bluuebunny/crossref_metadata_2025_split huggingface dataset:
DRES-01. EFFICACY OF EGFR PLUS TNF INHIBITION IN A PRECLINICAL MODEL OF GLIOBLASTOMA
Authors: Guo Gao , Gong Ke , Sarkaria Jann , Habib Amyn 
Published: November 2019

Abstract
EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition is not effective in treating this tumor. EGFR inhibition may fail because EGFR is not a driver of the malignant phenotype in GBM, or because adaptive compensatory mechanisms are triggered by EGFR inhibition that prevent cell death from a loss of EGFR signaling. We have recently identified a TNFα-JNK-Axl-ERK signaling axis that mediates primary resistance to EGFR inhibition in GBM. Temozolomide (TMZ) is the most effective chemotherapy in GBM, although it has only a modest effect on overall survival. The efficacy of TMZ depends on the absence of the DNA repair protein O6-alkylguanine DNA alkyltransferase (MGMT) which reverses the DNA damage induced by TMZ. The MGMT promoter is hypermethylated in about 45% of GBMs, resulting in lack of MGMT expression. TMZ is less effective in MGMT unmethylated GBMs. Moreover, even initially responsive tumors develop a secondary resistance to TMZ. No treatment is effective in recurrent TMZ-resistant GBM. In this study, we compare the efficacy of temozolomide versus EGFR plus TNF inhibition in an orthotopic model of GBM. We find that efficacy of the two treatments is similar in MGMT-methylated GBMs. However, in MGMT-unmethylated GBMs, a combination of EGFR plus TNF inhibition is more effective. We demonstrate that the two treatment approaches target distinct and non-overlapping pathways. Furthermore, and importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. Since the EGFR is expressed in the majority of GBMs, EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a broadly applicable and viable therapeutic approach in primary GBMs with MGMT unmethylation and in recurrent GBMs.
DRES-05. PREDICTORS OF SENSITIVITY TO COMBINED TEMOZOLOMIDE AND PARP INHIBITOR IN GLIOMA
Authors: Nagashima Hiroaki , Higuchi Fumi , Lee Christine , Rafferty Seamus , Miller Julie , Wakimoto Hiroaki , Cahill Daniel 
Published: November 2019

Abstract
Agents targeting the PARP enzyme family are under active development for the treatment of gliomas. PARP inhibitors (PARPi) can enhance the effect of temozolomide (TMZ) in IDH wild-type glioblastomas, and in addition recent studies have shown that PARP inhibitors can be selectively lethal in IDH1 mutant cancers. Here, we sought to identify predictors of sensitivity and resistance to PARP inhibition in gliomas. We treated 4 IDH1 mutant and 8 IDH wild-type glioma lines, as well as IDH1 mutant fibrosarcoma line HT1080, with TMZ, the PARPi olaparib, or the combination, and assessed cellular growth and survival. In dose response assessments, 7 out of 13 lines were sensitive to olaparib monotherapy (3 IDH1 mutant and 4 IDH wild-type). Combination with TMZ resulted in 6 of 13 lines responding to dual therapy, with an additive effect seen in 5 PARPi monotherapy sensitive gliomas. Notably, 5 of the 6 lines responsive to the combination harbored CDKN2A deletion, compared to none of the non-responsive lines (p=.0021). Treatment with CDK inhibitor palbociclib partially reversed sensitivity to TMZ+PARPi in HT1080, supporting a mechanistic basis for this association. PARPi sensitivity in glioma lines can be augmented by the addition of TMZ. CDKN2A deletion may serve as a potential biomarker identifying tumors sensitive to this combination therapy.
DRES-07. TMZ-LEV- IFN COCKTAIL REGIMEN SIGNIFICANTLY INHIBITED THE GROWTH OF GLIOMA IN VIVO
Authors: Ni Xiang-rong , Wang Jing , Chen Fu-rong , Cai Hai-ping , Yu Yan-jiao , Yang Qun-ying , Guo Chengcheng , Chen Zhong-ping , Qu Yue 
Published: November 2019

Abstract

OBJECTIVE
Temozolomide (TMZ), is the first line chemotherapeutic drug for glioma. Previous studies have suggested that interferon (IFN) and levetiracetam (LEV) could respectively reverse the resistance of TMZ by down-regulating MGMT expression. This study, we aim to investigate the therapeutic effect of a cocktail chemotherapy regimen combining TMZ, LEV, IFN in vivo.

