bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDIS-26. HIGH-THROUGHPUT DRUG SCREENING OF MENINGIOMAS IDENTIFIES HDAC INHIBITORS AS PROMISING TARGETS ACROSS GRADES
Authors: Tatman Philip , Fringuello Anthony , Wroblewski Teddy , Scherer Sam , Foreman William , Ryan Ormond D , Damek Denise , Lillehei Kevin , Jensen Randy , Graner Michael 
Published: November 2019

Abstract
Meningiomas are a common central nervous system (CNS) tumor, accounting for one third of CNS neoplasms. To date, no FDA approved pharmacotherapy exists for meningiomas. In an effort to identify potential treatments for meningiomas we created a culture system that allows us to grow and screen tumors across hundreds of compounds within two weeks of resection. We screened 32 meningiomas, six of which were World Health Organization (WHO) grade II, against the National Cancer Institute’s (NCI) FDA-approved cancer compound library and Caymen Chemical’s epigenetic inhibitor library, totaling to more than 300 compounds. The NCI library was screened at 1um, and the Caymen library was screened at 5um. Each library was screened in triplicate, allowing us to calculate statistical significance. We used an MTS assay to determine cell viability after three days. The data was background subtracted and normalized to controls. Significant changes in cell viability were determined for individual drugs using a Mann-Whitney-U test compared to untreated controls. On average, regardless of grade, 5.9 compounds per hundred screened significantly reduced tumor viability. We identified four compounds in the NCI FDA-approved library that reduced cell viability, on average across all tumors screened, by at least 50%: romidepsin, panobinostat, daunorubicin, and carfilzomib. Using the same criteria, we identified the following drugs from the Caymen epigenetic library: LAQ824, panobinostat, and HC toxin. Of the six compounds implicated as possible treatments for meningiomas, four are histone deacetylase (HDAC) inhibitors. HDAC inhibitors may represent a promising target for the treatment of meningiomas. Based on this data, we have begun in vivo work using PDX mouse models to investigate the therapeutic potential of HDAC inhibitors for the treatment of meningiomas.
DDIS-29. BRAIN-PENETRANT MICROTUBULE-TARGETING AGENT, ST-401, KILLS GLIOBLASTOMA THROUGH A NOVEL MECHANISM
Authors: Horne Eric , Xu Cong , Vicente Juan-Jesus , Cimino P J , Wagenbach Michael , Hamel Ernest , Gussio Rick , Diaz Philippe , Uhlenbruck Benjamin , Deckwerth Thomas , Wordeman Linda , Holland Eric , Stella Nephi 
Published: November 2019

Abstract
Glioblastomas are particularly sensitive to mitotic disruption when compared with nonmalignant cells and thus microtubule-targeting agents (MTA) represent promising therapeutics to treat patients with glioblastomas; but few such compounds pass the blood brain barrier. We developed a series of modified carbazoles, evaluated their anti-cancer activity in glioblastoma cells in culture and identified ST-401 as the most potent compound (IC50, 10 – 102 nM, depending on the cell line). Testing of ST-401 on the NCI 60 cancer cell panel indicated that its anti-tumor activity does not correlate with any of the compounds tested thus far through this platform but showed weak correlations for taxol (p=0.46) and vinblastine (p=0.34). Thus, ST-401 may kill cancer cells through a novel mechanism related to disruption of MT function. Biochemical analysis indicates that ST-401 binds to the colchicine site of tubulin and inhibits tubulin assembly. Real-time imaging of MT dynamics in cells in culture shows that ST-401 reduces MT assembly rates but in a reversible fashion. ST-401 potently blocks mitotic progression and triggers cell death in multiple glioblastoma lines in culture, including patient-derived glioblastomas of the proneural, mesenchymal and classical subtypes. We established the maximum tolerated dose (MTD) of ST-401 in mice (20 mg/kg/bdip) and found that its acute i.p. injection results in micromolar amounts of ST-401 in mouse brain. Using this treatment regimen, we found that ST-401 reduces tumor growth and doubles overall survival in a human tumor xenograft mouse model system. ST-401 also increases by 2-fold overall survival in the genetic RCAS-PDGF glioblastomas mouse model treated with standard care (radiation and Temodar® treatments). Histological analysis of RCAS-PDGF glioblastoma tissue shows that ST-401 triggers mitotic arrest of glioblastoma cells. ST-401 represents a promising lead compound for the treatments for patients diagnosed with glioblastomas.
EPID-07. HEMATOLOGICAL ADVERSE EVENTS IN GLIOBLASTOMA PATIENTS TREATED WITH TEMOZOLOMIDE
Authors: Garcia Catherine , Myint Zin , Jayswal Rani , Butts Allison , Weiss Heidi , Villano John 
Published: November 2019

Abstract

BACKGROUND
Temozolomide (TMZ) is the cornerstone for glioblastoma (GBM) treatment. A significant proportion of patients develops hematologic toxicities with limited investigations on outcomes and risk factors for their development.

