bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-40. SPECIFIC DENDRIMER-MEDIATED DELIVERY OF IMMUNOTHERAPY BLZ945 TO TUMOR-ASSOCIATED MACROPHAGES IMPROVES THERAPEUTIC EFFICACY IN GLIOBLASTOMA
Authors: Liaw Kevin , Reddy Rajsekhar , Sharma Rishi , Salazar Sebastian , Jinemez Ambar , Kannan Sujatha , Kannan Rangaramanujam 
Published: November 2019

Abstract
Patients with glioblastoma have failed to see improved outcomes despite the discovery of powerful anti-cancer drugs because such therapies do not adequately cross the blood-brain barrier and penetrate into solid tumors to access pathological cells. In addition to these delivery challenges, tumors polarize host macrophages into tumor-associated macrophages (TAMs), which suppress the tumor-killing response and create a growth-conducive immune environment for cancer cells. As a result, TAMs are promising therapeutic targets but translational efforts targeting them have largely failed due to low response rates and high systemic toxicities. Therefore, a vehicle that carries immunotherapies into the brain, deep into solid tumors, and specifically to TAMs while remaining inactive in the body provides a promising clinical strategy. Here, we present hydroxyl-terminated polyamidoamine (PAMAM) dendrimers as novel targeted drug delivery systems to overcome these delivery challenges in the GL261 mouse model of glioblastoma. Upon systemic administration, these dendrimers, without any targeting ligands, are able to cross the blood-brain barrier, distribute uniformly throughout the solid glioblastoma tumor, and localize specifically within TAMs. Dendrimers display high tumor specificity (>5-fold compared to the contralateral hemisphere) and minimal systemic accumulation (< 5% initial dose remaining in livers or kidneys after 24 hours). We then conjugated BLZ945, a potent immunotherapy that prevents tumors from recruiting TAMs, to the dendrimer via pH-sensitive linkers for triggered intratumoral and intracellular release. We find that a single systemic dose of dendrimer-delivered BLZ945 halfway through disease progression prolongs survival by >30% compared to free BLZ945 and untreated cohorts. These survival benefits were accompanied by amelioration of disease progression and improved motor function. Finally, we demonstrate that repeat dosing of dendrimer-delivery BLZ945 in combination with current standard of care temozolomide provides robust, synergistic improvements to survival and disease severity. These studies validate the potential of dendrimers for localized immune manipulation in glioblastoma.
EXTH-47. THERAPEUTIC REVERSAL OF PRENATAL PONTINE ID1 SIGNALING IN DIPG
Authors: Harris Micah , Yadav Vivekanand , Stallard Stefanie , Woo Rinette , Siddaway Robert , Qin Tingting , Mullan Brendan , Miklja Zachary , Siada Ruby , Ravindran Ramya , Cao Xuhong , Pasternak Amy , Castro Maria , Lowenstein Pedro , Mody Rajen , Chinnaiyan Arul , Hawkins Cynthia , McAllister Sean , Desprez Pierre , Venneti Sriram , Koschmann Carl 
Published: November 2019

Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are lethal brain tumors with no effective therapies other than radiation. Inhibitor of DNA binding (ID) proteins are key regulators of tissue and lineage-specific gene differentiation during embryogenesis. Previous work has shown that H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes, but this has not been validated in human DIPG, nor has the regulation and targetability of ID1 been explored in DIPG. Analysis of multi-focal post-mortem tumor and normal brain tissue (n=52) as well as multiple human datasets revealed ID1 to be elevated in DIPG. Elevated ID1 was found to correlate with reduced survival in DIPG. In a multi-focal autopsy DIPG case, we found ID1 expression to be heterogeneous and to correlate with tumor invasion. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) was used to quantify H3K27ac and H3K27me3 at ID1 gene regulatory regions (promoters/enhancers) in multi-focal post-mortem tissue. The ID1 loci was found to be epigenetically poised for up-regulation (elevated H3K27ac and low H3K27me3) in DIPG tissue, regardless of H3 or ACVR1 mutation status, compared to normal brain. Analysis of publically-available ISH and ChIP-sequencing data revealed elevated ID1 expression and ID1-enhancer H3K27ac in prenatal mouse hindbrain compared to prenatal forebrain, prenatal midbrain, and all postnatal brain regions. ID1 shRNA-mediated knockdown of primary human H3K27M DIPG cells (DIPG007) resulted in significantly reduced invasion and migration. As cannabidiol (CBD) has successfully been used to therapeutically target ID1 in pre-clinical models of adult human cancers, we treated DIPG007 cells with CBD and found reduced viability at clinically relevant dosing (IC50=2.4 uM) with dose-dependent reduction in ID1 protein. ID1 knockdown and CBD treatment studies in murine models of DIPG are ongoing. These findings indicate that a multifactorial (genetic and regionally-based) epigenetic upregulation of ID1 drives DIPG invasiveness and is targetable with CBD.
EXTH-48. GALECTIN-1 INHIBITION SENSITIZES RADIATION TREATMENT IN A PRE-CLINICAL MODEL OF GLIOBLASTOMA
Authors: Henderson Fraser , Das Arabinda , Kanginakudru Indira , McDonald Daniel G , Kosnik Infinger Libby , Vandergrift III William , Varma Abhay , Vanek Kenneth N , Lindhorst Scott , Patel Sunil , Cachia David 
Published: November 2019

Abstract
Radioresistance remains a major clinical challenge in glioblastoma (GB) therapy. However, the mechanism for the development of radioresistance in GB is unclear. Mounting evidence suggests that Galectin-1 (Gal1: a carbohydrate-binding protein galectin-1) contributes to the radioresistance of GB tumors. Recently, several Gal1-targeting compounds have emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic β-sheet conformation. Our study aimed to reduce galectin-1 expression using OTX008 in a human GB pre-clinical model. For these studies an in vivo GL261 murine models of GB were utilized to assess efficacy of treatment with radiation plus OTX008. Our results demonstrated that inhibition of Gal-1 with OTX008 plus radiation showed significantly decrease in GB growth rate and improved survival in in vivo. OTX008 treatment plus radiation was associated with downregulation of Gal1 and Ki67 in treated tumors, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with radiation therapies, principally when OTX008 was administered first. This study provides insights of Gal-1inhibitory effects of OTX008 and its enhancement of the efficacy of radiotherapy in mouse models of GB suggest that further studies are warranted.
EXTH-52. CO-TARGETING ONCOSTATIN M RECEPTOR USING MONOCLONAL ANTIBODIES IN COMBINATION WITH PRESENT STANDARDS OF CARE FOR GLIOBLASTOMA
Authors: Burban Audrey , Sharanek Ahmad , Jahani-Asl Arezu 
Published: November 2019