METHODS
Glioma cell lines U251 and SKMG-4 (MGMT protein expression positive), U138 and GSC-1(MGMT protein expression negative) were used for producing xenograft tumors. The xenograft tumors were established by subcutaneously injecting 1×106 glioma cells into female BALB/C nude mice and divided into 5 treatment groups: Control, TMZ, TMZ+IFN, TMZ+LEV, TMZ+LEV+IFN. The treatment with TMZ (50 mg/kg, i.p.), IFN (2×105 IU, s.c.), LEV (150 mg/kg, i.p.) once a day for five consecutive days and xenograft tumors were measured every two days.

RESULTS
We identified that U138, U251, SKMG-4 tumor growth among TMZ, TMZ+IFN, TMZ+LEV, TMZ+LEV+IFN were all significantly inhibited (P< 0.05), compared with the control. As for U251 and SKMG-4, tumor killing effect of all 4 treatment groups were not different (P > 0.05). In the treatment of mice bearing U138 glioma, the tumor weight of TMZ+LEV+IFN (0.2688±0.1169 g) group was the lowest and significantly lower than that of TMZ+LEV (0.6574±0.08174g, P=0.0261), TMZ+IFN(0.6108±0.07317 g, P=0.0381), and TMZ (0.9054±0.07154 g, P=0.0017) group. Glioma stem cells GSC-1 was highly resistant to TMZ, tumor volume of TMZ group was not different from control group (P >0.05). While compared with TMZ (1.993±0.1274 g) group, in TMZ+IFN (1.506±0.1223g, P=0.0203), TMZ+LEV (1.178±0.1807g, P=0.0042), and TMZ+LEV+IFN (1.049±0.2171 g, P=0.0038) groups, GSC-1 tumor growth were significantly inhibited(P< 0.05).

CONCLUSION
Our data demonstrate that both IFN and LEV can sensitize TMZ effect on glioma in vivo, even for MGMT(+) tumors, and TMZ-LEV-IFN cocktail regimen seems the best. Key words: glioma, TMZ, LEV, IFN
DRES-08. CLINICAL SIGNIFICANCE OF HYPERMUTATION IN GLIOMAS
Authors: Touat Mehdi , Li Yvonne , Boynton Adam , Spurr Liam , Iorgulescu Bryan , Birzu Christina , Pal Sangita , Ferrer-Luna Ruben , Geduldig Jack , Bellamy Charlotte , Younan Nadia , Baldini Capucine , Verreault Maite , Guillerm Erell , Ammari Samy , Beuvon Frederic , Mokhtari Karima , Alentorn Agusti , Dehais Caroline , Houiller Caroline , Laigle-Donadey Florence , Lee Eudocia , Nayak Lakshmi , Carpentier Alexandre , Cornu Philippe , mathon Bertrand , Bi Wenya , Chiocca Ennio , Alexandrescu Sanda , Chi Susan , Haas-Kogan Daphne , Alexander Brian , Huang Raymond , Ligon Azra , Coulet Florence , Delattre Jean-Yves , Hoang-Xuan Khe , Meredith David , Santagata Sandro , Duval Alex , Sanson Marc , Cherniack Andrew , Wen Patrick , Reardon David , Marabelle Aurelien , Idbaih Ahmed , Beroukhim Rameen , Bandopadhayay Pratiti , Bielle Franck , Ligon Keith 
Published: November 2019

Abstract

BACKGROUND
Hypermutation is an emerging biomarker for predicting response to immunotherapy in cancer patients, however its clinical value in gliomas is not established. We sought to assess the determinants of hypermutation in gliomas, and its value for predicting response to standard of care and immune checkpoint blockade (ICB).

METHODS
We performed comprehensive genomic characterization of 2,420 clinically annotated gliomas. We assessed the clinical and molecular characteristics associated with hypermutation and relationships between hypermutation and response to cancer treatments.

