bluuebunny/crossref_metadata_2025_split huggingface dataset:
PDCT-08. SUPERIOR OUTCOME FOR BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION
Authors: Nobre Liana , Zapotocky Michal , Ramaswamy Vijay , Ryall Scott , Bennett Julie , Balaguer Guill Julia , Baroni Lorena , Bartels Ute , Bornhorst Miriam , Boue` Daniel , Chintagumpala Murali , Cruz Ofelia , Dahiya Sonika , Dirks Peter , Dunkel Ira , Eisenstat David , Finch Elizabeth , Finlay Jonathan , Frappaz Didier , Luisa Garre Maria , Gauvain Karen , Grete Bechensteen Anne , Hansford Jordan , Hauser Peter , Huang Annie , Karajannis Matthias , Kaur Gurcharanjeet , Larouche Valerie , Lassaletta Alvaro , Leary Sarah , Lin Frank , McKeown Tara , Milde Til , Morales La Madrid Andres , Morse Helena , Mushtaq Naureen , Osorio Diana , Packer Roger , Pavelka Zdenek , Salgado Duarte , Sabel Magnus , Solano Palma , Su Jack , Sumerauer David , Toledano Helen , van Tilburg Cornelis , Wilson Bev , Bouffet Eric , Hawkins Cynthia , Tabori Uri 
Published: November 2019

Abstract

BACKGROUND
Children with pediatric low grade glioma’s (PLGG) harboring BRAF V600E mutation have poor outcome due to relative resistance to chemo-radiation and higher risk of malignant transformation. However, the role of targeted BRAF inhibition in these tumors is poorly defined.

METHODS
We assembled an international cohort of children with BRAF V600E mutant gliomas treated with BRAF inhibition, from 29 centers participating in the PLGG taskforce, and collected response, survival and molecular parameters.

RESULTS
Sixty-seven patients were treated with BRAFi (56 PLGG and 11 high grade gliomas) for a median time of 17.4 months (6 – 61 months), with 13 PLGG treated upfront. Objective responses was observed in 80% of PLGG patients compared to 28% with conventional chemotherapy (p< 0.001). Rapid responses were observed in most PLGG patients (median of 4 months), sustained in 86% of tumors up to 5 years while on therapy. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. Seventeen patients with PLGG discontinued BRAFi and 76.5% (13/17) progressed rapidly after discontinuation (median time 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies such as concomitant homozygous deletion of CDKN2A or H3K27M mutation were not associated with lack of response to BRAFi. Overall these responses translated to 2-year progression-free survival of 0.636 (95%CI 0.505–0.802) and 0.43 (95% CI 0.32–0.57) for BRAFi and chemotherapy treated BRAF V600E PLGG respectively (p=0.003).

CONCLUSION
The use of BRAFi results in objective, robust and durable responses in BRAF V600E PLGG and is associated with favorable survival. Larger prospective studies will be required to determine appropriate regiments, and long-term functional outcomes with BRAFi therapy in childhood gliomas.
PDCT-12. CLINICAL EFFICACY OF ONC201 IN THALAMIC H3 K27M-MUTANT GLIOMA
Authors: Rahman Kawakibi Abed , Gardner Sharon , Chi Andrew , Kurz Sylvia , Wen Patrick , Arrillaga-Romany Isabel , Batchelor Tracy , Butowski Nicholas , Sumrall Ashley , Shonka Nicole , Harrison Rebecca , DeGroot John , Mehta Minesh , Odia Yazmin , Hall Matthew , Daghistani Doured , Cloughesy Timothy , Ellingson Benjamin , Umemura Yoshie , Schwartz Jonathan , Yadav Vivekanand , Cartaxo Rodrigo , Miklja Zachary , Bruzek Amy , Siada Ruby , Mullan Brendan , Stallard Stefanie , Muruganand Ashwath , Wierzbicki Kyle , Paul Alyssa , Wolfe Ian , Kumar-Sinha Chandan , Marini Bernard , Leonard Marcia , Garton Hugh , Mody Rajen , Robertson Patricia , Merdinger Krystal , Tarapore Rohinton , Oster Wolfgang , Allen Joshua , Koschmann Carl 
Published: November 2019

