bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDEL-09. HIGH DOSE MTX110 (SOLUBLE PANOBINOSTAT) SAFELY ADMINISTERED INTO THE FOURTH VENTRICLE IN A NON-HUMAN PRIMATE MODEL
Authors: Sirianni Rachael W , Kharas Natasha , Yu Bangning , Janssen Christopher F , Trimble Amanda , Ballester Leomar Y , Patel Rajan , Mohammad Afroz S , Elmquist William F , Sandberg David I 
Published: December 2020

Abstract

OBJECTIVE
This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma, UK) into the fourth ventricle of non-human primates.

METHODS
Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In Group I (n=2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess cerebrospinal fluid (CSF) distribution after short-term infusions. MTX110 (0.5 ml of 300 μM panobinostat solution) was infused into the fourth ventricle daily for five consecutive days. Serial CSF and serum panobinostat levels were measured. In Group II (n=2), fourth ventricle catheters were connected to a subcutaneously-placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5 daily infusions (0.5 ml of 300 μM panobinostat solution), were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and post-mortem histological analysis.

RESULTS
Neurological assessments, MRI, and histology confirmed catheter placement and an absence of neurotoxicity. Panobinostat was undetectable in serum collected two and four hours after infusions in all samples in both groups. In Group I, mean peak panobinostat level in fourth ventricle CSF (6242 ng/ml) was significantly higher than in lumbar CSF (9 ng/ml; p &lt; 0.0001). In Group II, mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than mean trough CSF level (33 ng/ml; p&lt;0.0001).

CONCLUSION
MTX110 can be safely delivered via 4th ventricle at supra-therapeutic doses. These results provide data for a pilot clinical trial in patients with recurrent medulloblastoma.
DDEL-12. NANOPARTICLE DELIVERY OF DOXORUBICIN FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Ung Caitlin , Tsoli Maria , Liu Jie , Cassano Domenico , Upton Dannielle , Ehteda Anahid , Mansfield Friederike , Failes Tim , Kavallaris Maria , Arndt Greg , Vittorio Orazio , Voliani Valerio , Cirilo Giuseppe , Ziegler David S 
Published: December 2020

Abstract
DIPGs are the most aggressive pediatric brain tumors. Currently, the only treatment is irradiation but due to its palliative nature patients die within 12 months. Effective delivery of chemotherapy across the blood-brain barrier (BBB) has been a key challenge for the eradication of this disease. We have developed a novel gold nanoparticle functionalised with human serum albumin (Au-NP, 98.8 ±19 nm) for the delivery of doxorubicin. In this study, we evaluated the cytotoxic efficacy of doxorubicin delivered through gold nanoparticles (Au-NP-Dox). We found that DIPG neurospheres were equally sensitive to doxorubicin and Au-NP-Dox (at equimolar concentration) by alamar blue assay. Colony formation assays demonstrated a significantly more potent effect of Au-NP-Dox compared to doxorubicin alone, while the Au-NP had no effect. Furthermore, western blot analysis indicated increased apoptotic markers cleaved Parp, caspase 3/7 and phosphorylated H2AX in Au-NP-Dox treated DIPG neurospheres. Live cell content and confocal imaging demonstrated significantly higher uptake of Au-NP-Dox compared to doxorubicin alone. Treatment of a DIPG orthotopic mouse model with Au-NP-Dox showed no signs of toxicity with stable weights being maintained during treatment. However, in contrast to the above in vitro findings the in vivo study showed no anti-tumor effect possibly due to poor penetration of Au-NP-Dox into the brain. We are currently evaluating whether efficacy can be improved using measures to open the BBB transiently. This study highlights the need for rigorous in vivo testing of new treatment strategies before clinical translation to reduce the risk of administration of ineffective treatments.
DDEL-13. FOCUSED ULTRASOUND MEDIATED BLOOD BRAIN BARRIER DISRUPTION IN A MURINE MODEL OF PONTINE GLIOMA: A SAFETY AND FEASIBILITY STUDY
Authors: Englander Zachary , Wei Hong-Jian , Pouliopoulos Antonios , Upadhyayula Pavan , Jan Chia-Ing , Spinazzi Eleonora , Canoll Peter , Bruce Jeffrey , Feldstein Neil , Zacharoulis Stergios , Konofagou Elisa , Wu Cheng-Chia 
Published: December 2020

