bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANGI-04. A NOVEL TROY-JAK1 SIGNALING COMPLEX IN GLIOBLASTOMA INVASION
Authors: Ding Zonghui , Kloss Jean , Tuncali Serdar , Tran Nhan , Loftus Joseph 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common and deadly malignancy of the central nervous system in adults with a median survival of about 15 months after diagnosis. Its aggressive and highly infiltrative nature renders the current standard treatment of maximal surgical resection, radiation, and chemotherapy relatively ineffective. Identifying the molecular events that regulate GBM migration/invasion is required to develop more effective therapeutic regimens to treat GBM. Expression of TROY, an orphan receptor of the TNFR superfamily, increases with increasing glial tumor grade, inversely correlates with patient survival, stimulates GBM cell invasion in vitro and in vivo, and increases resistance to temozolomide and radiation therapy. Conversely, silencing TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in a preclinical intracranial xenograft model. Thus, the TROY signaling pathway represents an attractive therapeutic target. We previously reported that increased TROY expression strongly activates NF-kB. We have identified for the first time that TROY forms a unique signaling complex with JAK1. Interaction with TROY stimulates phosphorylation of JAK1 and significantly increases the activation of STAT3. TROY specifically associates with JAK1 as it does not associate with other JAK family members. Co-immunoprecipitation analysis demonstrated that TROY interacts with JAK1 through its cytoplasmic domain as a TROY variant without its extracellular domain associates with JAK1 while a TROY variant without a cytoplasmic domain fails to bind JAK1. Luciferase reporter assay confirmed that full length TROY or a variant lacking the extracellular domain are able to induce STAT3 activation, but not a TROY variant lacking the cytoplasmic domain. Pharmacological inhibition of JAK1 by the FDA approved inhibitor ruxolitinib or knockdown of JAK1 by siRNAs significantly inhibited TROY-induced STAT3 activation and GBM cell migration. Together, our data indicate that the TROY-JAK1 complex represents an unappreciated therapeutic target to inhibit glioma invasion and decrease therapeutic resistance.
SCIDOT-14. ENHANCING BRAIN RETENTION OF A KIF11 INHIBITOR SIGNIFICANTLY IMPROVES ITS EFFICACY IN A MOUSE MODEL OF GLIOBLASTOMA
Authors: Gampa Gautham , Kenchappa Rajappa , Mohammad Afroz , Parrish Karen , Kim Minjee , Sarkaria Jann , Rosenfeld Steven , Elmquist William 
Published: November 2019

Abstract
Glioblastoma, the most common and lethal of brain tumors, is both highly invasive and proliferative. This allows tumor cells to infiltrate into regions of the brain with an intact blood brain barrier and be protected from effective therapeutics. Thus, an ideal glioblastoma therapy needs to target cellular components that drive both invasion and proliferation, with inhibitors that penetrate the blood brain barrier. The mitotic kinesin KIF11 meets these criteria and it can be targeted with ispinesib, a highly specific small molecule inhibitor. However, to be effective, ispinesib needs to cross the blood brain barrier and be retained within brain long enough to target glioblastoma cells when they are vulnerable, during mitosis.. We have examined the factors that affect distribution of ispinesib to both brain and glioblastoma. We find that delivery of ispinesib is limited by P-gp and Bcrp-mediated drug efflux at the blood brain barrier. Consequently, ispinesib levels are significantly lower in the infiltrative tumor margin relative to the tumor core, where the blood brain barrier is defective. We also show that elacridar—an inhibitor of the P-gp and Brcp efflux transporters—enhances delivery of ispinesib, and that co-administration of ispinesib with elacridar markedly slows tumor proliferation and prolongs survival in a mouse model of this disease. These results demonstrate the feasibility and efficacy of combining a potentially ideal therapeutic with a compound that enhances brain retention of this therapeutic, and provides support for utilizing this approach in clinical investigations of KIF11 inhibitors in GBM.
SCIDOT-15. DISRUPTING THE BLOOD-BRAIN BARRIER IN NEURO-ONCOLOGY: INNOVATIONS, ACHIEVEMENTS, AND LESSONS LEARNED FROM CLINICAL TRIALS
Authors: Philtheos Justine , Abbasian Aram , Karmur Brij , Mansouri Alireza 
Published: November 2019

