bluuebunny/crossref_metadata_2025 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

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

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

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

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

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

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

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

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

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

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.
DDEL-07. BARRIER TO PROGRESS: DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) INDUCES A TIGHTENED BLOOD-BRAIN BARRIER PHENOTYPE
Authors: Ung Caitlin , Upton Dannielle , Venkat Pooja , Pandher Ruby , Mayoh Chelsea , Tsoli Maria , Ziegler David
Published: November 2023

DIPG is an incurable paediatric brainstem tumour. Treatments have been significantly hindered by the necessity for drugs to penetrate the blood-brain barrier (BBB). We, and others, have shown that the BBB remains intact in DIPG, and it is thought that the BBB in the brainstem may be even less permeable in the presence of DIPG tumor cells. We performed in vivo studies in orthotopic DIPG mouse models that showed higher efficacy of mTOR inhibitor, temsirolimus, in cortex-injected DIPG compared to brainstem-injected DIPG. Analysis showed significantly increased survival, higher temsirolimus levels and decreased proliferating tumour cells in the cortex. Subsequently, the effect of DIPG on brain vasculature was interrogated by single-cell RNA sequencing. Microvascular endothelial cells were isolated from the brainstem and cortex, where DIPG cells or Matrigel were implanted. Transcriptomic analysis of DIPG-injected brainstem uncovered significant downregulation of inflammatory pathways, especially P38MAPK, downregulation of antigen presentation, and increased transporter Mfsd2a, suggesting a tightened BBB. Apoptotic signalling pathways were significantly upregulated, particularly MCL-1. Further analysis into cortex-injected DIPG revealed downregulation of interferon β pathways, suggesting a leakier phenotype. To overcome the tightened barrier in the brainstem, MCL-1 inhibitor S63845, was investigated as a BBB modulator. S63845 significantly reduced transendothelial electrical resistance, increased tracer dye leakage in an in vitro BBB transwell model with DIPG and decreased protein expression of claudin-5. In vivo, S63845 increased permeability to 3kDa Texas-red dextran after a single dose in DIPG mouse models. Overall, this study revealed that DIPG directly affects endothelial cell pathways associated with BBB permeability, resulting in a tightened BBB and reduced therapeutic efficacy. S63845 represents a promising BBB modulator that can be easily administered and may facilitate the delivery of therapeutics through the constricted BBB. This discovery has the potential to enhance the activity of anti-DIPG therapeutics that were previously considered impenetrable.
DDEL-10. RETROSPECTIVE REVIEW OF INTRA-CSF DRUG DELIVERY: SAFETY AND DRUG DISTRIBUTION PROFILES OF INTRACEREBROVENTRICULAR (ICV), LUMBAR INTRATHECAL (LIT), AND INTRA-CISTERNA MAGNA (ICM) INJECTIONS
Authors: Lee Grace , Glicksman Marcie , Patel Rajan , Vanjani Nisheka , Kumthekar Priya
Published: November 2023

INTRODUCTION

The blood-brain barrier and blood-CSF barrier limit the uptake of CNS-targeted therapeutics. Given this limitation, intra-cerebrospinal fluid (CSF) drug delivery can be utilized. Here we review and compare thesafety and drug distribution of the different intra-CSF drug delivery methods.

METHODS

A retrospective literature review of the three most common CSF access methods (intracerebroventricular (ICV), lumbar intrathecal (LIT), and intra-cisterna magna (ICM)) was performed. The search consisted of human clinical trials published on PubMed from 2000 to present, with the following terms: intracerebroventricular/intraventricular/ICV, intrathecal/IT, cisterna magna/ICM/IT-CM, drug delivery, drug administration, and CSF.

