bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-41. IMPROVING THE RADIOSENSITIVITY OF DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG) BY TARGETING HYPOXIA AND MITOCHONDRIAL METABOLISM
Authors: Shen Han , Chang Cecilia , Ing Prunella , Cook Kristina , McKelvey Kelly , Lai Joey , Gloss Brian , Prior Victoria , O'Neill Geraldine , Blackburn Anneke , Gee Harriet , Hau Eric 
Published: November 2021

Abstract
DIPG is the leading cause of brain tumor-related death in children. Radiotherapy is the only treatment that offers transient benefit and provides palliative care. DIPGs are hypo-perfused with tumor cells being exposed to hypoxia, a potent barrier to effective radiotherapy. Reducing the oxygen consumption rate (OCR) is therefore a potential strategy to reduce tumor hypoxia. We therefore performed a high-throughput screening with 1963 FDA-approved drugs that could reduce tumor hypoxia and OCR, thereby improving radiosensitivity of DIPGs. A subset of anti-diabetic drugs was identified, with phenformin amongst the most potent. It significantly reduced OCR in a panel of DIPG cultures and subsequently suppressed hypoxia in 3-dimensional DIPG neurosphere models that mimic the hypoxic microenvironment. In addition, phenformin demonstrated greater anti-tumor activity and radiosensitizing effect with much lower doses compared with metformin, a less potent biguanide that improved radiosensitivity of DIPG in a patient-derived xenograft (PDX) model in our previous study. The effect of phenformin was further enhanced by combining a second drug dichloroacetate that simultaneously attenuated phenformin-induced acidification rate. Specifically, the combination of phenformin and dichloroacetate induced higher levels of hypoxia inhibition, reactive oxygen species, DNA damage and apoptosis. RNA sequencing demonstrated significant changes induced by the combination treatment in cell-cycle, DNA repair, unfolded protein response and alternative energetic pathways. These changes were further validated by PCR array and western blotting at mRNA and protein levels. In addition, two master regulators that enhance the metabolic capacity of tumor cells through increased glycolysis thus contributing to radioresistance, HIF-1α and c-Myc, were also significantly suppressed by combination treatment. Ultimately, the triple combination of phenformin, DCA and irradiation demonstrated the most potent efficacy in inducing DNA damage, apoptosis and clonogenic inhibition in DIPG cultures. This promising triple combination therapy is currently being tested in our PDX cohort in vivo.
EXTH-49. FOCUSED ULTRASOUND AND 5-ALA MEDIATED ELIMINATION OF DIFFUSE MIDLINE GLIOMA
Authors: Schaab Luana , Ferry Yann , Ozdas Mehmet , Kritzer Bettina , Mourabit Sulayman , Marcus Stuart , Nazarian Javad 
Published: November 2021

Abstract
Diffuse midline glioma (DMG) is a devastating and incurable childhood brain cancer. With a median survival of only 9 to 11 months, over 90% of children affected by DMG die within two years of diagnosis. Despite decades of research and a growing understanding of the biology of these tumors, there have been no advancements in therapies for DMGs. Tumor heterogeneity and diffuse infiltration in inoperable brain regions make these tumors uniquely difficult to manage both surgically and pharmacologically. Therefore, there is an urgent need for the exploration of novel treatment regimens. Focused Ultrasound (FUS) is an emerging technology with significant clinical potentials. Sonodynamic therapy (SDT) is an up-and-coming treatment strategy aiming to non-invasively eliminate tumor cells by acting through compounds known as sonosensitizers, which render tumor cells sensitive to ultrasound energy. Recently, 5-Aminolevulinic acid (5-ALA), an FDA-approved molecule, has been proposed as a sono-sensitizing agent. 5-ALA mediated SDT prolonged survival in C6 rat glioma models by selective elimination of tumor cells upon sonication. Mechanistically, it is thought that 5-ALA uptake and metabolic conversion into Protoporphyrin IX (PpIX) occurs preferentially in tumor cells due to differential activity of enzymes involved in heme metabolism. Here, we investigated SDT in DMG cells treated with 5-ALA. PpIX fluorescence increased linearly up to 24 h upon 5-ALA treatment and accumulated significantly more (1.6-fold, p &lt; 0.01) when compared to C6 cells. Consequently, FUS sonication of 5-ALA treated DMG cells at 250 kHz significantly (p &lt; 0.05) decreased DMG cell viability compared to treatment with 5-ALA or FUS alone. Here, we show the first 5-ALA mediated sonodynamic effect in DMG cells, leading to enhanced cell death. Our findings provide a rationale for considering clinical investigation of 5-ALA mediated sonodynamic therapy in DMG.
EXTH-52. SYSTEMIC AND BRAIN PHARMACOKINETICS OF THE AMP-ACTIVATED PROTEIN KINASE SELECTIVE INHIBITOR SBI-0206965 AS A POTENTIAL THERAPEUTIC AGENT FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME
Authors: Desai Janki , Gawali Mruniya , Karve Aniruddha , Gudelsky Gary , Sallans Larry , Dasgupta Biplab , Seibel William , Desai Pankaj 
Published: November 2021