Abstract
Glioblastoma Multiform (GBM) is the most aggressive primary tumor in the adult brain. The present standard of care includes surgical removal of the tumors followed by treatment with Temozolomide (TMZ) and radiation therapy. Despite intense efforts and advances in surgery and combination therapy, the median survival rate for GB patients remain 16 months following diagnosis. EGFRvIII/STAT3 signaling plays critical roles in GBM pathogenesis. We have recently discovered that the tumorigenic capacity of EGFRvIll/STAT3 pathway crucially depends on the cytokine receptor for Oncostatin M (OSMR). OSMR is a required co-receptor of EGFRvIII and a direct transcriptional target of STAT3. Strikingly, OSMR is highly expressed in brain tumor stem cells (BTSCs), a population of self-renewing malignant stem cells within GBM that contribute to tumor growth, recurrence and therapeutic resistance. We have generated therapeutic monoclonal antibodies against OSMR (OSMR mAb) that function as powerful inhibitors of OSMR. Treatment of BTSCs with OSMR mAb resulted in inhibition of OSMR-mediated signaling pathways and significantly impaired the phosphorylation of STAT3. Strikingly, treatment of BTSCs with OSMR mAb significantly attenuated BTSC self-renewal in limiting dilution assay and sensitized their response to tyrosine kinase inhibitors (TKI), ionizing radiation and TMZ. Using patient derived stem cell tumor xenografts, we have shown that OSMR mAb significantly reduced tumor growth compared to IgG control. Together, our findings suggest that targeting OSMR using therapeutic monoclonal antibodies in combination with EGFR inhibitors and/ or the current standard of care may provide a promising therapeutic strategy for glioblastoma.
EXTH-57. PRECLINICAL COMBINATION OF ONC201 WITH RADIOTHERAPY OR TEMOZOLOMIDE IN GBM, DIPG AND ATRT CELL LINES RESULTS IN DOPAMINE RECEPTOR ANTAGONISM, ATF4 INDUCTION AND CELL DEATH
Authors: Zhou Lanlan , El-Deiry Wafik 
Published: November 2019

Abstract
CNS tumors are one of the most lethal cancers in children and young adults. We previously reported that first-in-class small-molecule imipridone ONC201 can antagonize dopamine receptor D2 (DRD2), inactivate ERK/AKT, induce the integrated stress response (ISR), upregulate pro-apoptotic TRAIL receptor DR5, deplete cancer stem cells, and induce growth arrest or cell death in tumor cells. ONC201 crosses the blood-brain barrier and has induced durable tumor regressions in adult and pediatric H3K27M-mutant glioma patients. We hypothesized that ONC201 may synergize with radiotherapy or temozolomide in brain tumors. Glioblastoma (GBM: SNB19, T98G and U251), diffuse intrinsic pontine glioma (DIPG: SF8628) and atypical teratoid rhabdoid tumor (ATRT: BT-12, BT-16) cell lines were tested using cell viability or colony formation assays with ONC201 up to 20 μM alone or in combination with radiotherapy up to 8 Gy or temozolomide up to 100 μM. We observed synergy between ONC201 and radiation or temozolomide by multiple assays. We observed induction of PKA substrate phosphorylation as a marker of DRD2 antagonism, induction of ATF4 as a marker of ISR activation, and multiple markers of cell death in treated brain tumor cells. We are evaluating the relevance of mitochondrial protease ClpP, a recently described binding target of ONC201, in ONC201-induced glioma cell death. We have observed that knockdown of ClpP strongly protects multiple human cancer cell lines from ONC201-mediated cytotoxicity. Thus, we are exploring the potential interplay between ClpP, dopamine receptors, the ISR and TRAIL signaling pathways after single agent or combinatorial treatments. Our data suggests that ONC201 may be combined synergistically with temozolomide or radiation to address gliomas, along with potential pharmacodynamic biomarkers.
EXTH-62. STEM CELL DELIVERY OF ONCOLYTIC ADENOVIRUS DNX-2401 FOLLOWING SURGICAL RESECTION FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Gopakumar Sricharan , Gumin Joy , Daou Marc , Ledbetter Daniel , McDonald Malcolm , Hossain Anwar , Hingtgen Shawn , Ewend Matthew , Lang Frederick 
Published: November 2019

Abstract

BACKGROUND
The oncolytic virus DNX-2401 (Delta-24-RGD) is a novel treatment of GBM. While prior studies have examined intratumoral injection of DNX-2401 into recurrent GBM, the potential of delivering DNX-2401 into the surgical resection cavity using tumor-tropic human mesenchymal stem cells (MSCs) has not been evaluated. We hypothesize that exploiting a fibrin-based scaffold for transplanting MSCs loaded with DNX-2401 (MSCs-DNX-2401) into the resection cavity will improve viral delivery, decrease GBM recurrence, and extend overall survival.