RESULTS
Hypermutation occurred predominantly as an adaptive resistance mechanism to temozolomide in gliomas and was most prevalent in recurrent gliomas with MGMTpromoter methylation (33.8%), IDH1/2mutation (41.0%) or 1p/19q co-deletion (59.5%). Hypermutation was almost always associated with molecular defects in DNA mismatch repair (MMR), and was associated with shorter survival after its appearance based on multivariate analysis (hazard ratio 1.91; 95% CI 1.24–2.94; P=0.004). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference.

CONCLUSIONS
Using the largest set of hypermutated gliomas described to date, this study establishes that mutational burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas
DRES-09. REGULATORY EFFECTS OF THE CILIARY GTPASE ARL13B ON PURINE METABOLISM IN GBM
Authors: Saathoff Miranda , Shireman Jack , Ali Eunus , Park Cheol , Ben-Sahra Issam , Ahmed Atique 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common form of adult primary brain cancer. Despite an aggressive treatment regimen – surgical resection, irradiation, and temozolomide (TMZ) chemotherapy – patients’ prognosis is still grim. TMZ acts by methylating purines, specifically at the O6 and N7 positions of guanine, to induce cytotoxic DNA double-strand breaks. We thus wanted to explore how purine metabolism may contribute to TMZ-resistance. In mammalian cells, purine nucleotides can be recycled by the salvage pathway or generated via de novo synthesis. The salvage pathway is energetically inexpensive relative to de novo thus, highly proliferative GBM cells preferentially utilize the salvage pathway. We have shown that salvage synthesis is reduced in response to TMZ (p-value=0.0021), hinting that the cells may utilize de novo to evade therapy induced alkylation of purines. Using immunoprecipitation-mass spectroscopy analysis, we found a novel interaction between the ciliary GTPase ARL13B and IMPDH2, the rate-limiting enzyme in de novo synthesis. We have shown that this interaction, occurring at the C-terminal domain of ARL13B, plays a significant role in the regulation of purine biosynthesis as abolishing it through ARL13B knockdown reduced flux through de novo (p-value< 0.0001) synthesis as measured by the specific activity of IMPDH2. Further, the lentiviral-mediated rescue of ARL13B brings IMPDH2 activity back to basal levels (p< 0.0001). Given its canonical function as a GTPase, we hypothesize that ARL13B acts as a novel regulator of de novo synthesis by sequestering GDP, allowing IMPDH2 to sense and respond to the cytosolic levels of guanine nucleotides. Without ARL13B the de novo pathway is halted, forcing the cells to rely on salvage to replenish nucleotide pools. Reliance on this pathway in the presence of TMZ causes cells to incorporate damaged nucleotides as a result of the drug’s alkylating action leading to the increased therapeutic efficacy of TMZ.
EPID-20. TRENDS IN GLIOBLASTOMA OUTCOMES OVER TIME, GEOGRAPHIC LOCATION AND TYPE OF INTERVENTION
Authors: Marenco-Hillembrand Lina , Wijesekera Olindi , Suarez-Meade Paola , Mampre David , Jackson Christina , Ortiz Kyle , Lesser Elizabeth , Hawayek Maria , Vivas-Buitrago Tito , Quinones-Hinojosa Alfredo , Chaichana Kaisorn 
Published: November 2019

Abstract

INTRODUCTION
The management of glioblastoma (GBM) has changed over time and varies based on geographic location. Despite its universally fatal prognoses, it is unclear if GBM outcomes have changed over time, if they vary by geographic location, and differ based on type of intervention. As a result, we conducted a systematic review of the literature to identify the average survival differences of GBM patients across time, between different continents, and among various treatments.

METHODS
The systematic review of PubMed included glioblastoma, GBM, and survival. Inclusion criteria consisted of full-text titles with human subjects, GBM/Grade IV astrocytoma, age >18 years old, and with available survival data.

