bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-40. PHOTODYNAMIC ONCOLYTIC VIRUS THERAPY FOR CENTRAL NERVOUS SYSTEM MALIGNANCIES
Authors: Shimizu Kazuhide , Kahramanian Andranik , Maehara Taketoshi , Wakimoto Hiroaki 
Published: November 2023

Abstract
Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective to treat cancers that evade conventional therapies, including central nervous system malignancies. Rationally designed combinatorial strategies can augment the efficacy of OVs by boosting tumor-selective cytotoxicity and modulating the tumor microenvironment (TME). Photodynamic therapy (PDT) of cancer not only mediates direct neoplastic cell death but also primes the TME to sensitize the tumor to secondary therapies. This allows for the combination of two potentially synergistic therapies with broader targets. Here, we created G47Δ-KR, clinical oncolytic herpes simplex virus G47Δ that expresses photosensitizer protein KillerRed (KR). Optical properties and cytotoxic effects of G47Δ-KR infection followed by amber LED illumination were examined in human glioblastoma (GBM) and malignant meningioma (MM) models in vitro. G47Δ-KR infection of tumor cells mediated KR expression that was activated by amber LED and produced reactive oxygen species, leading to cell death that was more robust than G47Δ-KR without light. In vivo, we tested G47Δ-KR-based PD-OV therapy employing intratumoral injection of G47Δ-KR followed by amber laser (wavelength: 585 nm) tumor irradiation in GBM and MM xenografts. PD-OV therapy was feasible in GBM and MM xenografts and resulted in potent anti-tumor effects that were superior to G47Δ-KR alone (without laser) or laser alone. RNA sequencing analysis of post-treatment tumor samples revealed PD-OV therapy-induced increases in TME infiltration of variable immune cell types. This study thus demonstrated the proof-of-concept that G47Δ-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.
EXTH-43. TARGETING THE DNA DAMAGE RESPONSE THROUGH COMBINATION MDM2 AND AKT INHIBITOR THERAPY IMPROVES TEMOZOLOMIDE EFFECTIVENESS IN CHEMO-RESISTANT GLIOBLASTOMA
Authors: Koenig Jenna , Bailey Barbara , Alfonso Anthony , Saadatzadeh M Reza , Bijangi-Vishehsaraei Khadijeh , Pandya Pankita , Damayanti Nur , Dobrota Erika , Young Courtney , Shannon Harlan , Pollok Karen 
Published: November 2023

Abstract
Temozolomide remains the lone pharmacotherapeutic option for glioblastoma (GBM), yet the development of resistance to temozolomide has been a major challenge contributing to the persistent median &lt; 2-year survival for patients after diagnosis. Tumor heterogeneity and induction of treatment response networks, such as the DNA damage response (DDR), are major contributors to temozolomide resistance in GBM. Targeting DDR treatment response networks, such as the MDM2/p53/p73 and PI3K/AKT/mTOR networks, with small-molecule inhibitors (SMIs) presents an opportunity to disrupt resistance mechanisms and enhance temozolomide efficacy. We utilized a triple drug combination of clinically relevant concentrations of the blood-brain-barrier penetrant SMIs of AKT (ipatasertib; GDC-0068) and MDM2 (idasanutlin; RG7388) with temozolomide to evaluate this targeted strategy using the recurrent, temozolomide-resistant, p53wt GBM10 xenoline. Proliferation studies demonstrated dose-related additive to synergistic inhibition of proliferation at clinically relevant concentrations of ipatasertib and idasanutlin. Further, IncuCyte live-cell imaging demonstrated dose-and time-related growth inhibition of these GBM cells and apoptosis marked by increased cleaved caspase 3 expression following the temozolomide+idasanutlin+ipatasertib triple combination treatment. Cells treated with temozolomide+idasanutlin+ipatasertib also displayed senescence phenotypes, with increased cell cycle arrest and elevated expression of SPiDER β-Gal expression and cell-cycle inhibitors such as p53 and p21. Experiments are in progress to determine the extent to which the effects of temozolomide+idasanutlin+ipatasertib combination therapy are dependent on p53 using siRNA knockdown of p53. In the present study, targeting the temzolomide-induced DNA damage response with idasanutlin+ipatasertib increased the effectiveness of temozolomide. These results indicate that this triple combination may be a promising approach to improving patient outcomes in temozolomide-resistant GBM.
EXTH-47. TUMOUR-TARGETED PAN-RAS INHIBITION AS A NOVEL THERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Sbergio Stefanie-Grace , Liang Peter , Beilhartz Greg , Patel Palak , Vadivel Arun Anguraj , Melnyk Roman , Hawkins Cynthia 
Published: November 2023

