bluuebunny/crossref_metadata_2025_split huggingface dataset:
CMET-42. USE OF STEREOTACTIC RADIOSURGERY AND OUTCOMES FOLLOWING RADIOTHERAPY FOR BRAIN METASTASES IN PATIENTS WITH PRIMARY LUNG CANCER – AN AUSTRALIAN POPULATION-BASED STUDY
Authors: Loon Ong Wee , Wada Morikatsu , Foroudi Farshad 
Published: November 2019

Abstract

INTRODUCTION
We aim to evaluate the use of stereotactic radiosurgery (SRS) among lung cancer (LC) patients who received radiotherapy (RT) for brain metastases (BM), and the associated outcomes.

METHODS
This is a population-based cohort of LC patients who received RT for BM between 2013 and 2016, as captured in the Victorian Radiotherapy Minimum Dataset. Brain RT was classified as SRS (including multi-fraction stereotactic RT) and non-SRS. Mortality data was captured through data linkage with the Victorian Cancer Registry (VCR). The primary outcomes were: proportion of patients who had SRS for BM, and overall survival (OS) following brain RT. Multivariable logistic regression was used to evaluate factors associated with SRS use. Kaplan-Meier method was used to estimate OS. Multivariable Cox regression was used to evaluate factors associated with OS.

RESULTS
1,002 LC patients were included in the study. 1,395 courses of RT for BM were delivered, of which one quarter (362/1,395) were SRS. Almost all SRS were delivered in metropolitan centres (347/362), and two-third in public institutions (235/362). In multivariate logistic regressions, increasing age (OR=0.91;95%CI=0.82–0.99;P=0.04) and treatment in regional centres (OR=0.13;95%CI=0.06–0.28;P< 0.001) were independently associated with lower likelihood of SRS use. Median follow-up was 3.3 months (IQR=1.3–7.8 months). 876 deaths were observed with 12-month OS of 16%. The 12-month OS for patients who had SRS were 38% vs. 12% in patient did not have SRS (P< 0.001). In multivariable Cox regressions, the use of SRS (HR=0.44,95%CI=0.37–0.54;P< 0.001) and female (HR=0.76;95%CI=0.67–0.87;P< 0.001) were associated with improved OS, while increasing age was associated with worse OS (HR=1.02;95%CI=1.01–1.03;P< 0.001).

CONCLUSION
This is the largest Australian study reporting on SRS use for BM in LC patients. We observed geographical variations in SRS use. We believe the impact of SRS use on OS is most likely due to patient selection for SRS.
COMP-01. MODELING THE EVOLUTION OF PLOIDY IN A RESOURCE RESTRICTED ENVIRONMENT
Authors: Andor Noemi , Barnholtz-Sloan Jill , Ji Hanlee 
Published: November 2019

Abstract
Progression of lower-grade gliomas (LGG) to glioblastoma (GBM) is accompanied by a phenotypic switch to an invasive cell phenotype. Converging evidence from colorectal-, breast-, and lung-cancers, suggests a strong enrichment of high ploidy cells among metastatic lesions as compared to the primary. Even in normal development: trophoblast giant cells are responsible for invading the placenta during embryogenesis and these cells often have tens of copies of the genome. We formulate a mechanistic Grow-or-go model that postulates higher energy demands of high-ploidy cells as driver of invasive behavior. The unit we are modeling is a cell, that comes with a certain ploidy, proliferation-, and death-rate. Variations in ploidy emerge as a result of chromosome missegregations. For each cell we calculate the probability of cell-division as a function of energy availability in the neighborhood vs. ploidy-dependent energy demand of the cell. Underlying this comparison is the dual role of integrin signaling: integrin-mediated signals allow cells to progress from G1 to S-phase. At the same time integrins mediate cell migration. The model was implemented as a cellular automaton and 2,500 simulations were ran at variable energies and missegregation rates. In low-energy environments high-ploidy clones were enriched at the leading edge of the tumor. This was not the case in high-energy environments. We applied the model to analyze previously published exome sequencing data from 14 multi-spatial and longitudinal LGG biopsies. Using the size and ploidy of co-existing clones as summary statistics for Approximate Bayesian Computation, we infer relative chromosome missegregation rates in primary LGG. A higher missegregation rate was predictive of faster progression of LGG to GBM (multivariate Cox: HR = 7.96, P = 0.041). Future validation experiments will evaluate the potential of the model to explain differences in the prognostic power of integrin signaling and cell cycle progression between males and females.
COMP-05. A DRUG ASSOCIATION MAP OF GLIOBLASTOMA INFORMS PRECISION TARGETING OF p53-DEPENDENT METABOLIC STATES
Authors: Johansson Patrik , Almstedt Elin , Doroszko Milena , Kundu Soumi , Vinel Claire , Lane David , Nestor Marika , Marino Silvia , Krona Cecilia , Nelander Sven 
Published: November 2019