Abstract
ONC201, the first bitopic DRD2 antagonist for clinical oncology, has shown efficacy in H3 K27M-mutant glioma. We performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). Elevated DRD2 expression was found in the thalamus of non-malignant brain tissue, leading to the hypothesis that thalamic tumors may be a particularly ONC201-sensitive sub-group. We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 as of the 05/22/2019 cutoff date, which included patients who had recurrent disease prior to initiating ONC201 (n=20; 15–73 years old) and post-radiation non-recurrent patients (n=11; 5–19 years old). As of 5/22/2019, 10 of 20 recurrent patients and 9 of 11 non-recurrent patients remain on-treatment. Median PFS has not been reached for either cohort: median follow-up of 2.2 months (range: 0.6–37.9) for recurrent patients and 10.6 months (range: 4.3–20.5) from diagnosis for non-recurrent patients. Best response so far by RANO includes 1 CR, 2 PR, 7 SD, 9 PD, 1 NE for recurrent patients and 1 PR, 7 SD, 3 PD for non-recurrent patients. Additionally, 3 recurrent (-66%, -47%, -34%) and 2 non-recurrent (-40%, -10%) patients experienced regressions but are not yet confirmed PRs. For recurrent patients, median onset of response is 3.5 months (range: 2.2–3.8) and median duration of response has not been reached with a median follow-up of 12.5 months (range: 8.1–32.8). Preliminary analyses demonstrated a strong correlation of cell-free tumor DNA in plasma and CSF with MRI response. In summary, ONC201 demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients, regardless of age. Micro-environmental DRD2 expression may enhance the overall ONC201 response and extend its therapeutic utility beyond H3 K27M-mutant glioma.
PDTM-06. DISULFIRAM-COPPER PROLONGS SURVIVAL AND REDUCES STEM-CELLNESS IN PEDIATRIC GROUP 3 MEDULLOBLASTOMA THROUGH NUCLEAR SEQUESTRATION OF NPL4
Authors: Serra Riccardo , Zhao Tianna , Casaos Joshua , Leviton Gorelick Noah , Mangraviti Antonella , Olivi Alessandro , Brem Henry , Jackson Eric , Tyler Betty 
Published: November 2019

Abstract
Medulloblastoma (MB), an aggressive pediatric brain malignancy, is commonly classified into four subtypes. Although survival has improved remarkably, Group 3 and Shh-driven tumors still experience high rates of recurrent and metastatic disease. Disulfiram (DSF), a safe and inexpensive drug, has shown an antitumor effect when administered with copper (Cu++) against other brain malignancies, and its repurposing to MB could benefit current standards of treatment. ONS76 (Shh-driven Tp53 wild-type), UW228 (Shh-driven Tp53-mutated), D425med and D341med (Group 3) lines were treated with DSF-Cu++and tested with viability, proliferation and clonogenic assays. Flow cytometry (FACS) with AnnexinV-PI, Ki67, PI/RNAse for necrosis and cell cycle, and CD133 and Aldefluor for cell-stemness were carried out. MB lines were tested with western blotting (WB) and immunofluorescence (IF) for NPL4(Nuclear protein localization protein 4 homolog), AIF (apoptosis-inducing factor), cleaved-PARP(Poly-ADP-ribose-polymerase), H2AX and other molecular targets. In vivo safety (n=8) and efficacy studies (n=16) were carried out on Nu/Nu athymic mice implanted intracranially (IC) with D425med cells, along with Hematoxylin/Eosin and immunohistochemistry analyses on brain samples. DSF-Cu++showed remarkable cytotoxic and anti-proliferative activity against all MB lines. In particular, NPL4, a protein involved in the ubiquitin signaling, appears to be the primary DSF target, as previously shown in other malignancies. Apoptosis quickly follows the Heat-Shock Response, as confirmed by FACS, WB and IF, and cell-stemness is decreased significantly by nanomolar doses of DSF-Cu++(p=0.002). Oral administration of DSF-Cu++was proven safe at doses of 100 mg/kg and significantly prolonged survival in IC xenografts (median 28.5 days; p=0.02) compared to controls (median 24 days). DSF, a compound used in the treatment of chronic alcoholism, has recently shown a remarkable effect in a number of malignancies when co-administered with Cu++. We provide proof of its potential as a chemotherapeutic for pediatric MB, and describe its molecular mechanism of action.
PDTM-08. SINGLE-CELL GENOMICS REVEALS TUMOR-INITIATING PROGENITORS AND ONCOGENIC CASCADES DURING TUMORIGENESIS AND RELAPSE IN MEDULLOBLASTOMA
Authors: Zhang Liguo , He Xuelian , Liu Xuezhao , Berry Kalen , Lu Richard 
Published: November 2019