Abstract

BACKGROUND
The blood-brain barrier (BBB) presents a formidable challenge for the development of effective therapeutics in neuro-oncology. Several strategies for the disruption of the BBB have been investigated in humans. An in-depth analysis of the concepts, design, and outcomes from these trials can provide insight into optimizing strategies for safe, selective, and efficacious BBB disruption for drug delivery.

METHODS
The clinicaltrials.gov database was searched on June 9th, 2019 using the term blood-brain barrier. Results were screened for studies relevant to neuro-oncology. When available, linked publications were also reviewed for supplemental information. The Pubmed database was also searched for BBB disruption strategies, to identify publications not linked to a trial registry. Details regarding patient eligibility, intervention, comparators, outcomes and other design criteria were extracted.

RESULTS
Among 288 registered studies, 42 were relevant to neuro-oncology. Drug-based methods predominated (33/42) but there has been a surge in device-based methods with all registrations after 2015. Mannitol was the most common drug-based method (16/33, 5 Phase II), followed by RMP-7 (8/33, 3 Phase II), Ang1005 (7/33, 4 Phase II and one pending Phase III), and Regadenoson (2/33, one Phase 0 and one Phase I). MR-guided focused ultrasound was the most common device-based method (5/9), followed by MR-guide laser ablation (2/9), Sonocloud (1/9), and transcranial magnetic stimulation (1/9). All device studies have been early phase. Most early phase studies focusing on safety and tolerability met objectives. Some Phase II studies showed preliminary efficacy but control arms were lacking. Many Phase II studies have been terminated/suspended.

CONCLUSIONS
Diverse BBB disruption methods have been investigated and most appear to be safe and tolerable. Advanced phase studies focusing on survival differences have been limited by heterogeneous tumors and lack of control arms. Objective establishment of BBB disruption was limited. Concerted and standardized clinical trial efforts are needed.
SCIDOT-22. INTRACEREBROVENTRICULAR DELIVERY OF TUMOR-HOMING CYTOTOXIC HUMAN INDUCED NEURAL STEM CELLS FOR TREATMENT OF BRAIN METASTASES
Authors: Jiang Wulin , Mercer-Smith Alison , Bago Juli , Khagi Simon , Anders Carey , Hingtgen Shawn 
Published: November 2019

Abstract

INTRODUCTION
Non-small cell lung cancer (NSCLC) and breast cancer are the most common cancers that metastasize to the brain. New therapies are needed to target and eradicate metastases. We have developed genetically-engineered induced neural stem cells (hiNSCs) derived from human fibroblasts that selectively home to tumors and release the cytotoxic protein TRAIL. Building on these results, we explored the efficacy of hiNSC therapy delivered via intracerebroventricular (ICV) injections for the treatment of metastatic foci in the brain for the first time.

METHODS
We performed in vitro efficacy and migration assays in conjunction with in vivo studies to determine the migration, persistence, and efficacy of therapeutic hiNSCs against H460 NSCLC and triple-negative breast cancer MB231-Br tumors in the brain. Following the establishment of tumors in the brains of nude mice, hiNSCs were injected directly into the tumor or the ventricle contralateral to the tumor. The migration and persistence of hiNSCs were investigated by following the bioluminescence of the hiNSCs. The therapeutic efficacy of the hiNSCs was determined by following the bioluminescence of the tumor. RESULTS/