Abstract

INTRODUCTION
Diffuse Intrinsic Pontine Glioma (DIPG) has a median survival of 9 months following diagnosis in children 7-9 years old. Current therapeutic options are limited to radiation and thus tumour specific vulnerabilities are the subject of ongoing research. One such vulnerability is RAS signalling due to its upregulation in DIPG. RAS regulates cellular proliferation and survival making it an attractive target. Based on diphtheria toxin (DT), we have developed a molecular chimera which selectively binds a DIPG cell surface receptor and releases a RAS cleaving peptidase (RRSP). We hypothesize that using a DIPG targeted RRSP conjugated chimera will reduce tumour viability and improve survival in DIPG models.

METHODS
Viability of SU-DIPG XIII, XVII, XXV, 36 and 50 cell lines treated with RRSP-DTB, and a DIPG targeted RRSP conjugated chimera was measured using CellTiterGlo Luminescent Assay. Proteomic analysis and single-cell RNA sequencing was used to identify a cell surface receptor upregulated on tumour cell populations from patient samples. SU-DIPG 36 orthotopic xenograft mice were treated with our DIPG targeted RRSP conjugated chimera or vehicle for one week delivered into the pons via osmotic pump and monitored using bioluminescent imaging.

RESULTS
RRSP-DTB successfully reduces DIPG cell viability in vitro with an EC50 between 0-3 picomolar, demonstrating successful toxicity mediated by RRSP. This is supported by ablation of RAS verified on Western Blot. ANTXR1 receptor was identified as upregulated in tumour cell populations, and a TEM8 conjugated RRSP chimera was developed. RRSP-TEM8 has an EC50 of 5-70 picomolar in vitro and significantly improves survival in vivo with a median survival of 68 days (n = 14) compared to the vehicle control (n = 14) 57 days (p = 0.02). Our results present a successful novel therapeutic as our RRSP chimera, RRSP-TEM8, effectively targets DIPG cells and reduces cell viability to improve survival.
EXTH-54. GB13 IS A POTENT TREATMENT FOR IL13RA2-EXPRESSING GBM AND DMG AND IMPROVES STANDARD-OF-CARE THERAPY
Authors: Rechberger Julian , Zhang Liang , Laukhuff Harrison , Woodruff Maija , Sarkaria Jann , Daniels David , Schrecengost Randy 
Published: November 2023