Abstract

PURPOSE
AMP-activated protein kinase (AMPK) is a molecular hub for cellular metabolic control. Recent evidence suggests that AMPK is a “druggable” novel target for the treatment of Glioblastoma Multiforme (GBM). However, AMPK-inhibitory compounds are largely limited to compound C, which has a poor selectivity profile. SBI-0206965 is a diaminopyrimidine derivative that directly inhibits AMPK with 40-fold greater potency and markedly lower kinase promiscuity than compound C. The current studies provide insights into systemic pharmacokinetics and plasma to brain partitioning of SBI-0206965.

METHODS
We conducted an intracerebral microdialysis study employing jugular vein-cannulated Sprague Dawley rats (males, 6- 8 weeks). Serial brain extracellular fluid (ECF) and venous blood samples were collected up to 10 hrs following intraperitoneal administration of SBI-0206965 (25 mg/kg). These samples were then quantitated for SBI-0206965 levels using a LC/MS method (Thermo Scientific LTQ-FT™, Ionization: Electrospray Ionization; positive ion). PK analysis was performed using the Non–Compartmental Analysis (Phoenix® WinNonlin 8.2 Certara USA, Inc.).

RESULTS
Plasma and ECF peak concentrations (Cmax) were 7.15 µM and 0.68 µM, whereas the time to peak (Tmax) were 0.5 and 1 hr, respectively. The plasma and brain ECF elimination half-lives were 1.5 and 3 hours, respectively. Plasma protein binding of SBI-0206965 was 82%. A comparison of the brain ECF Cmax and area under the curve (AUC) to corresponding plasma values suggested that the brain partitioning of the compound was 10-18%. When corrected for unbound fraction in plasma the AUC ratio was 0.86. Thus, these studies show that SBI-0206965 has adequate brain penetration. Further studies are now in progress to assess selectivity of SBI-0206965 for AMPK expressing cell lines, efficacy against patient-derived GBM and PK in tumor-bearing mice.

CONCLUSION
Results from this study will help to design optimal dosing regimen of SBI-0206965 in our efforts to explore AMPK as a GBM-specific drug target.
EXTH-53. ANTI-ROBO1 CAR T CELLS EFFECTIVELY TARGET MALIGNANT BRAIN CANCER
Authors: Chokshi Chirayu R , Brakel Benjamin , Rossotti Martin A , Venugopal Chitra , Salim Sabra , Bloemberg Darin , Vora Parvez , Henry Kevin A , Singh Sheila K 
Published: November 2021

Abstract
No standardized treatment exists for patients with recurrent glioblastoma (GBM). Given the aggressive nature of the disease and difficulty in modeling tumor recurrence, minimal efforts have been made to design rational therapies against it. The roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment and is aberrantly upregulated in glioma where it mediates glioma cell migration. Here, we present that ROBO1 is highly expressed on the surface of malignant and treatment-refractory brain tumor initiating cells (BTICs), prompting the development of an anti-ROBO1 CAR-T cell therapy. Using the binding region of a single-domain antibody targeting ROBO1, we developed second-generation anti-ROBO1 CAR-T cells specific and effective against ROBO1-expressing BTICs. Upon antigen exposure, anti-ROBO1 CAR-T cells upregulated markers of activation and degranulation. Additionally, treatment of orthotopic and patient-derived brain tumor xenograft models with anti-ROBO1 CAR-T cells resulted in reduced tumor burden and prolonged survival, demonstrating the therapy’s therapeutic potential for treating neoplastic brain malignancies.
EXTH-54. PHOTODYNAMIC ONCOLYTIC VIROTHERAPY INCORPORATING GENETICALLY ENGINEERED PHOTOSENSITIZER KILLERRED FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM MALIGNANCIES
Authors: Shimizu Kazuhide , Kahramanian Andranik , Wakimoto Hiroaki 
Published: November 2021