Abstract
Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas, the most common malignant pediatric brain tumor, remain elusive. Here, by utilizing single-cell analysis at different stages of tumorigenesis, we demonstrated a developmental hierarchy of diverse progenitor pools in sonic hedgehog (SHH)-medulloblastomas. Unexpectedly, we identified Olig2-expressing progenitors as transit-amplifying cells at the onset of tumorigenesis. Although Olig2+ cells become quiescent stem-like progenitors in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. High-level OLIG2 expression is associated with poor outcome in human SHH-medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2-ablation impeded tumorigenesis. Transcriptome and chromatin-occupancy profiling revealed that Olig2 modulates the chromatin landscape and activates oncogenic networks including HIPPO-Yap/Taz and Aurora-A/MycN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results raise the unanticipated possibility that glial lineage-associated Olig2-expressing progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting Olig2-driven oncogenic networks as potential therapeutic targets.
PDTM-14. INTERACTIONS BETWEEN IMMUNE MICROENVIRONMENT, STEM CELLS, AND CELL PROLIFERATION IN PEDIATRIC EMBRYONAL CENTRAL NERVOUS SYSTEM [CNS] TUMORS
Authors: Schafernak Kristian , Utagawa Emma , Mehta Shwetal , Di Modica Tiffany , Mufson Elliott , Perez Sylvia 
Published: November 2019

Abstract
Mounting evidence suggests the brain’s own immune cells, microglia, and perivascular macrophages play important roles in immune surveillance/inflammation, but also support proliferation/growth of gliomas, possibly through interactions with tumor stem cells. Immune cells are increasingly regarded as potential targets for cancer therapy, however, the immune microenvironment has not been well-studied in pediatric embryonal CNS tumors. In a series of 13 medulloblastomas, 7 PNETs and 6 ATRTs, we quantified the number of cells immunopositive for macrophage/microglia Ionizing calcium binding adaptor molecule 1 [Iba1], CD68 (expressed on both “M1” antitumor/proinflammatory macrophages and “M2” protumor/anti-inflammatory macrophages), CD163 (“M2” macrophages), CD3 (T-cell marker), CD4 (helper T cell), CD8 (cytotoxic T cell) and CD20 (B-cell marker) and correlated these findings with the stem-cell marker nestin and the Ki67/MIB1 proliferation index. Significant results were as follows: Across groups, CD68 showed a strong Spearman rank-order correlation with both CD163 (r=0.610, p=0.0007) and nestin (r=0.577, p=0.0017), while CD3 correlated strongly with CD8 (r=0.601, p=0.004), CD4 (r=0.526, p=0.005) and CD20 (r=0.499, p=0.008). Between groups, the number of CD163-positive cells was significantly higher in PNETs compared to medulloblastomas (p=0.035). Within the medulloblastoma group, CD68 showed a significant relationship with nestin (r=0.595, p=0.0387) and Ki67 (r=0.606, p=0.0333), and there was a robust correlation between CD4 and CD8 values (r=0.846, p=0.0000002). Within PNETs, there was a strong negative correlation between CD163 and nestin (r=-0.883, p=0.0000002), while CD68 correlated with CD4 (r=0.803, p=0.006). Within ATRTs, nestin and Ki67 were strongly correlated (r=1.000, p=0.0028) as were CD68 and CD163 (r=0.943, p=0.017). These data suggest a role for blocking embryonal CNS tumor-associated macrophages by inhibiting the CSF1R pathway (perhaps in conjunction with CD8-positive T cells which could antagonize the immunosuppressive function of tumor-associated macrophages) or reprogramming them from an M2 to an M1 phenotype (particularly in PNETs, which had the highest number of CD163-positive cells).
PDTM-18. COMBINED SUPPRESSION OF THE mTOR AND MAPK PATHWAYS INHIBITS GROWTH, DECREASES VASCULARITY AND INDUCES APOPTOSIS OR SENESCENCE IN PEDIATRIC LOW GRADE GLIOMA
Authors: Arnold Antje , Harris Lauren , Yuan Ming , Rodriguez Fausto , Eberhart Charles , Raabe Eric 
Published: November 2019

