed. RNA sequencing of their tumor tissue demonstrated significant enrichment for DNA damage response (DDR) pathways (MSigDB), chromosomal instability gene signatures (CIN70, CIN25), and proliferative gene signatures (PCNA25).

CONCLUSION
rGBM patients with elevated levels of MPG and DDR molecular signature may have impaired BER and respond better to TRC102+TMZ.
DNAR-07. MOLECULAR BIOMARKERS ASSOCIATED WITH TARGETED DISRUPTION OF ALTERNATIVE LENGTHENING OF TELOMERES IN ATRX-DEFICIENT GLIOMA MODELS
Authors: Waitkus Matthew , Brown Michael , Pirozzi Christopher , Reynolds Nathan , Brown Alexandrea , Strickland Laura , Reitman Zachary , Keir Steve , Khasraw Mustafa , Ashley David 
Published: November 2023

Abstract
Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism of telomere maintenance that occurs in approximately 10-15 percent of all cancers. ALT enables the replicative immortality of cancer cells and is characterized by elevated levels of DNA replication stress and telomere-localized DNA double-strand breaks (DSBs). In gliomas, ALT frequently co-occurs with inactivating mutations in ATRX, which is thought to promote ALT induction by disrupting ATRX-mediated histone H3.3 deposition at telomeres, thus leading to telomere synthesis by homology-directed repair mechanisms. To identify potential therapeutic vulnerabilities specific to ALT-positive tumors, we identified candidate ALT-positive cancer cell lines in the Cancer Dependency Map (DepMap) dataset and validated the presence or absence of ALT phenotypic markers, including ALT-associated PML bodies (APBs) and nuclear foci of single-stranded telomeric DNA (ssTeloC). Comparing ALT-positive cells to all other cancer cell lines in the DepMap dataset, we identified the replication fork remodeling enzymes SMARCAL1 and FANCM as gene dependencies with the highest degree of ALT-specificity. To validate SMARCAL1 as an ALT-specific dependency, we used inducible RNAi to deplete SMARCAL1 in ALT-positive glioma cells. SMARCAL1 depletion caused a marked increase in the abundance and intensity of ssTeloC nuclear foci, as well as increased γH2AX abundance in ALT+ glioma cells but not telomerase-positive cells. Inducible SMARCAL1 depletion did not coincide with detectable increases in apoptotic markers (e.g. caspase-3 cleavage). However, SMARCAL1 depletion caused a significant increase in the abundance of nuclear abnormalities indicative of mitotic catastrophe (e.g. micronuclei, nucleoplasmic bridges, and fragmented/multilobular nuclei). In an orthotopic model of ALT-positive glioma, doxycycline-inducible RNAi targeting SMARCAL1 extended the median survival of tumor-bearing animals to 155 days compared to 111 days in the non-targeting control condition. These data validate the therapeutic targetability of SMARCAL1 in ALT-positive gliomas and support the development of small molecule SMARCAL1 inhibitors for treatment of ALT-positive tumors.
DNAR-09. THE ROLE OF MSH2 IN GLIOBLASTOMA GROWTH AND TEMOZOLOMIDE RESISTANCE
Authors: Puigdelloses-Vallcorba Montserrat , Buonfiglioli Alice , Pinero Gonzalo , Chen Zhihong , Hambardzumyan Dolores 
Published: November 2023

Abstract
Despite all the advances in understanding and finding new therapeutic approaches, glioblastoma (GBM) remains incurable. The standard of care is surgical resection when feasible, combined with radiotherapy and chemotherapy using temozolomide (TMZ). Different mechanisms have been suggested to contribute to this failure: intrinsic or acquired resistance to TMZ and deficiencies in DNA mismatch repair (MMR) genes such as MSH2 that promote tumor progression. In this study, we have identified a correlation between low MSH2 expression and shorter patient survival utilizing patient GBM samples from the TCGA. Furthermore, we have generated immunocompetent genetically engineered mouse models (GEMMs) of GBM with germline or somatic loss of Msh2 to test the biological significance of Msh2 in GBM growth and resistance to TMZ and immunotherapy. We have generated tumors with reduced or abrogated Msh2 using GEMMs based on the RCAS/tv-a gene transfer system in combination with mice that exhibited heterozygous and homozygous loss of Msh2. Tumors with overexpression of PDGFB in combination with Tp53 silencing in mice with reduced or deficient Msh2 demonstrated shorter survival time and increased tumor growth compared to wild-type tumor-bearing mice. In addition, our results indicate that Msh2 deficiency increases the malignancy of gliomas. Finally, our data demonstrate that TMZ treatment for two weeks provides a significant survival advantage in WT tumor-bearing mice, while no efficacy was observed in tumor-bearing mice with either heterozygous or homozygous loss of Msh2, recapitulating what is observed in clinics. We are currently evaluating the role of Msh2 in the efficacy of immune checkpoint inhibitors in GBM.
DNAR-10. HETEROGENEOUS MGMT PROMOTER METHYLATION IN A MULTIFOCAL GLIOBLASTOMA: A CASE REPORT
Authors: Sloan Emily , Watson Joseph , Ahn Peter , Jay Ann , Minor Matthew , Komlodi-Pasztor Edina 
Published: November 2023