Abstract
GB13 is a novel biologic therapy in the final stages of preclinical development for the treatment of glioblastoma (GBM) and H3 K27-altered diffuse midline glioma (DMG) that has received Orphan Drug Designation by the Food and Drug Administration for treatment of malignant gliomas. GB13 targets a specific tumor-restricted receptor of interleukin 13 called interleukin 13 receptor alpha 2 (IL13Rα2). IL13Rα2 is highly expressed in malignant gliomas and, importantly, is not expressed on non-cancerous cells of the brain. GB13 consists of an engineered proprietary mutant of IL13, which binds exclusively to IL13Rα2, and is fused to a highly cytotoxic exotoxin molecule. In vitro data demonstrate that GB13 potently kills IL13Rα2+ cancer cells while sparing non-cancerous cells. These characteristics make GB13 an attractive agent for safe and efficacious targeting of tumor cells expressing IL13Rα2 in upcoming clinical trials. In the current studies, we employed patient-derived GBM and DMG cell and animal models to provide key conclusions that support GB13 as an effective treatment option for gliomas in the clinic. First, we demonstrated that single acute infusions of GB13 by enhanced delivery (CED) is effective at decreasing orthotopic tumor volumes and increasing animal survival and that a long-term infusion can more significantly extend animal survival. Second, we determined that IL13Rα2 is requisite for GB13 activity as tumors that do not express the receptor are insensitive to the cytotoxic effects of GB13, demonstrating a precise and clear biomarker for clinical trial patient selection. Finally, we determined that GB13 works in concert with clinical standard-of-care radiation therapy to increase cell death, compared to radiation alone. Based on this work, we and our clinical collaborators are confident that the current work confirms GB13 has many important characteristics as an exciting therapy, which continues development towards a Phase I clinical trial for both GBM and pediatric DMG.
EXTH-55. ALL-IN-ONE GENETIC CONSTRUCT TO KNOCKDOWN MIR-21 REDUCES GLIOMA PROLIFERATION IN VITRO
Authors: Nieland Lisa , Vrijmoet Anne , de Reus Alexandra , Kleinsteiver Benjamin , Broekman Marike , Breakefield Xandra , Abels Erik 
Published: November 2023

Abstract
Glioma, the most aggressive tumor of the CNS has poor patient outcome with limited effective treatments. CRISPR-CAS technology recently opened a new avenue for gene therapy and has been previously used to target non-coding RNAs, including microRNA-21, an oncogene associated with glioma progression. Here we show that an all-in-one construct containing both Staphylococcus Aureus Cas9 (SaCas9) guided by a single-guide RNA (sgRNA) specifically targeting miR-21 resulted in a deletion causing a downregulation of miR-21 expression levels and reduced proliferation in glioma cell lines. Here, we aim to design a single adeno-associated vector (rAAV) vector platform that express both saCas9 and sgRNA to target miR-21 in a glioma syngeneic mouse model. With the future goal to engineer a single AAV that can achieve therapeutic genome editing outcomes.
EXTH-56. CSF PENETRATION COMPARISON OF TWO ORAL FORMULATIONS OF APL-101 IN A PRE-CLINICAL NON-HUMAN PRIMATE MODEL
Authors: Cabanas Natalia Corvalan , McCully Cynthia Lester , Peer Cody , Gross Andrea , Glod John , Figg William , Shankarappa Priya , Warren Katherine , Widemann Brigitte 
Published: November 2023

Abstract
Vebreltinib (APL-101) is a potent c-Met inhibitor which has shown efficacy in murine pre-clinical models and is under clinical trial evaluation for several cancer types, including adult high-grade glioma. The capsule formulation (APL-101-Cap) was reformulated as a pill (APL-101-Pill) with the expectation of increasing bioavailability. We determined and compared the plasma pharmacokinetics (PK) and cerebrospinal fluid (CSF) penetration of APL-101-Cap and APL-101-Pill in a non-human primate (NHP) model. METHODS: Seven animals, previously developed as serial CSF access models, were utilized across all studies. One NHP was studied with both formulations. Both formulations were administered orally as a single drug/single dose in serial studies, followed by serial plasma and CSF sample collections from 0-96 hours. Dosages: APL-101-Cap 3.25 mg/kg (n = 3) or 6.5 mg/kg (n = 4) and APL-101-Pill 5 mg/kg (n = 4). The resulting plasma concentrations from each formulation were quantified by LC-MS/MS. PK parameters were calculated via noncompartmental methods, and results were analyzed to assess CNS penetration (AUCCSF:AUCPlasma) and compare formulations. RESULTS: Mean (range) for plasma and CSF PK exposure [AUCLAST (hr*ng/mL)] reported. APL-101-Cap plasma exposure, regardless of dose, was more variable than APL-101-Pill. APL-101-Pill had lower exposure in both plasma (AUC 1893.0 (841-2865)] and CSF [AUC 27.7 (5.0-65.0)] than APL-101-Cap regardless of dose [(3.25 mg/kg): plasma AUC 9621.0 (1331-23132) and CSF AUC 688.0 (24-1352); 6.5 mg/kg: plasma AUC 6208.0 (1424-19800) and CSF AUC 606.0 (34-1179)]. CNS penetrance was higher with APL-101-Cap (3.2% [0.5-5.8%] at 3.25mg/kg; 4.2% (2.4-6%) at 6.5 mg/kg), but also more variable when compared to APL-101-Pill (1.2% [0.6-2.3%]). For APL-101-Cap, one animal at 3.25 mg/kg and two animals at 6.25 mg/kg had undetectable CSF concentrations. CONCLUSION: In this NHP model, single-dose oral administration of APL-101-Pill resulted in lower, but less variable plasma and CSF exposure compared to APL-101-Cap. APL-101-Cap CSF exposure was unaffected by dose escalation.
EXTH-58. USING MEK INHIBITOR TO ENHANCEMENT 5-ALA MEDIATED SONODYNAMIC THERAPEUTIC EFFECT: A PRECLINICAL STUDY
Authors: Huang Chiungyin , Wei Kuo-Chen 
Published: November 2023