RESULTS

The search yielded 34 ICV, 72 LIT, and 6 ICM studies. To investigate the safety and drug concentration profiles of each delivery method, we excluded studies reporting drug adverse events (AEs) rather than AEs related to the specific drug delivery method, leaving 21 ICV, 30 LIT, and 1 ICM studies, all of which spanned oncology and non-oncology treatment studies. ICV-specific safety was addressed in 10 ICV studies, with infection (N=6) and device malfunction (N=2) being among the most frequently mentioned device/procedure-associated AEs. LIT-specific safety was provided in 17 studies, with post-procedural headache (N=9), infection (N=5), and pain (N=5) being among the most mentioned AEs. For drug distribution, 42.9% (N=9) of ICV studies concluded that ICV delivery achieved sufficient drug exposure in the CNS for a meaningful therapeutic benefit, with drug concentrations reaching minimum effective doses and/or achieving high therapeutic indices. The single ICM study with infusion of bupivacaine for pain management did not analyze safety or drug distribution. Meanwhile, 30.0% (N=9) of LIT studies reached the same conclusion or achieved concentrations consistent with predicted values.

CONCLUSION

The safety profiles of both ICV and LIT injections are acceptable, showing mostly mild-to-moderate device/procedure-associated AEs. Additionally, ICV achieves therapeutic goals more consistently than the other intra-CSF delivery methods.
DDEL-14. EXPLORING THE ROLE OF WNT PATHWAY INHIBITION ON GLIOMA STEM CELLS PROGRESSION AND BRAIN ENDOTHELIAL INTEGRITY
Authors: Tang Kayen , Kang Jeonghan , Conrad Christina , Lim Sanghee , Kwak Minhye , Cesaire Melissa , Jackson Sadhana
Published: November 2023

The blood–brain barrier (BBB) is a specialized neurovascular unit evolved to maintain brain homeostasis and prevent effective agents from reaching malignant brain tumors such as glioblastoma. The Wnt/β-catenin signaling pathway helps to ensure BBB integrity and previous studies demonstrate Wnt pathway inhibition increases BBB permeability. High grade gliomas express increased Wnt expression compared with normal tissue. We hypothesize that Wnt pathway inhibition in glioma stem cells (GSCs) will hinder progression, increase BBB permeability, and enhance overall treatment response. In this study, we transduced primary pediatric-derived glioma stem cells with lentiviral vectors overexpressing Wnt inhibitors (DKK1 or WIF1) and then characterized migration, proliferation, and cell cycle progression. WNT inhibition on brain endothelial cell integrity was evaluated with GSC conditioned media (GSC-CM) +/- CHIR99021 (Wnt pathway activator) for function via electrical cell-cell impedance and junctional expression. Wnt inhibitor overexpression was verified using RNAseq, proteomic analysis, and immunoblotting. We found that GSC-DKK1 demonstrated significantly decreased cell migration (p< 0.005) and proliferation (p< 0.0001). We also found that CHIR99021 treated GSC-CM endothelial cells displayed decreased tight junctional proteins and increased fenestration protein expression (p< 0.0005), correlating with a more porous endothelium. Overall, our studies showed Wnt inhibitor overexpressing GSCs impaired glioma progression in vitro and indirectly disrupted endothelial cell integrity. Future studies will evaluate orthotopic Wnt inhibitor overexpressing transplant rodent models to assess changes in BBB integrity, drug permeability, model survival, and treatment response. Further understanding of the Wnt pathway in both GSCs and the BBB has the potential for improved central nervous system treatment penetration and prolonged disease response.
DDEL-15. EXPLORING THE USE OF MACHINE LEARNING TO PREDICT BLOOD BRAIN BARRIER PERMEABILITY OF DRUG MOLECULES
Authors: Lim Megan Amber , Mostafa Wael Hassaneen
Published: November 2023

