bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-39. IDENTIFICATION OF AN AUTOPHAGY-RELATED GENE SIGNATURE AND ESTABLISHMENT OF A NOMOGRAM PREDICTING SURVIVAL OF LOWER-GRADE GLIOMA
Authors: Wen Lei , Wang hui , Lai Mingyao , Shan Changguo , Cai Linbo 
Published: November 2021

Abstract

OBJECTIVE
The aim of our study was to establish an autophagy-related signature for individualized risk stratification and prognosis prediction in LGG.

METHODS
RNA-sequencing data from The Cancer Genome Atlas (TCGA), Genome Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) were used. The 232 ARGs were obtained from the Human Autophagy Database (HADb). Univariate and Lasso regression were employed to identify differentially expressed autophagy-related genes (ARGs) and establish a prognostic signature whose performance was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell’s concordance index (C-index) and calibration curve.

RESULTS
Fifty-three autophagy-related DEGs were identified. Four autophagy-related genes (DIRAS3, GNAI3, PTK6, and BIRC5) were selected to establish the prognostic signature and verified in the CGGA validation cohorts. Univariate and multivariate Cox regression indicated that the autophagy signature (HR, 95%CI, P) was an independent predictor of prognosis in LGG. Finally, a prognostic nomogram incorporating age, grade, targeted therapy, new event, tumor status and autophagy signature achieved excellent predicative performance (AUC 0.907, 0.865 and 0.858 for 1-year, 3-year and 5-year survival, respectively) verified by Time-dependent ROC, C-index (0.844, 95% CI, 0.799 to 0.889; P = 1.01e-12) and calibration plots.

CONCLUSION
The present study constructed a robust four autophagy-related gene signature. A prognostic nomogram in risk stratification and prediction of overall survival in LGG was established. The findings may be beneficial to individualized survival prediction and medical decision-making for LGG.
CTNI-50. REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: A LARGE REAL-LIFE EXPERIENCE
Authors: Caccese Mario , Cerretti Giulia , Padovan Marta , Zagonel Vittorina , Lombardi Giuseppe 
Published: November 2021

Abstract

INTRODUCTION
Regorafenib (REG), an oral multikinase inhibitor, showed benefit in recurrent GBM (recGBM) patients in the REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recGBM patients treated at Veneto Institute of Oncology as off-label use.

MATERIAL AND METHODS
Patients receiving REG were entered prospectively on a clinical database. Data were retrospectively analyzed. The primary endpoints were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression by RANO criteria after Stupp protocol, ECOG PS ≤ 2. Patients received REG 160 mg per day for the first 3 weeks in a 4-week cycle. Kaplan-Meier method was used to estimate the survival, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events.

RESULTS
54 patients were enrolled: median age was 56, ECOG PS 0-1 in 91%, MGMTmet in 53%, second surgery at the time of relapse in 30%. Median follow-up was 11.1ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. MedianOS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; medianPFS was 2.3 ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. Disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT(2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%.

CONCLUSIONS
We reported a “real-world” experience of REG in recGBM patients. Results are close to those reported in REGOMA trial; we showed a longer OS. Toxicity was manageable. Encouraging clinical benefits of REG in recGBM population were confirmed.
CTNI-57. MATRix REGIMEN FOR NEWLY DIAGNOSED PRIMARY DIFFUSE B-CELL LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM
Authors: Green Richard , Guzman-Marin Ruben , Lam Keng , Thornton Colleen 
Published: November 2021

Abstract
We report our experience treating 20 patients with newly diagnosed primary diffuse B-cell lymphoma of the central nervous system with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 65 y; 8 patients were men and 12 were women. Eighteen had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 14 patients completed initial chemotherapy. Twelve of these 14 went on to transplantation; one patient had early disease progression, and in one no stem cells could be collected. All 4 patients over 70 y died early after 1-2 cycles; the median age of these was 80 y, and the causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One patient who completed the entire regimen including transplantation died of fungal pneumonia; the other 13 experienced no serious acute toxicity. One patient had late disease progression; one developed symptomatic leukoencephalopathy. Thirteen of the 20 patients remain alive. Median OS for the cohort is 698 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 70 y suggests that the regimen may be too toxic for elderly individuals.
DDRE-02. PATIENTS WITH LEPTOMENINGEAL METASTASES FROM NSCLC BENEFITED FROM INTRATHECAL PEMETREXED AFTER FAILURE TO TYROSINE KINASE INHIBITORS: TWO CASE REPORTS
Authors: Ye Minting , Wen Lei , Zhou Jiangfen , Cai Linbo 
Published: November 2021