Abstract

BACKGROUND
Drug delivery remains a major obstacle in DIPG, as the blood brain barrier (BBB) limits the penetration of systemic therapies to the brainstem. Focused ultrasound (FUS) is an exciting new technology that, when combined with microbubbles, can open the BBB permitting the entry of drugs across the cerebrovasculature. Given that the utility of FUS in brainstem tumors remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model.

METHODS
A syngeneic orthotopic model was established by stereotactic injection of PDGF-B+PTEN-/-p53-/- murine glioma cells (10,000/1ul) into the pons of B6 albino mice. A single-element, spherical-segment FUS transducer (center frequency=1.5MHz) driven by a function generator through a power amplifier (acoustic pressure=0.7MPa) was used with concurrent intravenous microbubble injection (FUS+MB) to sonicate the tumor on post-injection day 14. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen (KIS) testing was completed to measure motor function. Mice were either immediately sacrificed for histopathological assessment or serially monitored for survival.

RESULTS
In mice treated with FUS (n=11), there was no measured deficit in KIS testing. Additionally, the degree of intra-tumoral hemorrhage and inflammation on H&E in control (n=5) and treated mice (n=5) was similar. Lastly, there was no difference in survival between the groups (control, n=6, median=26 days; FUS, n=6, median=25 days, p&gt;0.05).

CONCLUSION
FUS+MB is a safe and feasible technique to open the BBB in a preclinical pontine glioma model.
DDEL-15. NANOTHERAPEUTIC TARGETING OF TUMOR ENDOTHELIUM FOR ENHANCING DRUG DELIVERY PAST THE BLOOD-BRAIN BARRIER
Authors: Kiguchi Hiro , Tylawsky Daniel , Vaynshteyn Jake , Gerwin Jeffrey , Manzari Mandana , Shah Janki , Li Na , Shamay Yosi , Greenblatt Matthew , Heller Daniel , Raju Praveen 
Published: December 2020

Abstract

OBJECTIVE
The Sonic Hedgehog (SHH) medulloblastoma subgroup accounts for ~25% of all cases and has an intermediate prognosis. Current therapies result in devastating morbidities including intellectual disability and secondary malignancies. Although molecularly targeted agents against the SHH pathway have demonstrated efficacy, on-target bone toxicities suggest new therapeutic approaches are needed.

METHODS
We investigated the SHH pathway inhibitor, vismodegib, packaged in a fucoidan-based nanoparticle (Fi-Vis) that targets P-selectin expressed on endothelial cells and induced by low-dose ionizing radiation (XRT) in a time- and dose-dependent manner. This P-selectin targeting nanoparticle shows selectivity toward tumor and not normal brain vasculature in a GEM SHH medulloblastoma model as assessed by ex vivo infrared imaging and molecular studies.

RESULTS
Quantitative RT-PCR analysis of SHH medulloblastoma following single dose XRT and Fi-Vis treatment (10mg/kg) showed synergistic reduction of Gli1 expression (&gt;90% target inhibition). We demonstrate that low-dose XRT (0.25Gy) can induce P-selectin expression specifically on medulloblastoma tumor endothelium and synergize with low-dose Fi-Vis (10mg/kg) to significantly enhance mouse survival (p&lt;0.01) compared to radiation or Fi-Vis alone. Assessment of bone toxicity using micro-CT and histological analysis following Fi-Vis administration in postnatal (P10) mice shows no bone toxicity when compared to free vismodegib. Finally, in vitro studies using bEnd.3 brain endothelial cells and in vivo studies using Cav1 knockout mice suggest a caveolin-1 mediated transcytosis mechanism for nanoparticle entry across the blood-brain barrier.