The blood-brain barrier (BBB) is a selective boundary of the central nervous system (CNS) that plays a critical role in protecting the brain microenvironment by allowing passage of certain molecules. Clinical experiments accurately determine which chemotherapy drugs effectively cross the BBB to reach the tumor site but are also time consuming and labor intensive. Machine learning offers the ability to rapidly screen large datasets of drug molecules and assess their potential for CNS therapeutic effect. The goal of this study is to compare the performance across machine learning, deep learning, and transfer learning methods in predicting BBB permeability on public drug datasets. The dataset used for training and validation was composed of 7,807 compounds compiled from 50 published resources. The machine and deep learning methods used in this study included support vector machines (SVMs), deep neural networks (DNNs), and graph convolutional neural networks (GCNNs). For transfer learning, we first trained DNN models to a single quantum chemical property before appending neural network layers and retraining to the new task of BBB permeability. The prediction accuracies on the validation set for SVM, DNN, GCNN, transfer learning of polarizability, and transfer learning of dipole moment were 82.33%, 83.09%, 87.14%, 76.89%, and 70.23%, respectively. Overall, the results indicate that GCNN was the best performing model. This highlights GCNNs ability to learn the molecular features most relevant to the predictive task in the first stage of the algorithm. Future work entails expanding the set of input features to include key chemical and structural information such as the presence or absence of certain functional groups as well as training more transfer learning models to other quantum chemical properties. This study further motivates the predictive capability of machine learning methods in identifying drug compounds with potential CNS-activity.
DDDR-28. DNA DAMAGE SENSING KINASES ATR AND ATM-DEPENDENT PHOSPHORYLATION OF RRM2 PROMOTES PROTEIN STABILIZATION AND CHEMO-ADAPTATION
Authors: McManus Graysen , Perrault Ella , Park Cheol , Ventrapragada Divya , Budhiraja Shreya , Buechler Killian , Stepniak Amelia , Mishra Snehasis , Miska Jason , Ahmed Atique
Published: November 2023

Glioblastoma (GBM) is a highly heterogeneous, primary malignant brain tumor in adults that shows limited response to standard-of-care therapies, such as chemotherapy and radiation. This is due, in part, to the development of therapeutic resistance. To characterize the adaptive mechanisms GBM cells use to evade the standard chemotherapy, temozolomide (TMZ), single-cell RNA sequencing analysis was conducted on an in vivo patient-derived xenograft (PDX) model of GBM, before, during, and following TMZ-based therapy. Our data revealed 149 genes to be uniquely expressed in the during-TMZ condition (p< 0.0001), including the rate-limiting regulatory enzyme of dNTP metabolism, ribonucleotide reductase (RNR) enzyme. Network analysis of pathways enriched during therapy revealed an interaction between the (RNR) enzyme, RRM2, and DNA damage response genes in the ATM and ATR kinase-signaling pathways. RRM2-dependent deoxynucleotide (dNTP) production is required for DNA repair and cell survival following TMZ treatment. Therefore, we investigated whether ATR and ATM kinases directly interact with RRM2 to promote its stability. TMZ treatment triggered the activation of DNA damage response machinery and protein kinases, ATM, ATR, CHK1, and CHK2, which physically interacted with RRM2 across multiple GBM PDX cell lines. Co-IP and immunoblot analyses along with cycloheximide chase analysis showed increased phosphorylation of the threonine residue on RRM2 during therapy, preventing its degradation. As such, we hypothesize that early DNA damage sensing by ATM and ATR kinases, and their subsequent phosphorylation of RRM2, promotes the maintenance of purine nucleotide pools needed for DNA repair and development of chemo-resistance. This novel and targetable TMZ response axis presents a promising clinical opportunity for GBM therapy, using FDA-approved inhibitors of these targets to block the purine metabolic adaptations that drive resistance and sensitize GBM cells to TMZ therapy.
DDDR-29. TARGETING FGFR FUSIONS: A CASE OF CATEQUENTINIB (AL3818) AND TEMOZOLOMIDE COMBINATION THERAPY FOR RECURRENT MGMT METHYLATED TACC-FGFR FUSION POSITIVE GLIOBLASTOMA
Authors: Seas Andreas , Patel Mallika , Kowalsky Martin , Rudd Daniel S , Jacobs Susanne D , Miller Elizabeth S , Volas-Redd Gena H , Johnson Margaret O
Published: November 2023

BACKGROUND

There is no gold-standard for the management of recurrent glioblastoma (GBM). However, advances at the interface of molecular testing and rational drug design have opened avenues for personalized medicine. Here we describe the case of a 52-year-old patient with recurrent GBM (WHO grade 4) with known FGFR3-TACC3 fusion and MGMT promoter methylation by Caris molecular profiling. Initial treatment included radiotherapy with concomitant and adjuvant temozolomide. However, after 18 months off therapy, the patient became clinically and radiographically progressive with multifocal disease. Herein, we describe our experience with temozolomide and catequentinib (AL3818) in a single patient.