Abstract

BACKGROUND
The incidence of leptomeningeal metastasis (LM) is 3%-5% in NSCLC patients; the incidence is even higher in patients with EGFR mutations or ALK gene rearrangement. The prognosis of NSCLC patients with LM is poor with an overall survival (OS) of 3 months with contemporary treatment.

METHODS
Here we report two cases of patients with leptomeningeal metastases from NSCLC who benefited from intrathecal pemetrexed after failure to tyrosine kinase inhibitors(TKIs).

RESULTS
A 53-year-old woman, diagnosed with adenocarcinoma of the lung with ALK rearrangement, suffered form right limb weakness, dysphagia after multi-line targeted therapy and radiotherapy for brain metastases. Evaluation revealed a rapidly progressing right brainstem mass and diffuse leptomeningeal enhanced. And cytological examination of CSF showed neoplastic cells, which definitely diagnosed as LM. After first intrathecal injection of 30mg pemetrexed every three weeks, the patient's symptoms improved. There were no significant treatment side effects and the quality of life was not affected during the five subsequent treatments. Another patient was a 32-year-old man, diagnosed with adenocarcinoma of the lung with EGFR E24-RAD51E4 fusion mutation with KPS score 30. LM was confirmed after multiline therapy. He suffered form blurred vision and drooping eyelid. Similarly, after first intrathecal injection of 20mg pemetrexed every week, the patient's symptoms improved and KPS score increased gradually. And level II leukopenia was detected during subsequent treatments. Combined with intrathecal pemetrexed progression-free survival (PFS) were 3 months in two NSCLC patients with LM harboring ALK/EGFR mutation . And the quality of life of patients were effectively increased.

CONCLUSION
Combination therapy third generation EGFR/ALK agents with intrathecal chemotherapy might be benefited in overall survival.
DDRE-06. TARGETING THE SPHINGOLIPID BALANCE VIA ACID CERAMIDASE INHIBITION TO DECREASE GROWTH OF TMZ-RESISTANT GLIOBLASTOMA AND BLOCK MIGRATION
Authors: Hawkins Cyntanna , Jones Amber , Ziebro Julia , Gordon Emily , Libby Catherine , Williford Sarah , Allegood Jeremy , Cooper Sara , Ramanadham Sasanka , Doan Ninh , Hjelmeland Anita 
Published: November 2021

Abstract
Dysregulated sphingolipid metabolism is associated with many cancers; allowing cells to evade apoptosis through increases in sphingosine-1-phosphate (S1P) and decreases in ceramides. Ceramides can be hydrolyzed by ceramidases to sphingosine, which can then be phosphorylated by sphingosine kinases to S1P. S1P allows cells to evade apoptosis and increase migration, while shifts toward ceramides favor cell death. Glioblastoma (GBM) exhibits shifts in the sphingolipid balance towards S1P, contributing to chemoresistance and migration. Understanding of sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target the dysregulation. Acid ceramidase (ASAH1), a key enzyme in the production of S1P, is highly expressed in GBM and is associated with worse survival of GBM patients, as per The Cancer Genome Atlas data. To address the altered sphingolipid metabolism and therapeutic resistance in GBM, we explored the efficacy of pharmacologic and genetic inhibition of ASAH1 in both parental and temozolomide (TMZ)-resistant patient-derived xenografts. Cells were infected with ASAH1 shRNA or treated with ASAH1 inhibitors and assessed for cell growth and migration. Our work suggests that pharmacologic inhibition of ASAH1 induces cell death and that this effect is maintained in TMZ-resistant cells. Furthermore, we find a novel role for carmofur, an ASAH1 inhibitor, in the inhibition of GBM migration. Together, these data suggest the potential utility of normalizing the sphingolipid balance in the context of GBM TMZ resistance.
DDRE-15. Sema3C SIGNALING CONFERS RESISTANCE TO Wnt INHIBITION IN GLIOBLASTOMA
Authors: Hao Jing , Han Xiangzi , Huang Haidong , yu xingjiang , Bao Shideng , Prayson Richard , Yu Jennifer 
Published: November 2021