METHODS
Our study combines data from the two largest group trials, RTOG 0525 and RTOG 0825, to analyze serious hematologic adverse events (HAE) associated with TMZ therapy for GBM. We analyzed frequency and outcomes of HAE during chemoradiation.

RESULTS
1154 patients were evaluated with a median age of 57 years. Over 79% of patients developed HAE during the entire course of GBM treatment. During chemoradiation the most common HAE during chemoradiation was lymphopenia (41.5%), followed by thrombocytopenia (39.0%), and anemia (35.3%). Of these, 34.1% were severe (Grade 3 or 4) and 65.9% were mild (grade 1 or 2). During maintenance the most common HAE was leukopenia (50.7%), followed by neutropenia (50.4%), and lymphopenia (45.3%). MGMT methylation was not associated with HAEs. A history of HAEs during chemoradiation was a protective factor for developing HAEs during maintenance. MGMT methylated and age younger than 50 were protective factors for mortality. Patients that presented HAEs anytime during treatment had a longer overall survival and progression free survival. There was no significant difference in survival between mild or severe HAEs.

CONCLUSION
HAE are common during chemoradiation with TMZ for GBM, but are more commonly grade 1 or 2 per CTCAE. HAE during GBM treatment is associated with decreased progression free survival and overall survival.
EPID-30. A TWITTER-BASED NETWORK ANALYSIS OF BRAIN TUMOR SOCIAL MEDIA (#BTSM)
Authors: Feliciano Josemari , Salmi Liz , Blotner Charlie , Hayden Adam , Nduom Edjah , Kwan Bethany , Katz Matthew , Claus Elizabeth 
Published: November 2019

Abstract

BACKGROUND
The Brain Tumor Social Media (#BTSM) Twitter hashtag was founded in February 2012 as a disease-specific hashtag for brain tumor patients. To understand #BTSM’s role as a patient support system we describe user descriptors, growth, interaction, and content sharing.

METHODS
We analyzed all tweets containing #BTSM from 2012 to 2018 using the Symplur Signals platform to obtain data and to describe Symplur-defined user categories, tweet content, and trends in use over time. We created a network plot with all publicly-available retweets involving #BTSM in 2018 to visualize key stakeholders and their connections to other users.

RESULTS
From 2012 to 2018, 59764 unique users participated in #BTSM, amassing 298904 tweets. The yearly volume of #BTSM tweets increased by 264% from 2012 to 2018 with #BTSM constantly trending in the top 15 list of disease hashtags, as well the top 15 list of tweet chats. Patient advocates generated the most #BTSM tweets (33.0%) while advocacy groups, researchers, caregivers and doctors, generated 28.8%, 7.0%, 4.6% and 3.9%, respectively. Physician use, although still low, has increased over time. The 2018 network plot of retweets including #BTSM identifies a number of key stakeholders from the patient advocate, patient organization, and medical researcher domains and reveals the extent of their reach to other users.

CONCLUSIONS
From its start in 2012, #BTSM has grown exponentially over time. We believe its growth suggests its potential as a global source of brain tumor information for patients, advocates, patient organizations as well as healthcare professionals and researchers.
EPID-31. EFFICIENT STUDY OF SURGICALLY TREATED MENINGIOMA THROUGH CLINICAL DATA STANDARDIZATION
Authors: Au Karolyn , Nassiri Farshad , Drummond Kate , Jenkinson Michael , Santarius Thomas , Barnholtz-Sloan Jill , jungk Christine , DiMeco Francesco , Galanis Evanthia , Saladino Andrea , Zhou Yueren , Suppiah Suganth , Aldape Kenneth , Zadeh Gelareh , Poisson Laila 
Published: November 2019