METHODS
MSCs-DNX-2401 were seeded in a fibrin matrix or suspended in PBS and placed in the upper wells of transwell plates with U87 cells placed below. After one week, U87 cells were counted to compare rates of cellular killing and confirm release of DNX-2401 from fibrin-seeded MSCs. U87 cells were transduced with mCherry-Luciferase and implanted into the brains of athymic mice (N=16). After fluorescence-guided surgical resection of glioma xenografts, MSCs (control) or MSCs-DNX-2401 were delivered in the resection cavity using a fibrin scaffold. Serial bioluminescence imaging (BLI) was used to monitor tumor recurrence.

RESULTS
In transwell experiments, MSCs-DNX-2401 seeded in fibrin were as effective as MSCs-DNX-2401 without the scaffold, indicating that fibrin did not negatively impact cell viability or viral release. In in vivo studies mimicking residual tumor after surgical resection, treatment of the post-resection cavity with MSCs-DNX-2401 suspended in fibrin permitted retention of MSCs-DNX-2401 within the tumor bed. Kaplan-Meier survival analyses revealed statistically significant improved survival after treatment with MSC-DNX-2401 in fibrin compared to controls with 50% of animals demonstrating complete responses according to BLI (p < 0.05).

CONCLUSION
Delivering DNX-2401 into the post-resection surgical cavity using MSCs seeded in fibrin is capable of eradicating residual GBM and prolonging overall survival. These studies support the clinical translation of this approach in newly diagnosed patients undergoing surgical resection of GBM.
EXTH-66. THERAPEUTIC VULNERABILITIES AND RADIOSENSITIZATION INDUCED BY IDH MUTANT DEPENDENT SUPPRESSION OF DNA DAMAGE REPAIR IN GLIOMA AND CHOLANGIOCARCINOMA
Authors: Wang Yuxiang , Wild Aaron , Chan Timothy 
Published: November 2019

Abstract
Mutations in isocitrate dehydrogenase (IDH) identified across cancer types lead to global changes to the epigenome that drive tumorigenesis. Yet, effectiveness of targeted therapies against mutant IDH remains unclear. Here we demonstrate that IDH-mutant glioma and cholangiocarcinoma patient specimens display elevated overall DNA damage responses. With tissue culture and multiple preclinical animal models of glioma and cholangiocarcinoma, we report that the reduced efficiency of DNA damage repair conferred by mutant IDH can be exploited by PARP inhibitors. Moreover, pharmacological effects of PARP inhibitors are dramatically enhanced by introducing concurrent, local ionizing radiation treatment to the animals. Thus, our study characterized the synergy of PARPi and radiation specifically towards IDH-mutant tumors, pointing out that in addition to ongoing trials using PARPi as mono agent, clinical trials that combine PARPi and radiation should be specifically considered. Furthermore, PARPi + RT may represent a readily translatable approach that is selective for tumor cells, transcends histologic origin, and has potential to improve outcomes in multiple diseases.
EXTH-69. NANOTHERAPEUTICS FOR NEUROSURGICALLY-APPLIED DRUG DELIVERY
Authors: Vasey Catherine , Taresco Vincenzo , Smith Stuart , Alexander Cameron , Rahman Ruman 
Published: November 2019