Abstract

BACKGROUND
Wnt signaling is widely dysregulated in cancer. The therapeutic potential of Wnt inhibitors appears promising in preclinical studies. However, they have uniformly failed clinical trials. How cancer cells develop Wnt inhibitor resistance is poorly understood. Current Wnt inhibitors are designed targeting either ligand or receptor. We hypothesized cancer cells will bypass ligand-receptor interaction through an unknown mechanism. We focused on the neurodevelopmental signaling program of Semaphorin 3C (Sema3C) that is upregulated in 85% of GBM and regulates glioma stem-cell-driven tumor progression.

RESULTS
Porcupine inhibitor LGK974 reduced TCF1 expression in the GBM tumor mouse models, suggesting successful target engagement in vivo. However, it failed to prolong the overall survival. Sema3C expression strongly correlated with TCF1 expression in human GBM samples by immunohistochemical analysis. Genetic inhibition of Sema3C and TCF1 together prolonged animal survival more than either alone, indicating better control of Wnt pathway signaling with dual pathway blockade. Immunofluorescence and cell fractionation studies revealed that Sema3C signaling drove β-catenin nuclear accumulation. Sema3C regulates transactivation of Wnt target genes including TCF1, c-Myc and c-Met. Sema3C pathway activates Rac1. It is reported that Rac1 activates β-catenin and promotes β-catenin nuclear accumulation. In GSCs, constitutively active Rac1 restored β-catenin nuclear localization and rescued TCF1 and c-Myc down-regulation in the setting of Sema3C silencing. Sema3C can drive canonical Wnt signaling even when Wnt ligand secretion is blocked. Together, the data support that GSCs can escape Wnt inhibition through Sema3C and Rac1.

CONCLUSIONS
Sema3C signaling drives canonical Wnt signaling, providing an escape mechanism for cancer cells despite Wnt ligand-receptor interruption. Sema3C-β-catenin signaling promotes GSC self-renewal and tumor progression. Upstream Wnt pathway inhibition alone is insufficient to control tumors. Our data provide a therapeutic strategy of dual blockade of Wnt and Sema3C pathways to provide clinically significant tumor control.
DDRE-16. DRUG REPURPOSING SCREEN REVEALS GLIOBLASTOMA CELL LINE SUSCEPTIBILITY TO STATINS
Authors: Harwood Dylan , Michaelsen Signe , Mundt Filip , Kristensen Bjarne 
Published: November 2021

Abstract

BACKGROUND
The standard therapy for glioblastoma patients is tumor resection followed by radiotherapy and temozolomide chemotherapy. Although glioblastoma has been extensively molecularly profiled along with other cancers, this knowledge has not yet been translated into improved survival outcomes. We used a bioinformatics approach to identify potential novel therapeutic strategies for glioblastoma. OBJECTIVES: Comprehensive online datasets which have assessed up to 1376 cancer cell lines in multiple ways were interrogated to identify potential drug candidates for glioblastoma.

METHODS
Datasets included were from the cancer cell line encyclopedia (mRNA expression), the Achilles project (cell viability following Crispr-Cas9 knockout) and PRISM (drug treatment). A t-test comparing cell viability of glioblastoma cell lines versus other cancers was used to identify potential drug candidates, followed by the use of multiple statistical tools to investigate potential mechanism of action and status of biomarkers.

RESULTS
Fluvastatin and pitavastatin produced the most significant effects in glioblastoma cell lines. The anti-cancer properties of statins have previously been attributed to the inhibition of HMG-Coa reductase. Here, we found their effects correlated with erastin, an enhancer of ferroptosis and with gene knockout of UBIAD1, which participates in non-mitochondrial ubiquinone synthesis. These effects were both found in glioblastoma cells and other cancers with a mesenchymal-like phenotype.