Abstract
Pediatric low-grade glioma (pLGG) is the most common brain tumor in children. We and others have identified constitutive activation of the mTOR and MEK-pathway in pLGG. This led us to investigate TAK228, a mTORC1/2-inhibitor, and the FDA approved MEK-inhibitor, trametinib, in mono- and combination therapy in pLGG. We examined antitumor activity in four patient-derived pLGG cell models treated with TAK228, trametinib, and combination: JHH_NF1_PA1(NF1mut), BT40(BRAFV600E), Res186(PTEN-/-) and Res259(CDKN2A-/-). Treatment with TAK228 or trametinib reduced cell proliferation in a dose and time dependent manner (MTS-assay). The combination treatment exerted a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells (Chou-Talay method). The combination of TAK228 and trametinib increased apoptosis by up to 127% (p< 0.001 by 1-way ANOVA) in Res186 and Res259 cells as measured by cleaved caspase 3 immunocytochemistry. Trametinib and combination treatment induces senescence in JHH_NF1_PA1 cell line verified through increase in p27 protein expression (Western Blot) and positive b-galactosidase staining. Mono-treatment with TAK228 or vehicle showed no signs of senescence. We tested trametinib and TAK228 against the mutant BT40BRAFV600E patient-derived cell line in immunodeficient mice. The combination treatment showed greater antitumor activity than that of either mono-treatment in vivo. BT40 tumor growth was significantly decreased in combination compared to vehicle or either agent alone (p< 0.01). Combination treatment strikingly reduced the vascularization in the tumor tissue after combination treatment analyzed by CD31 and CD34 protein expression (Western Blot), compared to vehicle and mono-treatment. Our study provides evidence that pLGG-derived cell lines in vitro and in vivo are sensitive to mTORC1/2 kinase inhibition and MEK inhibition. Combination treatment with TAK228 and trametinib had a significant anti-tumor activity in vivo shown in survival rate, decreased tumor size, and reduced vascularity. These results provide the first strong rationale for combination therapy with TAK228 and trametinib for clinical consideration in pLGG.
PDTM-23. DELTA-24-RGD ONCOLYTIC ADENOVIRUS MEDIATES ANTI-TUMOR EFFECT IN LOCALIZED AND DISSEMINATED AT/RT MURINE MODELS
Authors: Garcia-Moure Marc , González Huarriz Marisol , Laspidea Virginia , Marrodán Lucía , Gomez-Manzano Candelaria , Fueyo Juan , Patiño-García Ana , Alonso Marta M 
Published: November 2019