Abstract

BACKGROUND
Photodynamic therapy (PDT) is a targeted cancer therapy utilizing tumor-specific accumulation of photosensitizers and generation of reactive oxygen species (ROS) upon receiving specific light. The deadly CNS malignancies, high-grade gliomas and malignant meningioma, represent excellent candidates for this therapeutic method due to accessibility to light irradiation at the time of surgery. On the other hand, oncolytic virotherapy using a genetically engineered oncolytic herpes simplex virus (oHSV), has been intensively investigated as a multi-mechanistic therapy against these tumors. One of the advantages of oHSV is its ability to incorporate therapeutic transgenes. Our study aims to address our hypothesis that incorporating KillerRed, the first fully genetically encoded photosensitizing fluorescent protein, into oHSV will establish photodynamic oncolytic virotherapy that enhances tumoricidal efficacy as a novel treatment approach to CNS neoplasms.

METHOD
The optical properties of the intracellular KillerRed protein expressed in cells were determined by scanning by a multi-mode microplate reader to determine the optimal irradiation wavelength. In vitro efficacy of KillerRed-mediated PDT was tested using human glioblastoma and malignant meningioma cell lines. oHSV G47delta expressing KillerRed was constructed by a bacterial artificial chromosome-based method. KillerRed-transduced cells were confirmed to express red fluorescence, followed by irradiation by an amber color LED. Cell death and viability were assessed by DAPI staining and MTS assay, respectively. ROS generation post light treatment was assessed by DCF-DA cellular ROS assay.

RESULTS
KillerRed had an excitation peak at 580-585nm in transduced cells. Light irradiation by an amber LED after infection with G47delta-KillerRed induced increased cell growth inhibition and death compared with virus infection without light or light alone. Increased ROS production was observed following KillerRed PDT.

CONCLUSION
G47delta-KillerRed enables a combination of oncolytic virus therapy and PDT to augment tumor killing. This approach is being tested in in vivo mouse models using potent focused laser irradiation.
EXTH-60. PRECLINICAL STUDY OF PAMIPARIB, A CNS-PENETRANT PARP INHIBITOR, IN IDH1/2 MUTATED GLIOMAS
Authors: Hong Christopher , Sundaram Ranjini , Bindra Ranjit 
Published: November 2021

Abstract
Our group has demonstrated that IDH1/2 mutated gliomas harbor intrinsic homologous recombination (HR) defects mediated by the oncometabolite, 2-HG, rendering them sensitive to PARP inhibitors. Here, we studied the efficacy of pamiparib, a CNS-penetrant PARP inhibitor with potent PARP trapping ability, in combination with temozolomide (TMZ) and radiation therapy (RT) in IDH1/2 mutated gliomas. We also studied the pharmacokinetics of BGB290 to demonstrate CNS penetrance. We performed a series of DNA repair functional studies with in vitro short- and long-term viability assays, as well as in vivo studies utilizing an orthotopically injected rat glioma model with bioluminescence. Pharmacokinetics was measured with a previously validated LCMS/MS technique. Short-term and long-term viability assays in paired isogenic IDH1 wildtype and mutant cell lines showed the IDH1 mutation conferred enhanced sensitivity to pamiparib with several-fold decreases in IC50, as well as TMZ and RT as expected. Combination treatment with pamiparib and TMZ or RT also demonstrated synergistic interactions in these same cell lines, dependent upon IDH1 mutation status. An ELISA assay confirmed PARylation inhibition by pamiparib at the nanomolar range in a dose-dependent manner. Pharmacokinetic analysis demonstrated favorable CNS penetration with tumor:plasma ratios ( &gt;0.20) observed with low (3 mg/kg) and high (6 mg/kg) doses of pamiparib, orally administered BID to rats harboring intrinsic rat glioma intracranial tumors. These levels persisted between 2 and 8 hours after last dosing. Pamiparib also selectively penetrated tumors over normal brain with normal brain:plasma ratios under 0.20. These data suggest pamiparib may selectively target IDH1/2 mutated gliomas and act synergistically with TMZ and RT to exploit intrinsic HR defects associated with these tumors. Pharmacokinetic analysis suggest favorable CNS penetration after standard bid oral administration. As such, these results lay the groundwork for study of pamiparib with TMZ and/or RT in patients with IDH1/2 mutated gliomas.
EXTH-71. FUNCTIONAL GENOMICS IDENTIFIES EPIGENETIC REGULATORS AS NOVEL THERAPEUTIC TARGETS FOR SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Tsiami Foteini , Piccioni Federica , Root David , Bandopadhayay Pratiti , Segal Rosalind , Tabatabai Ghazaleh , Merk Daniel 
Published: November 2021