RESULTS
9,162 articles were screened for survival data, 1728 were eligible, 405 complied with the inclusion criteria. Of the 405 studies, 179 (44.2%) were conducted in Europe, 151 (37.3%) in the Americas, 61 (15.1%) in Asia, 9 (2.2%) in Oceania, and 1 (0.2%) in Africa. Leading countries are the United States (33.1%), Germany (12.3%), and Italy (11.1%). Asia had the highest median survival (14.9 months), followed by Europe (13.2 months), and the United States (12.9 months) (P=0.003). Regarding treatment, survival was significantly higher after the introduction of the Stupp protocol (P< 0.001). Post-Stupp Studies had longer survival estimates (15.3 months, range: 3.8–29.6) than Pre-Stupp Studies (12.2 months, range: 2.3–28). In the included clinical trials (182), radiation (43.4%), temozolomide (25.3%), or other chemotherapies (24.2%) were the most common interventions. Clinical trial median survival estimates were significantly higher than all other studies (P< 0.017). Bevacizumab (19.3 months) and Temozolomide (15.9 months) had the longest recorded median survival estimates; while radiation (14 months), other chemotherapies, and carmustine (13.2 months) had the shortest (P=0.009).

CONCLUSION
This epidemiological study describes the current global state of GBM. Important differences regarding survival and treatment of patients with GBM were found.
EPID-25. HOW MANY PATIENTS IN A REAL WORLD GLIOBLASTOMA POPULATION MEET ELIGIBILITY CRITERIA IN CLINICAL TRIALS?
Authors: Skaga Erlend , Andrea Skretteberg Marthe , Børge Johannesen Tom , Brandal Petter , Osland Vik-Mo Einar , Helseth Eirik , Arne Langmoen Iver 
Published: November 2019

Abstract
In population series of glioblastoma (GBM) the median survival is < 1 year. For patients eligible for combined oncological treatment (surgery, radiotherapy (RT) and temozolomide (TMZ)) the median survival raises to 15 months. These patients are younger, have higher performance status and less comorbidity compared to the total GBM population. The extent of selection bias of GBM patients enrolled in clinical trials is, however, unclear. Using the Cancer Registry of Norway and the Brain Tumor Database of Oslo University Hospital, all patients diagnosed with GBM between 2012 and 2016 within a defined geographical area that received all oncological treatment at Oslo University Hospital were identified. Their hospital charts were retrospectively investigated and all patients were evaluated for the possibility to be included in clinical trials according to standard criteria from recent published phase 3 studies. We defined three time points for possible enrollment in trials: before-, halfway through-, and after concomitant RT/TMZ. We identified 424 patients of whom 26 (6.1%) did not undergo surgery. The median survival in the population was 11.7 months. Of the patients that underwent surgery (biopsy or resection), the median survival progressively increased with additional oncological treatment; no RT/TMZ 1.1 months, only RT 7.9 months, RT/TMZ 13.9 months. A potential study patient group≥18 years undergoing surgery for a supratentorial GBM with ECOG ≤2, with normal bone marrow, hepatic and renal function and no severe comorbidity or oncological disease constituted 54% of the population before start of RT/TMZ. Patients adhering to RT/TMZ-treatment and without tumor progression represented 46% and 43% of the population halfway through- and after concomitant RT/TMZ, respectively. The survival of patients that could be included in clinical trials was significantly higher (p< 0.001) than patients not fulfilling standard criteria. Our data suggest a significant patient selection in clinical trials from a real-world GBM population.
EXTH-05. THERAPEUTIC IMPLICATIONS OF TTFIELDS INDUCED DNA DAMAGE AND REPLICATION STRESS IN NOVEL COMBINATIONS FOR CANCER TREATMENT
Authors: Kumar Karanam Narasimha , Ding Lianghao , Aroumougame Asaithamby , Story Michael 
Published: November 2019