Abstract
Atypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD oncolytic adenovirus has already demonstrated its efficacy in Phase I/II clinical trials in adult patients affected by high grade gliomas with no evidence of severe side effects. Of interest for pediatric brain tumors, the safety of Delta-24-RGD is has been demonstrated in an ongoing Phase I clinical trial for the treatment of DIPGs (NCT03178032). For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of AT/RT. In vitro, the virus was able to infect and replicate in three different cell culture models of AT/RT, inducing a dose-dependent cytotoxic effect that results in IC50 values below 1 PFU/cell. In vivo, intratumor administration of the virus in mice bearing orthotopic localized AT/RT (supratentorial and infratentorial) extended significantly the survival the animals, leading to up to 20% of long-term survivors. We have also generated models of disseminated disease through intraventricular injection of the tumor cells, thus mimicking the lesions found in patients. AT/RT cell lines were transduced with a luc-expressing lentivirus in order to facilitate the follow up of these tumors. In disseminated AT/RT models, light emission reveals reduction of tumor growth in Delta-24-RGD treated animals in comparison to those mock treated, thus obtaining an increased overall survival. In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic choice for patients affected by AT/RT.
PDTM-28. AN OTX2-PAX3 SIGNALLING AXIS REGULATES GROUP 3 MEDULLOBLASTOMA CELL FATE
Authors: Zagozewski Jamie , Shahriary Ghazaleh , Morrison Ludivine , Stromecki Margaret , Fresnoza Agnes , Palidwor Gareth , Porter Christopher , Forget Antoine , Ayrault Olivier , Hawkins Cynthia , Chan Jennifer , Saulnier Olivier , Vladoiu Maria , Taylor Michael , Ramaswamy Vijay , Werbowetski-Ogilvie Tamra 
Published: November 2019

Abstract
The majority of Group 3 medulloblastomas (MB) exhibit amplification or increased expression of OTX2. OTX2 is primarily known as an oncogenic driver of tumor growth and cell cycle progression in Group 3 MB; however, its role as a repressor of differentiation is poorly characterized. Therefore, we utilized extensive patient data and mapped Group 3 MB chromatin dynamics in stem cell-enriched cultures to evaluate the divergent role of OTX2 in cell fate decisions in Group 3 MB pathogenesis. Several PAX genes were identified as novel OTX2 targets in Group 3 MB. Examination of patient data revealed that PAX3 and PAX6 expression is significantly reduced in Group 3 MB patients and is associated with significantly reduced survival. Functional evaluation of PAX3 and PAX6 expression showed that PAX3 expression significantly reduced self-renewal capacity of Group 3 MB tumorspheres in vitro and significantly prolonged survival and reduced tumor size in orthotopic xenograft models in vivo. RNA-sequencing of PAX3 and PAX6 gain of function (GOF) tumorspheres revealed mTORC1 signalling was specifically downregulated in PAX3 GOF, indicating this pathway may be critical for the survival and self-renewal differences observed between PAX3/PAX6 GOF models. Treatment of Group 3 MB with mTOR inhibitors reduced self-renewal in vitro and significantly prolonged survival and reduced tumor size in vivo. To further evaluate the role for this signalling axis in the Group 3 MB neural lineage hierarchy, we carried out scRNA-sequencing in tumorspheres from 4 Group 3 MB cell lines. Interestingly, a broad range of OTX2 expression was observed across single cell clusters, suggesting distinct OTX2 regulatory hierarchies are present in Group 3 MB. Collectively, our work demonstrates the multifaceted role of OTX2 as a regulator of cell fate decisions in Group 3 MB and identifies a novel role for mTORC1 signalling in Group 3 MB self-renewal and differentiation.
PDTM-44. ROLE OF ONC-206 IN REGULATING MEDULLOBLASTOMA TUMOR PROGRESSION
Authors: Malhotra Anshu , Liu Jingbo , MacDonald Tobey 
Published: November 2019