Abstract
Despite multimodal treatment, the median survival of Glioblastoma multiforme (GBM) patients remains less than 15 months, in considerable part due to diffusely infiltrative disease. Better treatment methods are necessary to eradicate residual tumour burden remaining beyond the resection cavity boundary. It is hypothesised that incorporating drug-loaded polymer pro-drug nanoparticles into a biodegradable microparticulate paste will lead to efficacious local delivery. We report the formulation of numerous self-assembling cytocompatible nanoparticles, based on different linear and branched polymeric architectures, amenable for localised intra-cavity delivery post-surgery. The polymers were synthesised by ring-opening polymerisation with organic catalysts, leading to controlled reaction kinetics and greater potential biomedical applicability. A simple nanoprecipitation technique was employed to gain nanoparticles with the size range of 60–130 nm, depending on the initial monomer ratios and polymeric architectures. Successful biocompatibility studies of the self-assembling nanoparticles have been carried out in vitro on the U87 glioma cell line. We demonstrated that copolymerisation of a monomer with functional capability enabled the successful conjugation of doxorubicin to the polymer chain. We will discuss strategies to incorporate pH-sensitive linkers to the polymeric backbone, which would allow controlled drug release in acidic microenvironments. Based on an increasing understanding of GBM intra-tumour heterogeneity, the capability to deliver multiple therapeutic moieties from single formulations is clinically-relevant. Thus, we hypothesised that polymers with a greater degree of branching over traditional linear structures would lead to greater drug loading, and successfully tested this hypothesis through the encapsulation of olaparib. Future work will assess the efficacy of the polymer pro-drug nanoparticles against both commercial and primary cell lines, and safety/efficacy of intra-cavity delivery using orthotopic syngeneic allografts, thus giving a more therapeutically-relevant insight into the activity of the formulations. This is the first study incorporating polymer pro-drugs of this type into an existing localised micro-scale delivery system for GBM therapies.
GENE-06. INTEGRATIVE ANALYSIS OF DNA METHYLATION SUGGESTS DOWN-REGULATION OF ONCOGENIC PATHWAYS AND REDUCED SOMATIC MUTATION RATES IN SURVIVAL OUTLIERS OF GLIOBLASTOMA
Authors: Kim Sojin , Dho Yun-Sik 
Published: November 2019

Abstract
The study of survival outliers of glioblastoma (GBM) can provide important clues on gliomagenesis as well as on the ways to alter clinical course on this almost uniformly lethal cancer type. However, there has been little consensus on genetic and epigenetic signatures of the long-term survival outliers of GBM. In this study, we compared the two groups of survival outliers of glioblastoma with IDH wild-type, consisting of the GBM patients who lived longer than 3 years (n=17) and the patients who lived less than 1 year (n=12) in terms of genome-wide DNA methylation profile. Statistical analyses were performed to identify differentially methylated sites between the two groups. Functional implication of long-term survivors of GBM (LTS-GBM)-specific sites were investigated by comprehensive enrichment analyses with genomic and epigenomic features. We found that the genome of LTS-GBM is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. In the LTS-GBM-specific sites distant from CGI, somatic mutations of GBM are enriched with higher DNA methylation, suggesting that the hypomethylation in LTS-GBM can contribute to reduce the rate of somatic mutation. On the other hand, the hypermethylation near CGIs associates with transcriptional downregulation of genes involved in cancer progression pathways. Using independent cohorts of IDH1/2- wild type GBM, we also showed that these two patterns of DNA methylation can be used as molecular markers of LTS-GBM. Our results provide extended understanding of DNA methylation, especially of DNA hypomethylation, in cancer genome and reveal clinical importance of DNA methylation pattern as prognostic markers of GBM.
GENE-11. LDSCORE REGRESSION IDENTIFIES NOVEL ASSOCIATIONS BETWEEN GLIOMA AND AUTO-IMMUNE CONDITIONS
Authors: Ostrom Quinn , Edelson Jacob , Byun Jinyoung , Han Younghun , Walsh Kyle , Amos Christopher , Bondy Melissa 
Published: November 2019

Abstract

BACKGROUND
Prior epidemiological studies in glioma have identified 25 germline risk variants, as well as risk associations with exposure to ionizing radiation (which increases risk) and history of allergies and aspirin use (which decrease risk). In this analysis we LDscore regression, which leverages single SNP associations and known patterns of linkage disequilibrium (LD) to estimate the genetic correlation between phenotypes, to confirm prior associations as well as attempt to identify novel phenotype associations for traits not previously assessed that may improve genetic prediction for glioma.