CONCLUSION
Co-culture results demonstrated that hiNSC therapy reduced the viability of H460 and MB231-Br up to 75% and 99.8% respectively compared to non-treated controls. In vitro migration assays showed significant directional migration toward both lung and breast cancer cells within 4 days. ICV-administered hiNSC serial imaging shows that cells persisted for >1 week in the brain. Fluorescent analysis of tissue sections showed that hiNSCs co-localized with lateral and contralateral tumors within 7 days. Using H460 and MB231-Br models, kinetic tracking of intracranial tumor volumes showed intratumoral or ICV-injected therapeutic hiNSCs suppressed the growth rate of brain tumors by 31-fold and 3-fold, respectively. This work demonstrates for the first time that we can effectively deliver personalized cytotoxic tumor-homing cells through the ventricles to target brain metastases.
SCIDOT-23. LOW INTENSITY PULSED ULTRASOUND ENHANCES BLOOD-BRAIN BARRIER OPENING AND IMPROVES RESPONSE TO IMMUNOTHERAPY FOR GLIOBLASTOMA
Authors: Sabbagh Aria , Marisetty Anantha , Ott Martina , Ling Xiaoyang , Barton Emily , Caruso Hillary , Kong Ling-Yuan , Rao Ganesh , Canney Michael , Heimberger Amy B 
Published: November 2019

Abstract
The blood-brain barrier (BBB) is a significant obstruction to the delivery of treatments for glioblastoma. Previous studies have demonstrated the use of Low Intensity Pulsed Ultrasound (LIPU) in combination with microbubbles as a safe and therapeutic method for temporary BBB disruption to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma. Glioblastoma has minimal T cell infiltration. In this work, we investigated if LIPU sonications (1 MHz, 0.3 MPa, 120 s duration) could enhance T cell delivery to the tumor microenvironment and enhance immunotherapy. NSG mice with established EGFRvIII+U87 tumors were treated intravenously with bioluminescent labeled epidermal growth factor receptor variant III (EGFRvIII) expressing chimeric antigen receptor (CAR) T cells with and without ultrasound BBB disruption. Combining systemic CAR T cell administration with ultrasound BBB disruption, resulted in a significant increase in CAR T cell delivery to the mouse CNS after 12 (p<0.005) and 24 hours (p<0.001) associated with enhanced median survival. In a second murine model of C57BL/6 mice bearing intracerebrally implanted GL261 gliomas, mice treated with anti-PD-1 and ultrasound BBB disruption survived 58 days relative to 39 days of mice treated with only anti-PD-1. Long-term survivors in the anti-PD-1 and anti-PD-1+ ultrasound treatment groups all remained alive after contralateral hemisphere rechallenge with GL261 glioma cells. LIPU-induced BBB disruption increases the delivery of immune therapeutics to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies to the clinic.
SCIDOT-27. TGFβ SIGNALING-INDUCED miRNA PARTICIPATES IN AUTOPHAGIC REGULATION BY TARGETING PRAS40 IN MESENCHYMAL SUBTYPE OF GLIOBLASTOMA
Authors: Xie Yingbin , Chen Luyue , Zhou Junhu , Wang Qixue , Wang Yunfei , Tan Yanli , Kang Chunsheng , Fang Chuan 
Published: November 2019