Abstract
TTFields are low-intensity, intermediate frequency, alternating electric fields which are applied to tumor regions using non-invasive arrays. TTFields is approved for the treatment of glioblastoma and mesothelioma with clinical trials ongoing in other cancer types. The mechanism of action for TTFields includes interference with mitosis, reduced DNA double strand break (DSB) repair capacity and the frank induction of DNA DSBs. The mechanism by which TTFields induces DNA DSBs appears to be through the enhancement of DNA replication stress with continued TTFields exposure. The induction of DNA DSBs appears to be as a result of significantly reduced expression of the DNA replication complex genes MCM6 and MCM10 as well as the Fanconi’s Anemia (FA) pathway genes. TTFields treatment increases the number of RPA foci, decreases nascent DNA length and increases R-loop formation which are markers of DNA replication stress. These results suggest that TTFields-induced replication stress is the underlying mechanism and cellular endogenous source of DNA DSB generation via replication fork collapse. The current study suggests that TTFields exposure causes a conditional vulnerability environment that renders cells more susceptible to chemotherapeutic agents that induce DNA damage and/or cause replication stress. Supporting this is the synergistic cell killing seen with TTFields exposure concomitant with cisplatin, TTFields plus concomitant PARP inhibition with or without subsequent radiation, or radiation given at the completion of a TTFields exposure. Finally, TTFields-induced mitotic aberrations and DNA damage/replication stress events, although intimately linked to one another as one can expose the other, are likely initiated independently of one another as suggested by the gene expression analysis of 47 key mitosis regulator genes. These results establish that enhanced replication stress and reduced DNA repair capacity are also major mechanisms of TTFields effects, effects for which there are therapeutic implications.
EXTH-29. GALECTIN-3 AS A POTENTIAL THERAPEUTIC TARGET IN RECURRENT ATYPICAL AND MALIGNANT MENINGIOMA
Authors: Das Arabinda , Martinez Santos Jaime , 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
Atypical and malignant meningiomas are rare tumors that unlike WHO I meningiomas are characteristically more aggressive in nature and are associated with higher recurrence risks of recurrence. In fact despite aggressive treatment of malignant meningiomas, the average 5-year survival rates are in the range of 30% to 60%. Still the standard of care for atypical and malignant meningiomas (AM and MM) has yet to be established. Our laboratory data demonstrated that galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in AM and MM as compared to normal tissue. However, the biological functions of Gal-3 in meningioma cells are not fully understood. To address this, we used either small interfering RNA (siRNA) to knock down Gal-3 expression or Gal-3 inhibitor, TD139 to suppress Gal-3 expression in in vitro cell culture model. Silencing or inhibiting of Gal-3 expression significantly decreased the protein levels of urokinase-type plasminogen activator receptor (uPAR) as well as uPAR’s downstream signaling transduction pathway, including phosphorylation of AKT. In both cases, we found that silencing of Gal-3 or inhibiting Gal-3 expression decreased the proliferative activity, and migratory potential of AM and MM cells. Furthermore, we demonstrated that TD139 inhibits MM growth in an in vivo xenograft MM model. Taken together, our results suggest that Gal-3 modulates uPAR expression and that Gal-3 may be a potential therapeutic target for the treatment of atypical and malignant meningiomas.
EXTH-42. QUANTITATIVE BIODISTRIBUTION OF ADOPTIVELY TRANSFERRED T CELLS IN BRAIN TUMOR-BEARING MICE
Authors: Hoang-Minh Lan , Pohl-Guimarães Fernanda , Rivera-Rodriguez Angelie , Currlin Seth , Otto Kevin , Rinaldi Carlos , Mitchell Duane 
Published: November 2019

Abstract

SIGNIFICANCE
Adoptive T cell therapy (ACT) has emerged as the most effective treatment strategy against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including those with lesions within the central nervous system. Importantly, immunologic surrogate endpoints that correlate with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth.

OBJECTIVE
We investigated the biodistribution of exogenously administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels.

METHODS
T cells were isolated from the spleens of DsRed transgenic C57BL/6 mice and injected intravenously, after in vitro expansion and activation, in murine KR158B glioma-bearing mice. To determine transferred T cell spatial distribution, brains, lymph nodes, hearts, lungs, spleens, livers, kidneys and stomachs were isolated for active clearing, immunostaining, and 3D imaging using light sheet microscopy, or processed for fluorescent immunohistochemistry and confocal imaging. Transferred T cell quantification in various organs was performed using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle labeling. T cell distribution was also assessed in vivo using IVIS and MPI.

RESULTS
The spleen, liver, and lungs accounted for more than 90% of transferred T cells in the body. The proportion of DsRed T cells in tumor-bearing brains was found to be very low, hovering below 1% (and representing ~15% of total tumor-infiltrating lymphocytes). Transferred T cells mostly concentrated at the periphery of the tumor mass and in proximity to blood vessels.

CONCLUSIONS
The success of ACT immunotherapy for brain tumors likely requires optimization of delivery route, dosing regimen, and modification of tumor-specific lymphocyte trafficking and effector functions in order to achieve maximal penetration and persistence at sites of invasive tumor growth.