CONCLUSION
Statins appeared to be especially effective against glioblastoma lines and the effect could be linked to ferroptosis and inhibition of UBIAD1. In vitro validation of this finding is ongoing.
DDRE-17. TARGETING GLIOBLASTOMA’S GALACTOSE SCAVENGING PATHWAY
Authors: Sharpe Martyn , Baskin Alexandra , Baskin Brianna , Baskin David , Raghavan Sudhir 
Published: November 2021

Abstract

BACKGROUND
We have recently shown that GBM use D-galactose (Gal) as a substrate, in vitro and in vivo. Gal is imported via Glut3 and/or Glut14 and metabolized through the Leloir pathway. We investigated 4-deoxy-4-fluorogalactose (4DFG) as the lead compound in a family of galactose-based antimetabolites. 4DFG is a potent chemotherapeutic in monotherapy and can bolster existing therapies.

METHODS
We examined the alteration of glioma metabolism in vitro and in vivo induced by 4DFG. 1H/13C-NMR and optical probes were used to interrogate the effects of 4DFG on glycolysis and mitochondrial respiration in primary glioma cell cultures. Labeled lectins were used to assay for the disruption of glycan synthesis induced by 4DFG. An intracranial model of primary GBM was used to assess efficacy and toxicity in vivo.

RESULTS
NMR reveals that at physiological concentrations of glucose, low concentrations of 4DFG (5 μM) is able to inhibit glycolytic and mitochondrial flux by approximately 12%, p&lt; 0.05. Analysis using lectins shows a collapse in general glycan synthesis, but most especially in the incorporation of both Gal and GalNAc sugars. In nude mice with intracranial primary GBM, six treatments of 4DFG increased survival from 23 to 50 days, p&lt; 0.002.

DISCUSSION
The ability of GBM to scavenge galactose allows us to target the Glut3/14 import and Leloir metabolic pathway using galactose-based anti-metabolites. Our first-generation compound is highly effective as a monotherapy, inhibiting glucose metabolism and glycan synthesis.
DDRE-26. INHIBITION OF PRMT5 SENSITIZES GLIOBLASTOMA MODELS TO TRAMETINIB TREATMENT
Authors: Banasavadi Yesh , Namagiri Sriya , Otani yoshihiro , Thammegowda Shilpa , Sur Hannah , Rivas Sarah , Bryant Jean-Paul , Chowdhury Ashis , Lewis Cole , Shimizu Toshihiko , Walbridge Stuart , Lee Tae Jin , Maric Dragan , Yoo Ji Young , Heiss John , Kaur Balveen 
Published: November 2021

Abstract
With limited effective therapeutic strategies, the prognosis for glioblastoma (GBM) is very poor. Our previous study shows that the expression of Protein Arginine Methyltransferase 5 (PRMT5) is upregulated in GBM; its inhibition promotes apoptosis and senescence in differentiated and stem-like tumor cells, respectively. MEK inhibitors, including trametinib, are currently under investigation for GBM therapy. In this study, we tested whether inhibition of PRMT5 can enhance the anti-GBM efficacy of trametinib. Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, ELISA, and western blot analysis were conducted. In vivo, PRMT5-intact and -depleted GBMNS were intracranially implanted in NSG mice and treated with trametinib by daily oral gavage, and tumor progression and mice survival rate were analyzed by MRI and Kaplan-Meier survival curve, respectively. Depletion of PRMT5 increased the cytotoxic effect of trametinib in GBMNS. Trametinib treatment increased the activity of ERBB3 and AKT; With PRMT5 knockdown, the activity of both AKT and ERBB3 decreased significantly. But, inhibition of ERBB3 alone failed to block the trametinib-induced AKT activity suggesting that even though PRMT5 regulates the activity of both ERBB3 and AKT, the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib treated GBMNS is because of AKT inhibition alone. In vivo, PRMT5-depletion extended the survival of the tumor-bearing mice that further increased in combination with trametinib treatment. Interestingly, trametinib treatment alone had no survival benefit.
DDRE-28. IDENTIFICATION OF SYNERGISTIC DRUG COMBINATIONS FOR THE THERAPY OF IDHmut GLIOMA
Authors: Warta Rolf , Stammler Florian , Unterberg Andreas , Herold-Mende Christel 
Published: November 2021