Abstract
Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. Because GBMs are genetically and functionally diverse, there is little systematic understanding of how hundreds of approved drugs may be active against GBM subpopulations. To identify new pharmacological subgroups of GBM, we studied comprehensively the variation in drug response across 100 well-characterised patient-derived GBM cell cultures and used statistical models to explain patient specific cellular drug response in terms of molecular markers, pathway signatures and drug mechanism-of-action. We find that the response to proteasome inhibitors, currently under clinical development for GBM, shows extreme variation across cases, which is phenocopied \emph{in vivo} and predicted by p53 pathway activity. The resistance to proteasome inhibitor response is explained by a subset of p53 functional GBM cases, which exhibit more efficient scavenging of reactive oxygen species (ROS), thereby protecting against ROS-dependent apoptosis. By interference against this protective feedback loop using secondary inhibitors, synergistic killing of GBM cells is achieved. Our results define a sizable metabolic subclass of GBM cells, with implications for precision and combination targeting.
COMP-07. MACHINE LEARNING PREDICTS PROGRESSION AND SURVIVAL IN GLIOMA USING RADIOHISTOGENOMIC FEATURES
Authors: Traylor Jeffrey , Ravikumar Visweswaran , Rao Arvind , Rao Ganesh 
Published: November 2019

Abstract

BACKGROUND
Random forest classifiers can predict survival and progression status with radiomic features. Here, we compare the predictions of radiomic, histomic, and genomic features on progression-free survival (PFS) and overall survival (OS) in patients with low-grade glioma (LGG).

METHODS
We identified patients from our institution and The Cancer Genome Atlas (TCGA) with LGG and analyzed histopathology, mRNA expression, and MRI sequences. Differential gene expression analysis was performed to obtain top gene expression values. Discriminative feature-oriented dictionary learning (DFDL)1 was used to extract histomic features from histopathology slides. Forty-four computer-derived texture features were extracted from segmented tumors for each MRI sequence. A random forest classifier with cross-validation was then used to evaluate binary predictions of PFS and OS using radiomic, genomic, and histomic features from institutional and TCGA data.

RESULTS
The out-of-bag (OOB) error rates for PFS and OS predictions from combined institutional and TCGA radiomic features (n = 104) was 0.22 and 0.15, respectively. Similarly, OOB error rates of PFS and OS predictions for institutional histomic features (n = 66) was 0.24 and 0.29, respectively. OOB error rates for predictions of PFS and OS from combined institutional and TCGA genomic features (n = 283) were 0.14 and 0.24, respectively. A combined model incorporating radiogenomic features from institutional and TCGA data performed slightly worse than either modality alone (PFS OOB error = 0.28, OS OOB error = 0.21), possibly due to fewer cases (n = 67).