Abstract
MGMT promoter methylation status is an important predictive biomarker for treatment response in glioblastoma. MGMT unmethylated glioblastoma has elevated levels of MGMT which ultimately leads to chemoresistance. Clinicians consider the MGMT methylation status when treatment recommendations are given, and clinical trials use this marker for the selection of a homogenous group of glioblastoma patients based on prognosis. Here, we present a case of multifocal glioblastoma with heterogeneous MGMT methylation status. A 56-year-old male presented with left leg weakness for 2 months and left arm weakness for 1 month. Imaging revealed a calcified, rim enhancing right temporoparietal cystic lesion and a heterogeneously enhancing right parietal mass. Perilesional edema surrounded and connected the two lesions. The patient underwent gross total resection of the parietal mass and pathology revealed a WHO grade 4 glioblastoma, IDH wildtype, unmethylated tumor. Postoperatively, the patient was neurologically intact. He completed a 6-week long course of concomitant chemoradiation without any significant side effects. Two weeks later the patient developed rapidly worsening headaches, nausea, vomiting, dizziness, and left side weakness. Imaging revealed significant enlargement of the previously unresected temporoparietal cystic lesion with marked increase in surrounding edema and a 2-3 mm right to left midline shift. Patient underwent craniotomy with cyst drainage and tumor resection of the right cystic temporoparietal lesion, demonstrating a WHO grade 4 glioblastoma, IDH wildtype, methylated tumor. Post-operatively the patient was again neurologically intact and started adjuvant temozolomide. MGMT methylation status of glioblastoma can alter recommendations for chemotherapy with temozolomide. MGMT methylation status might vary in distinct parts of the tumor as molecular heterogeneity is a hallmark of glioblastoma. This heterogeneity should be considered by clinicians when treatments are recommended and by clinical trials for glioblastoma patients, especially when multifocal lesions have a distinct radiographic appearance.
DNAR-11. NUCLEAR POTASSIUM GOVERNS NUCLEAR ENVELOPE INTEGRITY AND GENOMIC STRUCTURE IN MEDULLOBLASTOMA
Authors: Chan Jade , Hui Chi-chung , Huang Xi 
Published: November 2023

Abstract
Potassium is the most abundant intracellular cation with crucial functions such as regulating cell proliferation, migration, and differentiation. Potassium flux across cellular membranes is controlled by potassium channels. While the role of cytosolic potassium has been researched for many decades, very little is known about the modulation or significance of potassium in the cell nucleus. Here, we identify potassium channel subunit KCNG1 as a novel regulator of nuclear potassium in medulloblastoma (MB), the most common malignant pediatric brain tumour. Using genetically encoded Förster resonance energy transfer (FRET)-based potassium sensors, we show that KCNG1 regulates nuclear potassium level independently of cytosolic potassium level. KCNG1 knockdown alters the genomic architecture of MB cells by stabilizing G-quadruplex (G4) DNA, inducing DNA damage, and reducing nuclear envelope-associated heterochromatin. Ultimately, KCNG1 deficiency results in nuclear swelling, thereby compromising nuclear envelope integrity and inducing DNA spillage into the cytosol to activate the pro-inflammatory cGAS/STING pathway. Genetic knockdown of KCNG1 mitigates tumour growth and prolongs the survival of mice bearing MB of distinct subgroups. Altogether, our findings reveal that nuclear potassium regulates genomic structure and nuclear envelope integrity and demonstrate that targeting a nuclear potassium channel can be leveraged to activate immunogenic signalling in MB.
DDEL-04. MODULATION OF THE BLOOD-TUMOR BARRIER FOR IMPROVED DRUG DELIVERY IN GLIOBLASTOMA
Authors: Jimenez-Macias Jorge-Luis , Xu Zheyun , Anthony Doug , Brodsky Alex , Tollefson George , Hawkins William , Schmidt Andrea , Sun Michael , Hong Jason , Forrest Megan , Nowicki Michal , Bertone Paul , Lawler Sean 
Published: November 2023

Abstract
Effective drug delivery remains a major challenge in glioblastoma (GBM) treatment. Specialized intercellular endothelial cell tight junctions at the blood-brain and blood-tumor barriers (BBB/BTB) represent obstacles to therapeutic efficacy by limiting intratumoral drug uptake. To understand the factors at the BTB that limit drug accessibility we performed bioinformatics analysis of TCGA data which suggested enrichment of the tight junction protein VE-cadherin (CDH5). CDH5 expression at the BTB was confirmed by immunostaining of patient GBM specimens and spatial transcriptomics using the 10X Visium platform. We found that a broadly selective protein kinase inhibitor, 6-bromoindirubin-3’-acetoxime (BIA), potently down-regulated CDH5 in cultured human cerebrovascular endothelial cells (HCMEC/D3) at the transcriptional level and this correlated with decreased trans-endothelial electrical resistance (TEER) measurement. In vivo administration of BIA (20 mg/kg IP) to mice bearing intracranial GBM xenografts showed striking downregulation of CDH5 in tumor associated endothelium. Furthermore, increased BTB permeability was shown using fluorescent tracers as well as DCE-MRI, which demonstrated elevated Ktrans values 24 hours after BIA administration. Integrated phospho-proteomic and transcriptomic analysis of BIA treated HCMEC/D3 cells support a mechanism involving p38 MAP kinase regulation of Ets-family transcription factors that drive CDH5 expression. At least a 20-fold increase in intra-tumoral accumulation of cisplatin and temozolomide was observed using G9-pCDH GBM xenografts when administered 24 h after BIA treatment. No increased drug uptake was seen in healthy brain tissue, indicating specific targeting of tumor vasculature. Efficacy studies showed extended survival when using cisplatin in combination with BIA (median 27d, p=0.0016) when compared to cisplatin (18.5d), BIA (21.5d) and control (18d). Further efficacy studies are underway. These data therefore identify the GBM-associated vasculature as a target for small molecule inhibition of tight junction formation to enhance intratumoral drug uptake. Ongoing studies are investigating the potential of this approach with a range of agents.