Abstract
With increasing epidemiological and biological studies on meningiomas, standardized clinical data capture will be necessary to interpret results across studies and to translate them to clinical practice. To meet this need for consistent clinical data capture, the International Consortium on Meningioma, has developed a set of common data elements (CDEs), to be used across clinical and biological research. Building from terminology used in clinical practice and ongoing studies, we used a consensus-of-experts approach to arrive at a set of standardized and vetted data elements. Areas of focus include patient characteristics, patient history, radiological and intra-operative description, histological diagnosis and molecular testing, non-surgical interventions, and surveillance. These data elements are implemented in Research Electronic Data Capture (REDCap) forms. With REDCap implementation, components of the CDE set can be selected and instituted in a local REDCap instance for efficient study start-up. The scope of the current CDE set focuses on surgically treated meningioma. However, modular forms provide flexibility and to allow the scope to be expanded to include non-surgically treated meningioma. Dissemination plans are underway to introduce the CDEs to neuro-oncology researchers and clinicians through publication and presentations, where feedback will be solicited. Adoption of CDEs for research will improve consistency and interpretability across studies, expediting research in this frequently occurring tumor.
EXTH-03. TRIPTOLIDE, A NOVEL THERAPEUTIC AGENT FOR IDH1-MUTATED GLIOMA
Authors: Yu Di , Liu Yang , Xu Guowang , Yang Chunzhang 
Published: November 2019

Abstract

BACKGROUND
Isocitrate dehydrogenase (IDH1/2) mutations are common genetic abnormalities in human malignancies, which result in neomorphic enzyme activity that catalyzes 2-hydroxyglutarate (2-HG) production. While IDH mutations are recognized as critical cancer-associated genetic changes, the therapeutic options for IDH-mutated cancers remain limited.

METHODS
In the present study, we investigated the reactive oxygen species (ROS) scavenging pathways in patient-derived IDH1-mutated cells. Further, we investigated the protective role of glutathione de novo synthesis for IDH1-mutated cancer cells. Finally, we evaluated triptolide, a diterpenoid epoxide derived from Tripterygium wilfordii, as an experimental therapeutic for IDH1-mutated cells and xenografts.

RESULTS
We discovered that the neomorphic activity of IDH1 mutant enzyme triggers metabolic depletion and a substantial elevated burden of ROS scavenging in cancer cells. The nuclear factor erythroid 2-related factor 2 (NRF2)-guided antioxidant pathway plays a key role in maintaining redox homeostasis for IDH1-mutated cells. Triptolide serves as a potent inhibitor of NRF2 through enhancing the NRF2 ubiquitination and subsequently proteasomal degradation. Additionally, triptolide compromises the de novo synthesis of glutathione via suppression of NRF2-guided transcription of SLC7A11, which encodes cystine/glutamate transporter (xCT). Reduced availability of glutathione results in overwhelming oxidative damage in DNA and lipid, which translates into severe cytotoxicity and reduced xenograft expansion of IDH1-mutated cells.

CONCLUSION
Overall our findings highlight triptolide as a valuable synthetic lethality approach for IDH1-mutated malignancies by targeting NRF2-guided redox homeostasis.
EXTH-04. BLOCKADE OF NRF2/GLUTATHIONE METABOLISM AS A SYNTHETIC LETHALITY APPROACH FOR IDH1-MUTATED GLIOMA
Authors: Liu Yang , Lu Yanxin , Celiku Orieta , Li Aiguo , Yang Chunzhang 
Published: November 2019

Abstract

BACKGROUND
Mutations in isocitrate dehydrogenase (IDH1/2) are frequent genetic abnormalities in human malignancies. IDH1/2-mutated cancers are a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism and resistance to therapy. Molecular targeting approaches against this disease cluster remain limited.

METHODS
We investigated the redox homeostasis in IDH1 mutant-transduced cells and patient-derived brain tumor initiating cells. The importance of antioxidant genes was confirmed through COX regression analysis on a large cohort of lower grade glioma. We investigated the biologic impact of Nuclear factor erythroid 2-related factor 2 (NRF2) on the glutathione de novo synthesis in IDH1-mutated cells. Finally, we evaluated the value of targeting NRF2/glutathione metabolic pathway as a potential synthetic lethality approach for IDH1-mutated cell in vitro and in vivo.

RESULTS
We discovered that acquisition of cancer-associated IDH1 mutants results in constitutive activation of NRF2-governed cytoprotective pathways through decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1. NRF2 mediated the transcriptional activation of GCLC, GCLM and SLC7A11, which strengthens the glutathione de novo synthesis, and relieves the metabolic burden derived from IDH1 mutant neomorphic activity. Blockade of the NRF2/glutathione metabolic pathway synergizes with the elevated intrinsic reactive oxygen species, which results in overwhelming oxidative damage in IDH1-mutated cells, as well as a substantial reduction in tumor cell proliferation and xenograft expansion.