CONCLUSION
Our findings indicate combining radiomic and genomic features can predict PFS and OS in patients with LGG. The utility of this methodology may help to predict malignant transformation in LGG. REFERENCES: Vu TH, Mousavi HS, Monga V, Rao G, Rao UA. Histopathological image classification using discriminative feature-oriented dictionary learning. IEEE transactions on medical imaging. 2015;35(3):738–51.
COMP-12. SINGLE-CELL TRANSCRIPTOME PROFILING OF GBM TISSUE ACUTE SLICE CULTURES FOR PERSONALIZED DRUG SCREENING
Authors: Zhao Wenting , Spinazzi Eleonora , Dovas Athanassios , Upadhyayula Pavan , Marie Tamara , Sisti Michael , Bruce Jeff , Canoll Peter D , Sims Peter 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common and malignant type of primary brain tumor, and more effective treatment options are needed. Both inter- and intratumoral heterogeneity present major challenges to the application of targeted therapies in GBM. Therefore, precision medicine approaches to GBM would benefit significantly from the ability to predict drugs or drug combinations that target specific subpopulations of tumor cells. Model systems, such as adherent cell lines, neurospheres, patient-derived xenografts (PDXs), and patient-derived organoids, have been reported as platforms for drug screening and accessing drug responses. However, these models do not recapitulate the full heterogeneity of GBM tissue, lack key components of the tumor microenvironment or take weeks to months to establish, which limits the predictive power of drug response assays or delays clinical decision-making. To address these limitations, we are combining ex vivo slices of intact, patient-derived GBM tissue with single-cell RNA-seq (scRNA-seq) for small-scale drug screening and assessment of patient- and cell type-specific drug responses. We generated slices from both preclinical mouse glioma models and surgical specimens from GBM patients and showed that acute slices preserved both the tumor heterogeneity and tumor microenvironment observed in scRNA-seq of cells directly isolated from tumor tissue. To test drug responses, we treated tissue slices from GBM mouse models and five different patients with six drugs for 18hr. By performing scRNA-Seq and analyzing transcriptional profiles of treated and untreated control slices, we identified drug-induced transcriptional responses in specific subpopulations of tumor cells, patient-specific drug sensitivities, and drug effects conserved in both mouse and human tumors. The GBM tissue slices were generated immediately following surgical resection, and experiments were completed within 24 hours. With these features, our method is attractive for rapidly accessing cell type- and patient-specific drug responses and has potential for preclinical drug screening and guiding personalized treatment for GBM.
DDIS-05. IDENTIFICATION OF 2-FLUORO PALMITIC ACID AS A POTENTIAL THERAPEUTIC AGENT AGAINST GLIOBLASTOMA
Authors: Jiapaer Shabierjiang , Dong Yu , Kitabayashi Tomohiro , Furuta Taskuya , Sabit Hemragul , Zhang Jiakang , Zhang guangtao , Tanaka Shingo , Nakada Mitsutoshi 
Published: November 2019

Abstract

BACKGROUND
Glioblastoma (GBM) represents the most aggressive and frequent type of primary malignant brain tumors with a dismal clinical outcome. Though adjuvant temozolomide (TMZ) chemotherapy followed by surgical resection can extend patient`s post-operative survival, a considerable number of GBM cases are refractory to TMZ. Novel therapeutic agents that can overcome chemoresistance against TMZ are urgent. Drug repositioning is a process of identifying new indications for existing drugs and provides potential possibilities to discover new drugs. In this study, we explored novel anti-glioma agents which enhances the effect of TMZ with the strategy of drug repositioning.

METHODS
Drug library which contains 1300 diverse chemical compounds was screened using 2 kinds of glioma stem cell (GSC) lines to select novel therapeutic candidate. The effect of candidate drug on the proliferation of GSCs was estimated by sphere formation assay. To evaluate its efficacy against glioma cell biology, proliferation assay, matrigel invasion assay were performed. To clarify the mechanism of drug effects, we investigated target molecules by gelatin zymography and western blot.

RESULTS
Acyl CoA synthetase inhibitor named 2-fluoropalmitic acid (2-FPA) was selected as a novel candidate. 2-FPA suppressed proliferation of glioma cell lines by single administration and/or combination with TMZ. The sphere formation of GSCs was suppressed by combination therapy. Combination therapy enhanced TMZ effect. 2-FPA also suppressed invasion of glioma cell lines in a dose dependent manner. 2-FPA suppressed MMP-2 activity and phosphorylation of STAT3.