Abstract
Mesenchymal subtype of glioblastoma (mesGBM) is a refractory disease condition characterized by therapeutic failure and tumor recurrence, and for the past decade, no treatment option has improved the dismal prognosis of this disease. In Cancer Genome Atlas (TCGA) GBM datasets, two of the 840 transcriptomic signature genes for GBM subtyping, TGFβ1 and TGFβ receptor type II (TβRII), were exclusively upregulated in mesGBM, indicating hyperactive TGFβ signaling. In the present study, dysregulated microRNAs (miRNAs) were identified after LY2109761 (a TβRI/II inhibitor) treatment in a mesGBM-derived cell line. Importantly, several novel miRNAs that may be missing pieces of the puzzle of TGFβ signaling-mediated pathogenesis in mesGBM were identified. Novel_miR26/56/93/97/119 were validated by quantitative PCR to correlate with TGFβ signaling activity, and novel_miR56 was selected as a promising candidate for further functional verification. A proline-rich akt substrate of 40 kDa (PRAS40), which regulates autophagy initiation by targeting mTORC1, was confirmed to be a functional target of novel_miR56. Autophagy plays dichotomous roles in the determination of GBM cell fate, and in this study, TGFβ signaling-induced novel_miR56 seemed to inhibit autophagic activity in GBM and its mesenchymal subtype, resulting in the maintenance of proliferative capability. The pro-survival effect of novel_miR56 can be impeded by intentionally downregulating its expression both in vivo and in vitro. In summary, we provide novel insight into TGFβ signaling-mediated pathogenesis and targets for the development of novel therapeutic interventions for mesGBM.
SCIDOT-43. FINAL DATA ANALYSIS OF A PILOT STUDY TESTING THE EFFICACY OF USING LASER INTERSTITIAL THERMAL THERAPY (LITT) TO INDUCE TEMPORARY DISRUPTION OF THE PERITUMORAL BLOOD BRAIN BARRIER (BBB) TO IMPROVE EFFECTIVENESS OF BBB-IMPERMEANT CHEMOTHERAPY IN RECURRENT GLIOBLASTOMA
Authors: Tran David , Campian Jian , Shimony Joshua , Kim Albert , Ansstas George , Leuthardt Eric 
Published: November 2019

Abstract

BACKGROUND
Poor CNS drug delivery is a major limiting factor in GBM therapy. Since most recurrences occur peritumorally where infiltrating glioma cells reside, peritumoral BBB disruption may help improve drug delivery and efficacy. LITT, a minimally invasive cytoreductive treatment for brain tumors, may disrupt BBB as evidenced by post-ablation contrast enhancement.

METHODS
Patients with recurrent GBM were treated with LITT. The degree of post-LITT peritumoral BBB disruption was measured by the vascular transfer constant (Ktrans) in brain DCE-MRI. Serum levels of brain-specific enolase (BSE) were quantified as an independent measure of BBB disruption. Forty enrollments were planned with equal randomization to weekly low-dose doxorubicin, a BBB-impermeant chemotherapy, either during the BBB-permeable window (Early Dox) or after the resolution of disruption (Late Dox). The primary endpoint is 6-month PFS rate (6-PFS).

RESULTS
Peritumoral Ktrans peaked immediately post LITT, followed by a gradual decline for the next 4 weeks. Similarly, serum BSE concentrations peaked in 1–3 weeks after LITT before decreasing to baseline by 6 weeks. 41 patients were randomized to Early and Late Dox. 31 patients (14 Early and 17 Late Dox) were evaluable for the primary endpoint. MGMT promoter methylation rate was 28% and 47% in the Early and Late Dox arms, respectively. 6-PFS was 57.1% (8/14) in Early Dox compared to 35.3% (6/17) in Late Dox. PFS was 5.8 (95%CI: 4.1–6.3) months vs. 4.9 (95%CI: 2.4–6.3) months, while OS was 12.8 (95%CI: 7.8–14.5) months vs. 13.6 (95%CI: 10.2–17.1) months, for Early vs. Late Dox, respectively. The most common grade 3–4 toxicities were cytopenia observed in 6 (16%) patients.

CONCLUSIONS
LITT induces temporary peritumoral BBB disruption lasting 4–6 weeks, providing a rare opportunity to enhance local delivery of potentially efficacious but BBB-impermeant therapeutic agents. 6-PFS strongly favors dox given early during the window of BBB disruption, thus supporting the hypothesis.
RARE-46. MULTIMODAL TREATMENT OF TWO PATIENTS WITH DISSEMINATED JUVENILE PILOCYTIC ASTROCYTOMA
Authors: Gass David , Wait Scott , Jacobsen Chad 
Published: November 2019