METHODS

We reviewed the available literature on targeting FGFR3-TACC3 fusion positive glioblastoma with catequentinib (1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-Yl] oxy] methyl] cyclopropanamine dihydrochloride). Catequentinib is an oral small-molecule pan-kinase inhibitor with selective VEGFR2 inhibition, it is under investigation in multiple phase 2 and 3 clinical trials and can safely be administered concomitantly with temozolomide. We obtained single-patient Investigational New Drug (IND) approval and free drug was shipped directly from the manufacturer (Advenchen Laboratories; Jiangsu Chia-Tai Tianqing Pharmaceutical) to our institution’s investigational chemotherapy pharmacy. We administered catequentinib 12 mg by mouth for 14 days on and 7 days off of a 21-day cycle along with temozolomide 50mg/m2/day of a 28-day cycle with routine monitoring of laboratory parameters.

RESULTS

The combination of temozolomide and catequentinib was well-tolerated, resulted in clinical stability, and partial radiographic response at 3-month follow-up.

CONCLUSION

Catequentinib in combination with metronomic temozolomide was well tolerated in this single patient. This patient’s response shows the promise of intentional, patient-specific care at the intersection of molecular testing and rational drug design. The patient will continue therapy and updated clinical and radiographic outcomes will be presented.
EOLP-05. SUPPLEMENTAL ENTERAL NUTRITION DOES NOT IMPROVE SURVIVAL IN OLDER PATIENTS WITH PRIMARY MALIGNANT BRAIN TUMORS
Authors: Johnson Margaret O , Parish Alice , Cohen Seth M , Niedzwiecki Donna , Peters Katherine , Leiman David A
Published: November 2023

BACKGROUND

The risk of dysphagia increases with age and is prevalent among older adults with primary malignant brain tumors (PMBTs). As a result, patients with PMBTs may receive supplemental enteral nutrition (EN) but its impact on outcomes is uncertain. Therefore, we compared survival among Medicare beneficiaries with PMBTs and dysphagia by use of EN.

METHODS

We analyzed a Medicare 5% limited data set from 2013-2018. We included beneficiaries ≥65 years with PMBTs and solid tumors (lung, breast, melanoma, renal, and colorectal) identified by ICD9/10 codes. Predisposing conditions for dysphagia were excluded. To assess differences in survival of dysphagic patients by EN access (i.e., gastrostomy tube), hazard ratios and 95% confidence intervals (CI) from a Cox proportional-hazards model were calculated after adjusting for age, sex, race, and Elixhauser Comorbidity Index (ECI).

RESULTS

The rate of dysphagia among 79,926 beneficiaries was 4.7% (n=3,777), and significantly higher among those with PMBTs (11%, p< 0.01) compared to solid organ tumors with (8.0%) and without brain metastases (4.4%). Among patients with PBMTs, the presence of dysphagia was associated with lower survival compared to those without dysphagia (p< 0.001). For patients with PMBT and dysphagia, adjusted models showed no significant difference (p=0.08) in survival among those who received EN (N=78) compared to those that did not (N=271); however, those with EN had a 33% higher hazard of death compared to those without EN [HR= 1.34, 95% CI: (0.99, 1.81)].

CONCLUSION

Dysphagia is common among older patients with brain cancer and disproportionally affects those with PMBTs. The use of EN in this population-based study of Medicare beneficiaries did not significantly improve survival and there was a trend toward harm. Given the frequency of EN use and observed worse outcomes, further validation in a larger clinical dataset is warranted.
EPID-01. ANTINEOPLASTIC, RADIATION, AND SYNCHRONICITY EFFECTS ON BRAIN METASTASIS SURVIVAL: A RETROSPECTIVE POPULATION-BASED STUDY
Authors: Rincon-Torroella Jordina , Jiang Kelly , Parker Megan , Materi Joshua , Azad Tej , Kamson David , Kleinberg Lawrence , Ye Xiaobu , Bettegowda Chetan
Published: November 2023

INTRODUCTION

Brain metastases (BM) are the most common central nervous system tumors. The impact of oncological treatment on the prevention of BM is not well-defined. We report the effects of chemotherapy and radiotherapy directed at primary cancer on synchronous and metachronous BM survival.