METHODS
Summary statistics for all glioma, GBM, and non-GBM were obtained from a prior meta-analysis conducted by Melin, et al. Summary statistics for 13 immune- and atopy-related traits were obtained from the prior case-control studies and the UK biobank. Data were filtered to include only SNPs with imputation INFO value >0.7, and minor allele frequency >0.01, excluding SNPs within the HLA region. Pairwise genetic correlation between these traits was generated using LDSC. Associations were considered significant at p< 0.05

RESULTS
Significant negative correlations were identified between glioma and ulcerative colitis (rg= -0.4039, p=4.91x10-10), celiac disease (rg= -0.2028, p=1.18x10-4), lupus (rg= -0.0956, p=0.0083), and multiple sclerosis (rg= -0.5755, p=4.46x10-9). These associations were generally consistent in both GBM and non-GBM. There was a significant correlation between both self-reported (rg= -0.102, p=0.0233) and doctor diagnosed (rg= -0.116, p=0.0305) hayfever/allergic rhinitis and GBM only.

CONCLUSIONS
This analysis demonstrates a genetic basis for previously identified protective effect of allergic rhinitis on GBM, and identifies novel associations between multiple auto-immune traits and glioma. Further studies are necessary in order to confirm these associations and identify the mechanism through which increased immune activity may lower risk of glioma.
GENE-17. ATRX LOSS IN GLIOMA RESULTS IN EPIGENETIC DYSREGULATION OF THE G2/M CHECKPOINT AND SENSITIVITY TO ATM INHIBITION
Authors: Mullan Brendan , Qin Tingting , Siada Ruby , Ravindran Ramya , Garcia Taylor , Muruganand Ashwath , Harris Micah , Danussi Carla , Brosnan-Cashman Jacqueline , Pratt Drew , Zhao Xinyi , Rehemtulla Alnawaz , Sartor Maureen , Venneti Sriram , Meeker Alan , Huse Jason , Morgan Meredith , Lowenstein Pedro , Castro Maria , Yadav Vivekanand , Koschmann Carl 
Published: November 2019

Abstract
Gliomas are a leading cause of cancer mortality in children and adults and new targeted therapies are desperately needed. ATRX is a chromatin remodeling protein that is recurrently mutated in H3F3A-mutant pediatric GBM and IDH-mutant grade 2/3 adult glioma. We previously showed that loss of ATRX in glioma results in tumor growth and additional tumor mutations. However, the mechanism driving these phenotypes has not been fully established. We found that in ChIP-Seq datasets of mouse neuronal precursor cells (NPCs) and experimental models of human glioma cells, ATRX binds and regulates the chromatin state of promoters and enhancers for gene sets associated with regulation of the cell cycle G2/M checkpoint. In line with this, analysis of single-cell seq (sc-seq) data from IDH-mutant gliomas (n=16) shows that ATRX-mutant tumors (IDH-A) demonstrate a population of cycling cells with dysregulated cell cycle phase gene set expression when compared to ATRX-wildtype tumors (IDH-O). In glioma models, ATRX-deficient cells exhibit a seven-fold increase in mitotic index at 16 hours after sub-lethal radiation and enhanced activation of the master cell cycle regulator ATM with radiation. Treatment of ATRX-deficient gliomas with ATM inhibitors results in a selective increase in dysfunctional cell cycling and increased radio-sensitization in ATRX-deficient glioma cells. Using an ATM-luciferase reporter in orthotopically-implanted human GBM cells, both AZD0156 and AZD1390 demonstrate in vivo pathway inhibition. Mice intra-cranially implanted with ATRX-deficient GBM cells demonstrate a doubling of median survival compared to radiated controls (p=0.0018) when treated with AZD0156 combined with radiation. This study demonstrates that ATRX-deficient glioma display epigenetic dysregulation of the G2/M checkpoint, which opens a new window for therapies targeting this unique phenotype.