Abstract
Juvenile Pilocytic Astrocytoma (JPA) is characterized by an indolent course with excellent survival if gross total resection is achieved. However, a rare subset of these low-grade neoplasms will disseminate. We present two patients with disseminated JPA and review the multimodal treatment approach required to manage this disease. CLINICAL IMPORTANCE: Disseminated JPA is a low-grade tumor with a chronic relapsing course. Radiation has previously been successful, however, the significant treatment volume needed for disease control is toxic in young children. Approaches using repeated surgical resections and multiple chemotherapy regiments to postpone time to radiation is becoming a standard approach. CLINICAL OUTCOME: Our first patient is a 7-year-old girl who had four progressions in her primary third ventricular mass in the last 2 years. Her disseminated disease has been stable throughout treatment. Initially, she underwent subtotal resection of third ventricular mass, which showed JPA, with negative BRAF v600e and negative BRAF fusion. After observation, she had her first progression and was treated with vincristine and carboplatin. Three months later she had her second progression and then treated with six cycles of selumetinib. Next, she received weekly vinblastine prior to her fourth progression. She then underwent gross total resection of her primary mass and has disease stability for five months. Our second patient is a 13-year-old male who had two progressions in last seven years. After initial subtotal resection, he had local progression and had a second resection of cerebellar mass. After four years of stability, the mass disseminated to his thoracolumbar spine. He underwent resection of spinal tumor which showed positive BRAF fusion and then treated with carboplatin and vincristine. He is showing mild response to treatment after 6 months of chemotherapy. CONCLUSION: We demonstrate that with using multimodal treatment with surgery and chemotherapy regiments, radiation for young children can be postponed.
ANGI-13. PLEXIN-B2 FACILITATES DIFFUSE GLIOMA INVASION BY REGULATING CELL ADHESION AND ACTO-MYOSIN DYNAMICS
Authors: Huang Yong , Tejero Rut , Lee Vivian , Junqueira Alves Chrystian , Foty Ramsey , Dai Guohao , Zou Hongyan , Friedel Roland 
Published: November 2019

Abstract
Diffuse invasion of glioblastoma (GBM) cells into brain tissue is a key factor for its high lethality. GBM cell migration is affected by functions of plexins, which are transmembrane receptors of semaphorins that regulate cell adhesion and cytoskeletal dynamics. Expression of Plexin-B2 is upregulated in GBM and correlates with malignancy. We show here that Plexin-B2 activity regulates biomechanical properties of GBM cells, promoting invasive growth. Plexin-B2 activity increased the capacity of GBM to invade as dispersed single cells by reducing the cell-cell adhesiveness between GBM cells, indicating that a major function of Plexin-B2 activity is to downregulate cell-cell adhesion systems. RNA-Seq analyses also revealed that GBM stem cells (GSC) with deletion of Plexin-B2 altered expression of genes related to cell adhesion and the matrisome, indicating compensatory mechanisms in cellular dynamics. Interestingly, in vivo intracranial transplant studies demonstrated that growth and invasion of Plexin-B2 mutant GSC was impaired, with mutant cells invading shorter distances and migrating mainly as groups of cells forming chains. Plexin-B2 mutant cells also were more likely to adhere to the vasculature, rather than to fiber tracts, suggesting altered biomechanical properties. This shift may be related to high stiffness of basal lamina of the vasculature, as Plexin-B2 KO cells have a preference for migration on stiff substrate in vitro. Intriguingly, the loss in Plexin-B2 expression also changed the distribution of the mechanosensor transction factor YAP, with high expression of Plexin-B2 correlating with increased nuclear YAP. Structure-function analyses revealed that the Ras-GAP domain as main signaling output of Plexin-B2. The Rap proteins are pleiotropic regulators of cell adhesion and actomysosin contractility. Our data also showed that overexpression of Plexin-B2 can lead to decreased levels of Rap1/Rap2. Thus, Plexin-B2 acts as a key regulator of the adhesion and contractility of GBM cells, thereby facilitating their diffuse invasion.
CBMT-06. HIGH LEVELS OF GATA-4 IN MALIGNANT MENINGIOMA LEAD TO LOWER miR-497~195 CLUSTER EXPRESSION IN TISSUE AND BLOOD
Authors: Negroni Catarina , Ercolano Emanuela , Adams Claire , Baiz Daniele , Kurian Kathreena M , Hilton David , Oliver Hanemann Clemens 
Published: November 2019