Abstract
The potential of sonodynamic therapy (SDT) using sono-sensitive molecules such as 5-aminolevulinic acid to treat brain tumor is highly noted for glioma treatment. However, the accumulation of 5-ALA in glioma cells is limited by the heterogeneous cell types of GBM. MEK inhibitor is known to be effective on enhance the accumulation of 5-ALA in glioma cells, therefore, we aim to study the effect of MEK inhibition on sonodynamic therapy. MEK inhibitor trametinib were systemically administered to animals bearing subcutaneous tumor xenograft 24 hours prior to treatment. Subsequently, the effects of 5-ALA-mediated sonodynamic therapy were determined by measuring the volume of tumor xenografts and the bodyweights animals. Glioma cells and tissue samples were collected, and the effect on MEK signaling pathway were evaluated by immunohistochemistry/PCR/Western blotting. For tumor growth data, comparison across multiple groups was performed with repeated measures two-way analysis of variance (ANOVA). Animals were divided into 5 groups: control, focused ultrasound (0.35 MPa.duty10%.10min), trametinib (1mg/kg), 5ALA (180mg/Kg) +FUS, trametinib(1mg/Kg)+5ALA(180mg/Kg) +FUS (n = 5 for each group). Following treatment, tumor growth was monitored by digital caliper twice a week. As compared with control group, the tumor size of trametinib+5ALA+FUS group is significantly less than control group (p = 0.0085, 0.0001 and 0.0255 at day 4, 7 and 11). No significant difference was observed in other groups verse control. The daily mice body weight records revealed no significant change, demonstrated no major toxicity was induced by the MEK inhibitor/5-ALA/sonodynamic combination treatment. Our study demonstrates that suppression of MEK pathway by MEK inhibitor trametinib significantly increase the accumulation of PpIX. In tumor animal models, mice pretreated with MEK inhibitor presented favorable response to 5-ALA mediated sonodynamic therapy. Our finding may suggest a new strategy to enhance the effect of sonodynamic therapy.
EXTH-59. IDENTIFICATION OF GROWTH HORMONE RECEPTOR AS A RELEVANT TARGET FOR PRECISION MEDICINE IN LOW-EGFR EXPRESSING GLIOBLASTOMA
Authors: Verreault Maite , Vilchis Irma Segoviano , Rosenberg Shai , Lemaire Nolwenn , Schmitt Charlotte , Guehennec Jeremy , Royer-Perron Louis , Thomas Jean-Leon , Lam Tukiet T , Dingli Florent , Loew Damarys , Ducray Francois , Paris Sophie , Carpentier Catherine , Marie Yannick , Laigle-Donadey Florence , Rousseau Audrey , Pigat Natascha , Boutillon Florence , Bielle Franck , Mokhtari Karima , Frank Stuart J , de Reynies Aurelien , Hoang-Xuan Khe , Sanson Marc , Goffin Vincent , Idbaih Ahmed 
Published: November 2023