Abstract
Medulloblastoma (MB) is among the most common malignant pediatric brain tumors. Among its four molecularly heterogeneous clinical variants, sonic hedgehog (SHH) subgroup comprises 30% of all MBs and is characterized by constitutive activation of the canonical SHH signaling pathway. Although Smoothened (Smo) inhibition has emerged as a promising therapeutic target for this tumor entity, primary or acquired resistance impedes its clinical efficacy. Thus, further insight into the molecular mechanisms underlying acquired resistance to Smo inhibition are urgently needed to overcome this challenge. Here, we performed a genome-wide CRISPR/Cas9 knockout screen in a murine and a human SHH-MB cell line, SMB21 and DAOY, respectively, in order to unravel tumor-specific genetic vulnerabilities. Our data provide functional evidence that SMB21 cells highly depend on key members of the SHH pathway such as Smo and Gli1 for their survival. In contrast, none of those positive regulators of SHH signaling scored in DAOY cells, suggesting that they are not a faithful human model of this tumor subtype. Of note, functional genomics identified SMB21-context specific essentialities beyond the SHH pathway that include epigenetic regulators such as Dnmt1, Smarca5 and Smarca4. Further in vitro pharmacological validations demonstrate that Dnmt1 inhibition is efficacious in clinically relevant concentrations in SHH-associated cell lines, both sensitive and resistant to Smo inhibition, suggesting novel therapeutic avenues for SHH-MB. By employing genome-scale knockout screens in murine cell lines faithfully recapitulating the biology of human SHH-MB, we aim to decipher synthetic lethal interactors for Dnmt1 inhibitors that could potentially serve as a combinatorial treatment approach for SHH-MB. Finally, genetic ablation and pharmacological inhibition of epigenetic regulators will be evaluated in in vivo mouse models of SHH-MB. Summarizing, our data highlight the potential of inhibitors of epigenetic regulators in SHH-MB sensitive, as well as resistant to Smo inhibition.
EXTH-76. DEVELOPING THE NOVEL COMBINATION THERAPY OPTIONS FOR CANCER THERAPY USING TUMOR TREATING FIELDS TOGETHER WITH THE CHEMO AGENTS TARGETING THE REPLICATION STRESS PATHWAY
Authors: Karanam Narasimha Kumar , Story Michael 
Published: November 2021

Abstract
Tumor Treating Fields (TTFields) as a component of cancer therapy has been shown to provide significant clinical benefit. The disruption of mitosis was identified as the first mechanism of action, however, a novel role for TTFields outside of mitosis where TTFields downregulates the Fanconi’s Anemia genes and proteins results in replication stress and reduced DNA repair capacity. Given these results we hypothesized that TTFields would increase the sensitivity of tumor cells to chemotherapy agents that increase replication stress. An analysis of agents that target replication stress in different ways was initiated. PARP1: Targeting PARP1 protects DNA breaks by recruiting DNA repair and checkpoint proteins to the sites of damage. Using the PARP1 inhibitor olaparib followed by radiation resulted in synergistic cell killing compared to radiation or olaparib alone or in combination. Etoposide: Etoposide forms a ternary complex with topoisomerase II and prevents re-ligation of DNA strands to elicit DNA strand breaks and replication stress. When combined with TTFields cell killing increased synergistically vs. etoposide alone. AZD6738: ATR is an essential kinase regulator of the replication checkpoint that plays a critical role in safeguarding genome integrity from replication stress. The advantage of combining TTFields with the ATR inhibitor-AZD6738 was tested for cell killing and the combination vs. AZD6738 was found to be synergistic. Irinotecan: Irinotecan traps topoisomerase I- DNA in a ternary cleavage complex and inhibits the initial cleavage reaction and re-ligation steps resulting in increased replication stress. Irinotecan and TTFields was tested and found to be highly effective at tumor cell killing. Collectively, our results suggest that it is likely of considerable clinical benefit to combine TTFields with chemotherapy agents that cause replication stress. This notion may explain the results of a number of clinical trials and suggests that there may be novel TTFields/replication stress-inducing chemotherapy agent combinations worth exploring.
QOLP-09. AUTONOMY DURATION AS ANALYZED BY KPS ≥ 70 CUMULATIVE TIME IN PATIENTS WITH BIOPSY-ONLY GLIOBLASTOMA (BO-GBM). A SUB-ANALYSIS OF THE TIMONE COHORT
Authors: Harlay Vincent , Loundou Anderson , Boucard Céline , Petrirena Gregorio , Barrie Maryline , Campello Chantal , Autran Didier , Padovani Laeticia , Figarella Dominique , Boissonneau Sébastien , Dufour Henry , Baumstark Karine , Tabouret Emeline , Chinot Olivier 
Published: November 2021

Abstract

BACKGROUND
Maintenance of autonomy is a crucial and understudied issue for glioblastoma patients whose outcome is poor. Biopsy-only glioblastoma (BO-GBM) present with short survival and independence is of particular importance. Our objective was to explore their functional outcome.