Abstract
Meningioma is the most common primary intracranial brain tumour, classified as benign (WHO I, 70%), atypical (WHO II, 30%) and anaplastic/malignant (WHO III, 1–3%). The 3-year recurrence rate for WHO I tumours is 40% and it is much higher in WHO II-III1. To date, meningioma classification is based only on histopathological characterization, and no circulating biomarkers have been identified to predict tumour progression2. Indeed, microRNAs are promising circulating biomarkers because they can be released from tumour cells into the blood stream via exosomes, showing potential to be used as liquid biopsies3. Previously, Cyclin D1 overexpression was suggested as a possible meningioma biomarker as it correlates with proliferative activity and tumour grade, while high levels of Cyclin E1 were shown to correlate with higher recurrence rates4,5. In this study, we showed, for the first time, that the transcription factor GATA-4 is overexpressed in malignant meningioma cells and tissues, controlling the miR-15 family (miR-15a/b-16-497-195) expression. Moreover, we proved that the miR-497~195 cluster not only regulates Cyclin D1-D2-D3 and E1 levels, but it also modulates GATA-4 expression in meningioma. Moreover, we showed that the levels of miR-497~195 cluster are significantly lower in exosomes derived from higher grade meningioma patients’ blood serum, supporting their potential as diagnostic biomarkers.
CBMT-11. HIGH MITOCHONDRIAL DNA COPY NUMBER IS ASSOCIATED WITH LONGER SURVIVAL IN YOUNG PATIENTS WITH GLIOBLASTOMA
Authors: Rousseau Audrey , Dardaud Laure-Marie , Bris Céline , Desquiret-Dumas Valérie , Boisselier Blandine , Tabouret Emeline , Mokhtari Karima , Figarella-Branger Dominique , Procaccio Vincent 
Published: November 2019

Abstract
Young patients (< 40 years-old) with glioblastoma (GB) may carry IDH1/2 mutations or rarely, H3F3A/HIST1H3B mutations. Some instead harbor chromosome (chr) 7 gain, chr 10 loss, and EGFR amplification (amp). IDH1/2 mutations are associated with longer survival in contrast to H3F3A/HIST1H3B mutations. Novel reliable prognostic factors are needed in GB. Mitochondria (mt) are responsible for ATP production through oxidative phosphorylation. High mtDNA copy number (CN) has been associated with variable outcomes in cancer. The mtDNA-CN was assessed by RT Q-PCR in 66 GB from patients 18 to 40 years-old. Whole mitochondrial genome sequencing was performed in 18/66 GB. 17/66 (25.8%) cases harbored IDH1-R132H mutation; 29/66 (44%) had chr 7 gain/chr 10 loss and/or EGFRamp; 4/66 (6%) harbored H3F3A/HIST1H3B mutations. The remaining cases (24.2%) had no key genetic alterations. The mtDNA/nuclearDNA ratio was subdivided into groups: Low and High according to the median (mtDNA-CN median 194.9). 33 patients displayed a low ratio (≤ median) whereas 33 displayed a high ratio (> median). The overall survival in the High vs Low group was significantly longer in the whole cohort (Log-rank test, 31.8 vs 14.2 months, p= 0.019) and the chr7+/chr10-/EGFRamp subgroup (37.8 vs 12.1 months; p= 0.0117). There was still a trend towards longer survival in the High vs Low group within the other genetic subgroups (IDH-mutant; no genetic alteration) except for the H3-mutant GB (4 patients). Analyses on 232 patients 18 to 84 years-old showed that among patients < 56 years-old, the High group (58 cases) had a longer survival compared to the Low group (59 cases) (27.3 vs 15 months; p= 0.023). High mtDNA level is linked to oxidative metabolism (which decreases tumor aggressiveness) and cell differentiation. Increasing mtDNA-CN might induce tumor cell differentiation and slow disease progression. In conclusion, mtDNA-CN may be a novel prognostic biomarker in GB.