Abstract
New therapeutic approaches are needed to improve the prognosis of Glioblastoma (GBM) patients. With the objective of identifying alternative oncogenic mechanisms to abnormally activated EGFR signaling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis of gene expression profiles in a series of 54 human GBM samples. We identified that Growth Hormone Receptor (GHR) signaling defines a distinct molecular subset of GBMs devoid of EGFR overexpression. GHR overexpression was detected in one third of patients and was associated with low levels of SOCS2 expression due to SOCS2 promoter hypermethylation. In GBM patient-derived cell lines, GHR signaling modulates the expression of proteins involved in cellular movement, promotes cell migration, invasion and proliferation in vitro, and promotes tumorigenesis, tumor growth and tumor invasion in vivo. GHR genetic and pharmacological inhibition reduced cell proliferation and migration in vitro. GHR signaling pathway thus emerges as an oncogenic signaling pathway in low EGFR-expressing GBMs and as a promising therapeutic target. This study pioneers a new field of investigation to improve the prognosis of GBM patients.
EXTH-60. OVERCOMING THE LEPTOMENINGEAL SEEDING OF MEDULLOBLASTOMA BY TARGETING HSP70
Authors: Choi Seung Ah , Ha Saehim , Kim Seung-Ki , Hwang Do Won , Heung Sekhoeun , Phi Ji Hoon 
Published: November 2023

Abstract
Purpose The development of leptomeningeal seeding (LMS) through the cerebrospinal fluid (CSF) is a common in medulloblastoma (MB) and a major cause of treatment failure. The mechanism of MB LMS remains unclear and effective treatment options are urgently required. This study aimed to discover molecules that can specifically target seeding cells by making a cellular model of MB LMS and analyzing their specific genetic and functional characteristics. METHODS: By repeated transplantation, separation, culture, seeding and non-seeding MB cells were isolated. The cellular characteristics of each group were compared and differentially expressed genes (DEGs) were determined through gene expression profiling. The therapeutic effect of the selected inhibitor on the selected protein was tested in vitro and in vivo. RESULTS: We separated seeding and non-seeding cells triply, with the DEGs analysis indicating that heat shock protein 70 (HSP70) was in the highest rank in the expression profile of the seeding cells, and pathway enrichment analysis revealed that the metabolism was the main pathway enriched in seeding cells. The proliferation of seeding cells (S3) was slower than that of non-seeding cells (N3), but there was no significant difference in viability. Notably, the wound-healing of S3 was delayed, but the adhesion ability on collagen was higher than N3. We tested the effect of HSP70 suppression. Among the six HSP70 inhibitors, VER155008 was efficiently sensitive to S3, and suppression of MRP proteins with HSP70 was observed. Importantly, the treatment of VER155008 reduced LMS along the spinal cord in vivo. In addition, a synergistic effect was observed in the combination treatment of VER155008 with 4-hydroperoxycyclophosphamide. CONCLUSION: Our study suggests that targeting HSP70 can be a promising treatment option to suppress the LMS of MB.
EXTH-61. A MULTI-TARGETED APPROACH TO EVALUATE THERAPEUTIC SELECTION AND EFFICACY IN PRECLINICAL GBM MODELS
Authors: Eastwood Emily , Carapia Bianca , Rodriguez Javier , Buck Kristen , Corcoran Bridget , Chien Yuan-Hung , Andrews Warren , Do Long , Nakashima Jonathan , Sperry Jantzen 
Published: November 2023