CONCLUSION
2-FPA was identified as a novel potential therapeutic agent against GBM.
DDIS-35. RelA-ACTIVITY IS ESSENTIAL FOR CANNABIDIOL-MEDIATED CYTOTOXICITY IN AN IDENTIFIED SUBSET OF GLIOBLASTOMA
Authors: Volmar Marie , Nagl Bernhard , Haug Alisha , Richter Sven , Alenezi Haithanm , Herold-Mende Christel , Lamszus Katrin , Synowitz Michael , Schick Joel , Kälin Roland , Glass Rainer 
Published: November 2019

Abstract
Glioblastoma (GBM) therapy could strongly profit from simplified procedures for personalized medicine. Cannabidiol (CBD) is explored for GBM-patients, but the mode of drug-action is largely unknown and stratification markers are missing. We investigated CBD-induced cytotoxicity in a panel of human primary GBM cells as well as transgenic mouse gliomas and in different orthotopic or transgenic in vivo models. We observed therapeutic efficiency of CBD in a subset of GBM, obtained genetic markers indicating CBD-sensitive GBM and found that the p53 status segregated cell-death modes. Genome wide loss of function screening, transcription factor binding studies and knockout-models indicated a central for role for NFkB (RelA) in CBD-initiated GBM-death. CBD mediated nuclear import of RelA lacking an essential post-translational modification and reduced RelA-activity. CBD altered redox levels specifically in drug-sensitive GBM and ROS-levels in unstimulated GBM predicted therapeutic response. Hence, quantifying ROS in GBM represents a simple bioassay to identify individuals potentially profiting from CBD-application in neurooncology.
DDIS-37. SMALL MOLECULE AUTOPHAGY ACTIVATORS IN GROWTH INHIBITION OF GLIOBLASTOMA
Authors: Waters Ariana , Nurmammadov Elmar , Nomura Natsuko , Babic Ivan , Kesari Santosh , Yenugonda Venkata 
Published: November 2019

Abstract
Glioblastoma (GBM) is one of the most lethal human tumors, and despite considerable advances in multimodality treatments consisting of surgical removal, radiation and chemotherapy, overall survival is 14 to 16 months after diagnosis. Therefore, there is a need to target non-apoptotic death pathways and inhibit pro-survival signaling mechanisms that contribute to both tumorigenesis and treatment resistance. Depending on tumor type and environment, autophagy modulation plays an important role in tumor cell survival and inhibition pathways. Increasing evidence supports that chemical modulation of autophagy inhibition and activation holds a therapeutic potential and these studies have led to the initiation of multiple clinical trials combining chemotherapeutic agents and autophagy inhibitors and activators for various cancer types. However, recent studies have also demonstrated a therapeutic potential for enhancers of autophagy in GBM. This clearly demonstrates the need for further investigation into the autophagy induced mechanism of GBM, and the development of better treatments. We have identified a new chemical entity VMY-BC-1 that showed promising effects in both serum and patient-derived glioma cell lines. Drug target engagement studies identified an autophagy induction protein, UNC-51 like kinase 1 (ULK1), as the main target of VMY-BC-1, in which VMY-BC-1 covalently bound to the protein’s active pocket and increased ULK1 phosphorylation.ULK1 is a component of the ULK1 complex (ULK1-ATG13-FIP200) that is essential for inducing autophagy, a lysosome-dependent mechanism of intracellular degradation for maintaining cellular homeostasis. Additionally, our molecule cross talks to the apoptotic and DNA damage pathways, which could potentially overcome treatment resistance.VMY-BC-1 is orally bioavailable, brain penetrant, and inhibits cell invasion and tumor growth in GBM flank models, making this small molecule an ideal candidate for further development. We hypothesize that activating ULK1-modulated autophagy will be a therapeutic strategy for GBM growth inhibition
DRES-03. PARP INHIBITOR, INHIBITION OF HOMOLOGOUS RECOMBINATION, OR DIANHYDRODULCITOL CAN OVERCOME TEMOZOLOMIDE-RESISTANCE IN GLIOMA CELLS
Authors: Ohba Shigeo , Hirose Yuichi 
Published: November 2019