Abstract

OBJECTIVE
Isocitrate Dehydrogenase (IDH) mutation in glioma results in a multitude of biological differences with consequences for survival and therapy response. Therefore, IDH mutated (IDHmut) and wildtype (IDHwt) tumors are regarded as separate entities with the need for adjusted therapy like the combination of procarbazine, CCNU and vincristine (PCV). However, as vincristine has often severe side effects like neuropathy new effective therapy options are required. Therefore, we searched for combinations of FDA-approved drugs which effectively inhibit the growth of IDHmut cells in vitro.

METHODS
We tested different drug combinations of a drug library consisting of 146 FDA-approved drugs on two established IDHmut GSC lines. Based on a previous single agent drug screen, six drugs were selected (Idarubicin, Ixazumib, Ponatinib, Neratinib, Romidepsin) to be combined with all 146 drugs of the library. Cell viability was assessed by the CellTiterGlo 3D assay (Promega) in 96 well plates, while Caspase-Glo 3/7 3D assay was used to measure induction of apoptosis.

RESULTS
Out of 1460 drug combinations tested altogether 21 synergistic drug combinations could be identified and validated. The combination with the highest blood-brain-barrier permeability score was further investigated. Finally, drug-concentrations elucidating the highest synergistic effect on proliferation was further studied in a 8-point dose-response matrix followed by validation in additional four IDHmut GSC lines.

CONCLUSION
This work can lay the foundation for future improvements of the therapy of patients suffering from LGGs.
DDRE-32. SETD2 HISTONE METHYLTRANSFERASE MUTATION STATUS PREDICTS TREATMENT RESPONSE IN GLIOBLASTOMA: STRATEGIES TO OVERCOME CHEMORESISTANCE
Authors: Goldstein Michael , Gabriel Nishanth , Inkman Matthew , Zhang Jin , Dahiya Sonika 
Published: November 2021

Abstract
A major challenge in GBM treatment is tumor resistance to radiation and chemotherapy. A hallmark of GBM is the frequent mutation of epigenetic modifiers resulting in alteration of epigenetic signaling pathways. However, the effect of epigenetic signaling on chemotherapy response in GBM remains unknown. SETD2 is a histone methyl transferase that facilitates H3K36 tri-methylation. Here, we unveil the role of SETD2 mutations that frequently occur in GBM in tumor resistance to temozolomide chemotherapy. Targeted sequencing of the SETD2 gene in GBM tumor samples revealed that SETD2 mutations are associated with reduced overall survival in patients with methylated MGMT (methyl-guanine methyl transferase) promotor who received temozolomide. Consequently, we demonstrate that loss of SETD2 results in reduced H3K36me3 levels and a profound temozolomide resistance in GBM cells. MGMT-deficient tumors can acquire chemoresistance due to disrupted mismatch repair (MMR), a DNA repair pathway that converts primary temozolomide-induced DNA lesions into toxic DNA double-strand breaks. Strikingly, we found that SETD2 loss abrogates the expression of the MMR factor MSH6 indicating that chemoresistance in SETD2-deficient cells us due to disrupted MMR. Mechanistically, we show that SETD2 regulates MMR by promoting transcription of the MSH6 gene in GBM. Epigenetic modifiers have specific antagonists capable of reversing chromatin alterations induced by these modifiers. This provides a unique opportunity to restore chemotherapy response in SETD2-mutant GBM by targeting the antagonists of SETD2. We demonstrate that combined targeting of H3K36me3-specific histone de-methylases KDM4A and NO66 restores H3K36me3 levels along with MSH6 expression and sensitivity to temozolomide in SETD2-deficient GBM cells. Thus, our findings establish SETD2 mutation as a novel molecular marker predictive of chemotherapy response in GBM and provide a framework for a novel approach to overcome chemotherapy resistance in this malignant brain tumor by targeting an epigenetic pathway.