Abstract
Glioblastoma (GBM) is a devastating primary brain cancer with approximately 10,000 new US diagnoses annually. The current standard of care for GBM includes surgical resection followed by radiation therapy (RT) and temozolomide (TMZ), however there is near universal recurrence and development of resistance after treatment. Relapse in disease is tightly linked with dynamic changes in gene expression during tumor evolution, highlighting the need for stronger preclinical GBM models. Here we report developing a pair of patient-derived xenograft (PDX) models from surgical resections obtained from initial GBM incidence in a patient (CRT00433) and subsequent recurrence following treatment (CRT00435) in order to study disease progression and novel treatment strategies. Recent studies have suggested the utilization of combination therapy approaches for GBM patients to address TMZ resistance. To this end, Certis has developed a personalized, AI-based approach to predict and test combination therapies for CRT00433/435. Accuracy of the predicted sensitivities to treatment was then evaluated in vivo using both subcutaneously and orthotopically engrafted mouse modeling. Luciferase-tagged CRT00433 and CRT00435 spheroid cell lines were transduced with firefly luciferase and implanted intracranially by stereotactic surgery for orthotopic monitoring. Optical bioluminescence imaging (BLI) and MRI were used to assess therapeutic response of AI-predicted combination therapies and standard of care (RT and/or TMZ). Both in-life imaging and terminal histologic analysis of the tumors confirmed high fidelity to several of the therapies tested. In all, these results demonstrate a novel, combinatorial platform with which to assess therapeutic efficacy in GBM and exploit the overall ability of this deadly disease to adapt to an ever-changing molecular and genetic landscape.
EXTH-71. AUTOMATED AND MULTIPLEXED COMBINATORIAL DRUG SCREENING OF FDA-APPROVED DRUGS IDENTIFIES POTENTIAL SYNERGISTIC DRUG PARTNERS FOR THE TREATMENT OF AGGRESSIVE MENINGIOMAS
Authors: Jungwirth Gerhard , Braun Viktor , Warta Rolf , Abdollahi Amir , Unterberg Andreas , Herold-Mende Christel 
Published: November 2023

Abstract
The goal of combinatorial therapy is to improve the effectiveness of treatment by targeting multiple aspects of cancer cells or by overcoming resistance to single drugs. In search of effective synergistic drug combinations for the treatment of aggressive meningiomas, we performed an automated and multiplexed combinatorial drug screening of 166 FDA-approved anticancer drugs in three grade 3 meningioma cell lines. Three anaplastic meningioma cell lines (NCH93, IOMM-Lee, and KT21-MG1) were stably transduced with blue, green, and red fluorescence proteins. The cell lines were multiplexed into 384-well plates and treated in 5x5 dose-response matrices (1 to 1000 nmol/L) for 48 hours by the automated liquid handler Hamilton MicroLAB STAR®. The drug library consisted of 166 FDA-approved anticancer drugs. To demultiplex cell viability from a single well, fluorescence as a surrogate marker for viability was measured before adding an ATP-based end-point viability assay, which served as an independent combined result of all cell lines (combined group). Synergism was calculated by the ZIP Synergy model and was defined as a ZIP score over 10. This drug screening effort generated 13695 unique drug-drug combinations per cell line. Most synergistic combinations were observed in the combined group (n = 188, 1.37%), followed by IOMM-Lee (n = 157, 1.14%), and KT21-MG1 (n = 122, 0.88%). The lowest number of synergistic combinations was observed in NCH93 (n = 75, 0.54%). Interestingly, 86 combinations were uniquely found in IOMM-Lee, 54 in KT21-MG1, and 20 in NCH93, indicating specific tumor vulnerabilities. 19 drug combinations were observed in all cell lines. Of those, the drugs Temsirolimus, Gemcitabine, and Romidepsin were highly enriched. For example, mTORi Temsirolimus concordantly showed strong synergism with the androgen receptor antagonist Darolutamide in all cell lines (ZIP score: 27.75, P&lt; .0001). This comprehensive combinatorial drug screening identified synergistic drug-drug partners for the treatment of aggressive meningiomas. Validation studies in patient-derived meningioma organoids are ongoing.