METHODS

A large nationwide multi-institutional claims-based platform (TriNetX Diamond Network) was queried. Patients diagnosed during 2013-2023 with the 15 most common primary cancers that metastasize to the brain were included. Metachronous was defined as BM diagnosed > 2 months after primary cancer. Cohorts were propensity score matched for age, extracranial metastasis, and adjuvant therapy. Kaplan-Meier plots were used to compare survival.

RESULTS

113,827 (38%) patients with synchronous and 187,036 (62%) with metachronous BM were identified. Patients with synchronous BM had 26 months shorter median survival compared to metachronous BM (11 vs. 37 months, HR 2.17, 95%CI 2.14-2.19, P< 0.0001). However, no survival advantage was observed from the time of BM diagnosis (11 vs. 12 months, HR 1.06, 95%CI 1.05-1.08, P=0.411). Antineoplastic treatment prior to BM improved median BM-free survival by 13 months (4 vs. 18 months, HR 1.66, 95%CI 1.77-1.82, P < 0.0001) and median OS by 17 months (25.15 vs. 42.26 months, HR 1.48, 95%CI 1.46-1.51, P< 0.0001). Radiation therapy prior to BM incurred a significant but smaller increase in median BM-free survival by 6 months (5 vs. 11 months, HR 1.27, 95%CI 1.26-1.29, P< 0.0001) and median OS by about 3 months (30.13 vs. 32.82 months, HR 1.06, 95%CI 1.04-1.08, P < 0.0001).

CONCLUSION

Once BM is diagnosed, the synchronicity of diagnosis does not predict survival. Antineoplastic and radiation treatment directed at primary cancer may improve BM-free survival and OS. Studies characterizing the BM-free effects of molecular markers, chemotherapy, and radiotherapy are necessary to improve screening, prevention, and treatment.
EPID-06. TARGETED AGENTS IN PATIENTS WITH RECURRENT GLIOBLASTOMA– A SYSTEMATIC META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS
Authors: Ippen Franziska Maria , Scherm Angelika , Kessler Tobias , Hau Peter , Baurecht Hansjörg , Wick Wolfgang , Knüttel Helge , Leitzmann Michael F , Seliger Corinna
Published: November 2023

BACKGROUND

Glioblastoma (GB) is the most common malignant primary brain tumor in adults and associated with a dismal prognosis. While the standard of care for newly diagnosed GB is defined in current treatment guidelines, recommendations for recurrent GB are less well established. The current systematic meta-analysis of recently published randomized controlled trials (RCTs) represents the strongest available evidence on targeted agents in patients with recurrent GB.

METHODS

Cochrane Library, Pubmed, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform and Google Scholar were searched ranging from the year 1954-2022 for RCTs of targeted therapies in patients with recurrent GB. Hazard Ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were extracted to perform a random-effects meta-analysis.

RESULTS

16 RCTs (n=3,025 patients) were included in the meta-analysis. Experimental treatment was either compared to lomustine (CCNU) alone, in combination with CCNU/temozolomide (TMZ) to CCNU alone or to bevacizumab alone. In these three subgroups, targeted agents associated with improved OS compared to the control arm were regorafenib (RR= 0.50; 95% CI 0.33-0.75), Depatux- M+ TMZ (RR= 0.66; 95% CI 0.44-0.93) and rindopepimut + bevacizumab (RR= 0.53; 95% CI 0.32-0.88). Treatment with bevacizumab + CCNU (RR= 0.49; 95% CI 0.35-0.69) and regorafenib (RR= 0.65; 95% CI 0.44-0.95) were associated with improved PFS.