CONCLUSION
Our findings suggest that blockade of the NRF2/glutathione synthetic pathway is a novel targeting strategy for IDH1-mutated malignancies.
EXTH-12. RADIATION ENHANCES MELANOMA RESPONSE TO IMMUNOTHERAPY AND SYNERGIZES WITH BENZODIAZEPINES TO PROMOTE ANTI-TUMOR ACTIVITY
Authors: Pomeranz Krummel Daniel , Nasti Tahseen , Izar Benjamin , Xu Maxwell , Lowder Lindsey , Press Robert , Kaluzova Milota , Kallay Laura , Rupji Manali , Burnham Andre , Li Guanguan , Ahmed Taukir , Rosen Havi , Connolly Erin , Keskin Havva , Ben Thomas Midhun , Curran Walter , Kudchadkar Ragini , Weinberg Brent , Olson Jeffrey , Schniederjan Matthew , Neil Stewart , Su Jing , Lawson David , Cook James , Jenkins Andrew , Kowalski Jeanne , Khan Mohammad , Sengupta Soma 
Published: November 2019

Abstract
Melanoma brain metastases (MBM) occur in ~50% of advanced melanoma patients. It is unclear if systemic therapies synergize with radiotherapy (RT) and what the impact of RT timing has on efficacy. We find that RT followed by ICI (immune checkpoint inhibitors) (RTàICI) improves MBM patient survival compared to other combination strategies, also shown here in a murine melanoma model. RNA-seq of MBM tumors in the RTàICI group exhibit overrepresentation of genes implicated in NFKB signaling. There is also expression of GABAA receptor subunits across both treatment groups. We show that melanoma cells express functional GABAA receptors and that benzodiazepines impair tumor growth. Combination of sub-lethal RT doses with benzodiazepine results in significant ipsilateral and out of field abscopal anti-tumor activity, which is associated with enhanced tumor infiltration with poly-functional CD8 T-cells. This study provides evidence that RT enhances MBM response to ICI and synergizes with benzodiazepines to promote anti-tumor activity.
EXTH-15. INCREASING THE TRAFFICKING OF DENDRITIC CELLS VIA CXC CHEMOKINE SIGNALING PATHWAY LEADS TO IMPROVED ANTI-TUMOR EFFICACY OF DENDRITIC CELL VACCINES
Authors: Dastmalchi Farhad , Karachi Aida , Yang Changlin , Azari Hassan , Vlasak Alex , Saia Megan , Mitchell Duane , Rahman Maryam 
Published: November 2019

Abstract

Dendritic cell (DC) vaccine efficacy is directly related to the efficiency of DC migration to the lymph node after delivery to the patient. In this research we discovered increasing cell migration by utilizing sarcosine improved anti-tumor efficacy. We hypothesized that sarcosine induced cell migration was due to chemokine or cytokine signaling.

METHODS
To generate DC vaccines, DCs were harvested from bone marrow of wild type C57BL/6 mice and electroporated with OVA-mRNA. Human DCs were isolated from PBMCs. DCs were treated with sarcosine at 20mM. OT-I T cells were isolated from transgenic mice and injected intravenously into B16F10-OVA tumor bearing mice. Following T cell transfer, DC vaccines were injected intradermal. In vitro migration was analyzed via transwell migration assay. In vivo migration was evaluated by flow-cytometry and immunofluorescence microscopy. Gene expression in RNA was investigated in DCs via RT-PCR and Nanostring.

RESULTS
Sarcosine significantly increases human and murine DC migration in vitro. In vivo murine model, sarcosine-loaded DCs had significantly increased migration to both the lymph nodes and spleen after intradermal delivery. B16F10-OVA tumor bearing mice were treated with the sarcosine-loaded DC vaccines resulted in a significant survival advantage over control and naïve DC vaccines. Gene expression in RNA was investigated in DCs. CXCR2,CXCL3 and CXCL1 were found to be upregulated in sarcosine-loaded DCs. Further metabolic analysis demonstrated the upregulation of cyclooxygenase-1 and Pik3cg. In vitro DC migration in presence of CXCR2 neutralizing antibody showed sarcosine induced migration was abrogated by adding the CXCR2 neutralizing antibody in both human and murine DCs. Animals that treated with sarcosine-loaded DC showed significantly better tumor control compares to the animals receiving anti-CXCR2 antibody one hour before DC injection.