CONCLUSIONS
These data suggest applicability of combined XRT and tumor vasculature-targeted nanotherapeutic dose de-escalation strategies for SHH medulloblastoma with implications for other pediatric brain tumors.
DDEL-17. TRIPLE INTRAVENTRICULAR CHEMOTHERAPY FOR TREATMENT OF RELAPSED CHOROID PLEXUS CARCINOMA
Authors: Lau Grace , Janson Lisa , Drummond Julie , Zhukova Nataliya , Wood Paul 
Published: December 2020

Abstract
Limited evidence for the optimal management of relapsed choroid plexus carcinoma (CPC) exists, with a few case reports involving surgery, radiotherapy and intravenous chemotherapy. However, the safety and tolerability of intraventricular chemotherapy in this setting has not been widely studied. We describe a case where triple intraventricular chemotherapy was administered to a child with relapsed metastatic CPC. A 7-year-old male with a history of CPC presented with relapsed metastatic disease. At initial diagnosis at 4 years of age, treatment involved gross total resection of an intraventricular mass in the left temporal region followed by chemotherapy and autologous stem cell transplantation (SCT) according to HEADSTART II-D. One year after SCT, craniospinal radiation was delivered following radiological relapse, achieving a partial response. Given previous treatment-limiting myelosuppression, intraventricular chemotherapy via Ommaya® reservoir with thiotepa 5mg, etoposide 0.5mg and topotecan 0.4mg twice a week (non-weight-based dosing) was commenced taking into consideration pharmaceutical formulation aspects for optimal intraventricular drug delivery. After six cycles of intraventricular chemotherapy, palliative radiotherapy was administered due to radiological progression. Following completion, weekly triple intraventricular chemotherapy continued for 9 months. The patient remained out of hospital with the main side effects being fatigue and occasional nausea amenable to ondansetron. This case study demonstrates the safety and tolerability of a triple intraventricular chemotherapy regimen used to delay disease progression and prolong quality of life in a child with relapsed CPC in the palliative setting. This could provide an alternative treatment regimen for patients with relapsed disease.
DIPG-14. TARGETING POLO-LIKE KINASE 1 IN COMBINATION WITH KEY ONCOGENIC DRIVERS IN DIPG: FROM SINGLE AGENT TO COMBINATION STRATEGIES
Authors: Franshaw Laura , Hayden Elisha , Joshi Swapna , Liu Jie , Ehteda Anahid , Pang Chi Nam Ignatius , Tsoli Maria , Ziegler David S 
Published: December 2020

Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) are devastating paediatric brainstem tumours. Loss of function mutations in DIPG decrease genetic stability and impair DNA damage response pathways promoting tumourigenesis. Polo-like Kinase 1 (PLK1) is a pivotal controller of cell growth, regulating key intermediaries of DNA replication, homologous repair, the cell cycle and cell division. We have found DIPG cultures consistently overexpress PLK1 with inhibition resulting in decreased tumour cell growth, heightened cell cycle arrest and apoptosis. Single agent treatment using PLK1 inhibitors unprecedentedly doubled the median survival of animals harbouring DIPG tumours. Through gene expression analysis, we’ve showed PLK1 inhibition affected multiple pathways which control the cell cycle, cell death regulation, microtubule organization and regulation of cell migration. We found these pathways of differentially expressed genes were significantly enriched for known targets of both E2F1 and E2F4. Analysis of gene expression and proteomic studies also revealed PLK1 inhibition decreased the activation and expression of key tumour promoting mediators within multiple phases of the cell cycle, decreased expression of tumour promoters including MYC and the PI3K/mTOR pathway and reactivated tumour suppressors p53 and PTEN. Assessing these changes in the treated transcriptome and proteome, we aim to develop multiple potentially translatable combination treatment strategies for DIPG. We have performed mechanistic studies and identified synergism with PLK1 inhibitors and the epigenetic regulator panobinostat, bet/bromodomain inhibitor JQ1, dual PI3K/mTOR inhibitor bimiralisib and PI3K inhibitor BKM120. Finally, we found PLK1 inhibitors act as potent radiosensitizers, enhancing the therapeutic effects of radiotherapy in vitro and in vivo.
DIPG-15. POLYAMINE PATHWAY INHIBITION IS A POTENT NOVEL THERAPEUTIC STRATEGY AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Khan Aaminah , Gamble Laura , Upton Dannielle , Yu Denise , Ehteda Anahid , Pandher Ruby , Mayoh Chelsea , Burns Mark , Norris Murray , Haber Michelle , Tsoli Maria , Ziegler David 
Published: December 2020