CONCLUSION

In this systematic meta-analysis, we provide the current highest level of evidence for the role of targeted therapies in recurrent GB. Even though some studies revealed a benefit either for OS and/or PFS, results have to be critically reviewed regarding initial distribution of prognostic factors, underlying molecular mechanisms, sample size and trial design. There is a need for more specific and personalized study designs using newly obtained tumor tissue and close monitoring of treatment responses to allow for potential modification of treatment if needed.
EPID-08. CLINICAL AND MOLECULAR DETERMINANTS OF BLEEDING-RELATED ADVERSE OUTCOMES IN HIGH-GRADE GLIOMA
Authors: Dasgupta Pushan , Rousseau Justin
Published: November 2023

Cancer is an independent risk factor for the development of venous thromboembolism (VTE) however patients with high-grade glioma (HGG) including glioblastoma (GBM) are at a particularly high risk of VTE with an incidence up to 20- 30% per year. Patients are often placed on anticoagulation to reduce the risk of VTE. However, patients with primary brain tumors such as HGG are at increased risk for intracerebral hemorrhage (ICH) even without the administration of anticoagulation. The combination of risk factors for ICH with anticoagulation and HGG complicates decision-making. Currently it is not known which of the direct oral anticoagulants (DOACs) are safest for patients with HGG in terms of adverse bleeding-related outcomes such as ICH. Furthermore, a deeper understanding of the clinical and molecular determinants of bleeding-related adverse outcomes in HGG is not fully characterized. In this study, we gathered data on patients with HGG from two Ascension Seton Hospitals in the Austin metro area from July 1, 2017 through June 30, 2022. We identified 76 pathology-confirmed patients with HGG. Patients who were on rivaroxaban (3/7 (43%), p=.022) had a statistically significant association with more bleeding-related adverse events compared to those on apixaban (0/12 (0%)) or enoxaparin (0/5 (0%)) even though the groups were similar in terms of their characteristics including total time on the respective anticoagulation. Patients on anticoagulation vs those never on anticoagulation did not differ in terms of their studied demographic and clinical characteristics. Intriguingly, logistic regression analysis revealed that patients harboring isocitrate dehydrogenase (IDH) mutations had a statistically significant association with more adverse bleeding-related events even when controlling for other relevant factors (Odds Ratio compared to reference GBM: 115.7; p=.014). This study offers insights into our understanding of relevant factors associated with worse bleeding-related adverse outcomes such as ICH in patients with HGG.
EPID-18. THE GENOMIC ARCHITECTURE OF GLIOBLASTOMA PREDISPOSITION IS HIGHLY POLYGENIC IN PATIENTS WITH A POSITIVE FAMILY HISTORY OF GLIOMA
Authors: Walsh Kyle , Ostrom Quinn , Byun Jinyoung , Wimberly Courtney , Armstrong Georgina , Amos Christopher ,   GICC Collaborators, Bondy Melissa
Published: November 2023

BACKGROUND

Genetic predisposition to glioblastoma (GBM) is highly polygenic and typically reflects the additive contributions of many common polymorphisms. However, patients with a positive family history of glioma may have a monogenic cancer predisposition syndrome. Such patients would be expected to have reduced contributions from common risk alleles.

METHODS

We sought to compare the polygenic risk of GBM among patients with a confirmed family history of glioma to those with a negative family history. Study subjects included 1628 GBM patients from the GICC study, who completed detailed questionnaires regarding personal and family medical history and underwent genome-wide genotyping of blood-derived DNA on the Illumina OncoArray. Polygenic risk scores were generated based on the 17 independent hits discovered by genome-wide association study (GWAS), with variants weighted by their respective effect sizes.

RESULTS

As expected, polygenic risk scores were significantly higher in GBM patients than in cancer-free control subjects (P=6.6x10-57). A total of 78 GBM patients had a positive family history of glioma, validated by record review. Across strata of family history, we observed that GBM patients with a positive family history of glioma had higher polygenic scores than patients with a negative family history (P=0.039). These results were robust in sensitivity analyses, where each of the 17 contributing variants were excluded from the model, one at a time.

CONCLUSIONS

Polygenic risk scores for GBM are significantly higher in patients with a positive family history of glioma. This suggests that, while family history can be due to rare, penetrant alleles, a large contingent of familial GBM may arise in families with a heavy polygenic burden of GBM risk alleles. Strategies for rare variant discovery might consider a two-pronged approach of sequencing kindreds with multiple affected members, as well as solitary GBM diagnoses in patients that have low polygenic risk scores.