MATERIAL AND METHODS
A regional glioma SIRIC cohort was conducted at CHU Timone in 2014-2017 and we retrospectively reviewed the BO-GBM subgroup. We prospectively collected age, tumoral surface, treatment allocated and completed, and survival outcome. Functional independence was analyzed as a cumulative time of Karnofsky performance status (KPS) ≥ 70 from the date of diagnosis until death. We analyzed potential factors associated to time with KPS ≥ 70.

RESULTS
Among 535 patients enrolled in the cohort, surgery was restricted to biopsy in 139 patients (BO-GBM). Mean tumoral surface measured on gadolinium-enhanced T1-weighted MRI was 1198 mm2 (min: 65; max: 4515mm2). Forty-seven patients were referred to radiotherapy-temozolomide (RT-TMZ), 75 considered unfitted for RT received chemotherapy upfront (CT-UF), and 17 patients were referred to palliative care. Median OS was 7.5 months (95%CI: 6.0-9.2), 14.0 months (95%CI: 9.7-18.7) and 6.0 months (95%CI: 4.6-7.7) for BO-GBM, RT-TMZ and CT-UF respectively. At diagnosis, 81 (58.3%) patients presented with self-care capacity (KPS ≥ 70%). For these patients, median time of autonomy preservation was 7.6 months (95%CI: 6.1-9.0). Median time of autonomy preservation differed according to treatment modalities: it was 8.6 months (95%CI: 5.9-11.3) versus 6.3 months (95%CI: 2.9-9.7) for RT-TMZ versus CT-UF group respectively (p&lt; 0.001). In multivariate analysis, time with KPS ≥ 70 was correlated with age (p=0.001) and KPS at diagnosis (p&lt; 0.001).

CONCLUSION
Patients with inoperable GBM referred to radiotherapy-temozolomide present a valuable duration of functional independence, although shorter in patients not referred to RT. Duration of functional independence could be considered in addition to PFS and OS for treatment evaluation in patients with GBM.
QOLP-16. PATIENT-REPORTED SELECTION FOR INCIDENTAL FINDINGS IN A COMPREHENSIVE GENOMIC TRIAL: A DANISH SINGLE INSTITUTION EXPERIENCE FROM THE COPENHAGEN GLIOBLASTOMA COHORT
Authors: Nørøxe Dorte Schou , Poulsen Hans , Lassen Ulrik 
Published: November 2021

Abstract

INTRODUCTION
Participation in clinical trials is a high priority in the neuro oncology community and requires an informed, signed consent. However, patient information is increasingly complex as many trials include comprehensive molecular analyses and, according to Danish legislation, must include a statement about incidental findings. Incidental findings can range from variants of unknown significance to pathogenic variants in the mismatch repair-genes (MMR) and BRCA1-2. Pathogenic variants have been reported in 1-18% of cancers and can have significant influence for the patient and family. Patients with glioblastoma (GBM) can have impaired cognitive function, both due to GBM and due to morbidity after surgery. This can limit access to clinical trials as some patients might not understand the study information. We investigated whether patients were interested in participating in a comprehensive genomic trial and where they marked their preference of information for incidental findings.

PATIENTS AND METHODS
108 consents from a published study from the Copenhagen Glioblastoma Cohort were examined. The study period was 2016-2019 and included whole exome- and RNA sequencing. The consent included three alternatives to receive information about incidental findings; 1) none, 2) if incidental findings could be treated or future disease be prevented or 3) full information even though no treatment or prevention existed.

RESULTS
A total of 108/111 (97.3%) patients consented to participate. Each category was marked as follows: 33 (30.6%) marked 1), 24 (22.2%) marked 2) and 45 patients (41.7%) marked 3), respectively. Six consents were N/A as either two or no boxes were marked. No pathogenic incidental findings were identified.

CONCLUSION
We found a high interest in trial participation despite of complex study information. Information about incidental findings was spread between groups with majority of patients interested in receiving full information, suggesting that complex information does not hinder participation in molecular-based trials for GBM patients.