CONCLUSION
Sarcosine increases the migration of murine and human DCs via the CXC chemokine pathway. This platform can be utilized to improve existing DC vaccine strategies.
EXTH-22. ENHANCED DRUG DELIVERY AND CIRCULATION WITH THE NEURAPHERESIS™ SYSTEM FOR THE TREATMENT OF LEPTOMENINGEAL METASTASES
Authors: Marius Choiselle , Ripple Katelyn , de Castro George , Chen Yutong , Giamberadino Charles , Verbick Laura , McCabe Aaron , Fecci Peter , Lad Shivanand 
Published: November 2019

Abstract
Leptomeningeal Metastases, a severe late stage form of cancer progression in which malignant cells metastasize to the subarachnoid space (SAS) and leptomeninges, has a mean survival rate of 3–6 months with treatment. Standard of care intrathecal chemotherapy, delivered via an Ommaya reservoir, is limited by poor diffusion within the SAS and acute drug-related neurotoxicity. Neurapheresis™ therapy (NA) is a novel therapy that uses a dual lumen intrathecal catheter and extracorporeal filtration system to filter cerebrospinal fluid (CSF) in a closed-loop. We have previously demonstrated the ability of NA to decrease cancer cell burden in artificial CSF in vitro. Here, NA is shown to enhance chemotherapeutic drug circulation, delivered intraventricularly, throughout the SAS in vitro. NA was tested with a cranial-spinal model of the SAS that included ventricular, cervical and lumbar sampling sites. Drug distribution was tested by comparing the circulation of a 6mg, 3mL ventricular bolus injection of Methotrexate (MTX) in PBS over 48 hours with and without NA (2.0 mL/min flow rate). Ventricular, cervical, and lumbar samples were collected at t=0.5, 4, 8, 12, 24, and 48 hours following drug administration and analyzed by a MTX-specific enzyme-linked immunosorbent assay (ELISA). Compared to controls, NA demonstrated increased, faster distribution of MTX throughout the neuraxis, with an average increase in MTX concentration of 63.7% and 171.5% in the cervical and lumbar sites, respectively, across time points from 4 to 24 hours. The NA system also rapidly decreased the high, potentially neurotoxic concentration of MTX in the ventricles immediately following drug administration and out to 12 hours post-injection. Future in vivo and in vitro testing focuses on pharmacokinetics (PK) in both animals and an advanced 3D-printed human cranial-spinal model to further evaluate the ability of the NA system to enhance MTX distribution throughout the SAS, while simultaneously removing circulating tumor cells.
EXTH-34. IN VITRO TUMOR TREATING FIELDS (TTFIELDS) APPLIED PRIOR TO RADIATION ENHANCES THE RESPONSE TO RADIATION IN PATIENT-DERIVED GLIOBLASTOMA CELL LINES
Authors: Michelhaugh Sharon , Mittal Sandeep 
Published: November 2019

Abstract
Tumor treating fields are FDA-approved for treatment of newly-diagnosed and recurrent glioblastoma. Adding TTFields therapy to standard-of-care extended progression-free survival and overall survival in newly-diagnosed glioblastoma patients. In this study, cell lines generated from newly-diagnosed glioblastoma patients were treated in vitro with TTFields prior to irradiation to determine if the response to radiation would be altered. This study was approved by the WSU Institutional Review Board and written consent obtained from the patients. Single-cell suspensions generated from tumor tissues obtained from newly-diagnosed patients were cultured in DMEM/F12 media with 10% fetal bovine serum and gentamicin. Prior to TTFields initiation, cells were plated on plastic coverslips (5×104cells/coverslip) and incubated overnight. Then, TTFields were applied at 200 kHz with a field intensity of ~1.6 V/cm for 3 days. After TTFields application, cells were irradiated with 2, 4, or 6 Gy, or were untreated. After radiation delivery, cells were harvested and replated in a clonogenic assay. From each group, 3 coverslips were each replated in triplicate. After 3 days (3 doubling times), cells were stained with crystal violet and plates were scanned to determine cell counts. Treatment groups were compared to their control group with t-test. For both patient-derived GBM cell lines tested, TTFields prior to radiation decreased the number of crystal violet-stained cells in the clonogenic assay plates. In cell line 15–037, pretreatment with TTFields decreased cell counts by 16, 29, and 56% after 2, 4, or 6 Gy radiation, respectively, compared to the control cells with no TTFields pretreatment (p< 0.05). The response in 14-015S cells was less radiation dose-dependent, with the decrease in cell counts ranging from 33–47% control across the radiation doses (p< 0.05). These data suggest that the use of TTFields therapy prior to radiotherapy may enhance the response to radiotherapy in GBM patients.