Abstract
Glioblastoma is one of the most aggressive tumors in the central nervous system tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). The acquisition of resistance to TMZ and the heterogeneity of the tumor are considered to be associated with poor prognosis. TMZ is a DNA-methylating agent, delivering a methyl group to DNA (O6-guanine, N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to futile DNA mismatch repair (MMR), formation of double strand breaks and eventual cell death, when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The object of the study was to reveal the mechanisms of resistance to TMZ and to find the way to overcome the resistance in glioma. Several clones of TMZ-resistant U251 were obtained and analyzed. A clone showed high homologous recombination (HR), and inhibition of HR resensitized the clone to TMZ. MMR system was suppressed in the other clones. Inhibition of BER by PARP inhibitor resensitized them to TMZ. PARP inhibitor enhanced the TMZ-induced cytotoxicity in glioma cells with high expression of MGMT. Dianhydrodulcitol, alkylating agent, suppressed the proliferation in U251 and even U251-derived resistant clones. These effects were shown in U87MG-dereived resistant clones and MGMT-proficient cell lines. Moreover, inhibition of HR enhanced the cytotoxicity of dianhydrodulcitol. To select the appropriate treatment according to the mechanisms of resistance to TMZ can overcome the resistance in glioma cells.
DRES-06. PROSTAGLANDIN E RECEPTOR 3 MEDIATES RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA CELLS
Authors: Chen Dongjiang , Le Son , Thomas Nagheme , Tran David 
Published: November 2019

Abstract

OBJECTIVES
Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. However, most GBM patients eventually develop resistance to TTFields. The mechanism of TTFields resistance remains largely unexplored. Understanding how GBM cells circumvent the biophysical forces of TTFields and their downstream effects will improve therapeutic efficacy of this novel anti-cancer treatment modality.

METHODS
A panel of GBM cell lines were treated continuously with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally.

RESULTS
TTFields-induced chromosomal instability such as the formation of cytoplasmic micronuclei is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay. Using an innovative computational platform, we methodically dissected this stemness program in resistant cells. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked master regulator responsible for resistance. PTGER3 is rapidly upregulated in GBM cells upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Pharmacological inhibition of PTGER3 either using aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors resensitized cells to TTFields.

CONCLUSIONS
We have identified a novel pathway with PTGER3 at the apex that plays a critical role in TTFields resistance. This pathway is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.
DRES-12. QUANTIFYING INDIVIDUALIZED ABT-414 SENSITIVITY AND BLOOD-BRAIN BARRIER PENETRANCE FROM SERIAL IMAGING OF PATIENT-DERIVED XENOGRAFTS MODELS OF GLIOBLASTOMA
Authors: Urcuyo Javier , Christine Massey Susan , Marin Bianca-Maria , Sarkaria Jann , Swanson Kristin 
Published: November 2019

Abstract

INTRODUCTION
Glioblastoma (GBM) is an aggressive primary brain tumor, known for its poor prognosis. Due to its diffuse invasiveness into normal-appearing brain, localized treatments such as surgical resection and radiotherapy are typically supplemented with chemotherapy. However, to reach invading tumor cells, such antineoplastic drugs must cross the blood-brain barrier (BBB). That is, while angiogenesis induces BBB breakdown in dense tumor regions, the BBB remains rather intact for invading GBM cells. As a result, it is unclear whether BBB-impermeable drugs are delivered at a sufficient level to be effective.

METHODS
In order to study heterogeneity in BBB breakdown, experiments were conducted using both flank and intracranial patient-derived xenografts (PDXs) treated with the EGFR-targeted monoclonal antibody drug conjugate, depatuxizumab mafodotin (ABT-414). Time-series bioluminescence imaging (BLI) data was used to develop a differential equation model of tumor growth for three PDX cell lines. Data from untreated PDXs, both in flank and intracranially, were used to parameterize tumor proliferation rates. Flank PDX data were used to parameterize individual sensitivity to ABT-414, whereas intracranial PDX data were used to determine the proportion of drug exposed to the tumor.

RESULTS
Each PDX line differed in response to the study drug ABT-414. As expected, such heterogeneous responses can primarily be attributed to differences in both drug sensitivity and the proportion of drug that reached the tumor. Notably, the estimated proportion of drug that reached the tumor was highest in the PDX line with the longest survival times, despite also having higher estimates of resistance. This suggests that PDXs with greater overall BBB breakdown may respond better to this agent.

CONCLUSIONS
Although more cell lines are needed to validate our approach, parameterizing this model for PDXs gives valuable insight into the extent of BBB breakdown in patient GBMs and may aid in determining optimal therapies for individual patients.