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. Of the four different sub-groups, the Sonic Hedgehog (SHH) subgroup accounts for about 30% of human MBs. The current standard of care (resection, cranio-spinal irradiation, and chemotherapy) for MB is typically ineffective for SHH MB in non-infants and those with metastatic disease. Survivors are frequently beset with long-term side effects including cognitive deficiencies and a severely impaired quality of life. Taken together, there is a critical need for novel targeted therapies for SHH MB. Recently, promising preclinical and clinical results have been obtained in a variety of cancers treated with a small molecule antagonist, ONC-201, which acts against DRD2, a G-protein coupled receptor that is widely expressed in MBs and regulates pro-survival pathways in tumors. In the present study we report the activity of ONC-201 and another DRD2 antagonist, ONC-206, which binds DRD2 with increased affinity. We tested three different MB cell lines with varied levels of DRD2 expression against these drugs, and consistently observed increased cell death at lower doses of ONC-206 compared to ONC-201. Following literature reports about the mechanism of action of ONC-201, we also evaluated the role of ClpP gene in MB cell lines. ClpP is a mitochondrial protease that has been shown to directly bind ONC 201. We observed a decrease in the expression of this gene after treatment of MB cell lines with ONC-206. Current studies are focusing on exploring the mechanism by which ONC-206 affects MB growth and metastasis. Dissecting this mechanism will be pivotal in predicting the role of this small molecule as a pre-clinical therapeutic for MB treatment.
QOLP-01. THE DISCREPANCY IN GROWTH PROBLEMS BETWEEN PATIENTS WITH INTRACRANIAL GERM CELL TUMOURS ORIGINATING FROM DIFFERENT LOCATIONS
Authors: Li Bo , Li Youqi , Wang Jiayi , Qiu Xiaoguang 
Published: November 2019

Abstract

BACKGROUND
Growth problems are common in patients with intracranial germ cell tumours. However, the characteristics were not fully profiled, especially when stratified by orientation. Thus, we conducted this study.

METHODS
Patients newly diagnosed, ≤19 years, with confirmed pathology or tumour markers elevation were included. Patients with bifocal lesions or lost to follow-up were excluded. WHO AnthroPlus software, which was developed for the global application of the WHO Reference 2007 to monitor growth in children aged 5–19 years, was used. Based on age, sex, and height, the Z-scores of height(ZSOH) were calculated. A ZSOH< -1 indicates a slower physical development than that in peers, while a ZSOH >1 indicates faster growth than peers.

RESULTS
Among the 200 included patients, 75 had primary lesions originating from the sellar/suprasellar region(S/SS), 73 from the pineal gland(PG), and 52 from the basal ganglia/thalamus region(BG/T). At initial diagnosis, the median ZSOH in S/SS was -0.66(-3.76–3.05), which was significantly lower than that in PG(0.76,-2.23–5.19) and BG/T(0.64,-3.05–5.32)(p=0.001). However, the difference in ZSOH between PG and BG/T was comparable(p=0.61). In patients with S/SS who had paired data(n=36), the median ZSOH decreased from -0.22(-3.76–3.05) at diagnosis to -1.01(-3.42–1.89) at the last follow-up(p=0.001). The median ZSOHs in PG(n=38) and BG/T(n=28) remained in the normal range at last follow-up although the changes were statistically significant(p< 0.001). Linear regression analysis showed that, in S/SS, age at diagnosis(β=0.115,p=0.033), sex(β=1.337,p=0.002), radiotherapy dose(β=-0.061,p=0.007), and number of chemotherapy cycles(β=-0.177,p=0.038) were correlated with changes in median ZSOH. In BG/T, only the radiotherapy dose(β=-0.064,p=0.041) and number of chemotherapy cycles(β=-0.551,p=0.026) were correlated. However, none of the above were validated in PG.

CONCLUSIONS
Compared to intracranial germ cell tumours in the PG or BG/T, the growth problems in S/SS was more prominent and aggravated after treatments, especially in those with younger age, female sex, higher radiotherapy dose, and more chemotherapy cycles.