Abstract
DIPG is an aggressive paediatric brainstem tumour, with a median survival of less than 1 year. Polyamines are intracellular polycations that control important aspects of cell growth and are often upregulated in cancer. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is a key driver of polyamine synthesis. We investigated the efficacy of polyamine pathway inhibitors as a therapeutic strategy against DIPG. We found high expression levels of synthetic enzymes in the polyamine pathway in primary patient samples and cultures. Using cytotoxicity and clonogenic assays, we found that DFMO inhibited the proliferation of DIPG neurospheres. However, DIPG cells compensated for DFMO inhibition by increasing expression of the polyamine transporter SLC3A2. Gene expression analysis showed that the polyamine transporter, SLC3A2, was significantly overexpressed in DIPG compared with all other high-risk childhood cancers. Addition of polyamine transporter inhibitor AMXT 1501 to DFMO led to synergistic inhibition of DIPG proliferation. Consistent with the in vitro results, the combination treatment significantly prolonged the survival of mice bearing 3 different DIPG orthografts with 2/3 of the animals surviving up to 160 days. Addition of irradiation further improved the survival of mice treated with DFMO and AMXT 1501. Our results suggest that DIPG tumours are exquisitely sensitive to polyamine inhibitors and that dual blockade of polyamine synthesis and transport is a promising novel therapeutic strategy. AMXT 1501 is currently in clinical development for adult cancers (NCT03536728). A clinical trial for DIPG patients is planned through the CONNECT consortium.
DIPG-18. IDENTIFICATION OF TARGETABLE PATHWAY DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Parackal Sarah , Chong Wai Chin , Bradshaw Gabrielle , Sun Claire , Daniel Paul , Roussel Enola , Jayasekara Samantha , Crombie Duncan , Firestein Ron , Cain Jason 
Published: December 2020

Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive paediatric brainstem tumour with a dismal prognosis. Recurrent heterozygous mutations (p.K27M) in Histone H3 variant genes have been identified in the majority of DIPG cases. While the exact mechanism of H3K27M’s function is poorly understood, evidence suggests a role for epigenetic dysregulation in disease pathogenesis. This study aims to use functional genomics to identify novel therapeutic dependencies in H3K27M DIPG. DIPG drug sensitivity screening was carried out in twelve established and validated patient derived cell lines (10 H3.3K27M and 2 Wt) using an FDA approved drug library containing 1480 compounds. Highly prevalent targets identified from this screen include HDAC, microtubule, proteasome and CDK inhibitors. Additionally, a custom pooled CRISPR knockout library of druggable targets (300 genes, 1200 guide RNAs) was used to identify key DIPG cell survival pathways. To date five DIPG cell lines (1 Wt; 1 H3.1; 3 H3.3) have undergone screening. Knockdown of known DIPG driver genes (TP53; PDGFRA; PIK3CA and PIK3CR1) resulted in reduced cell viability, consistent with their proposed function and validating knockout screen utility. Preliminary data demonstrates Wt and H3K27M DIPGs cluster independently based on genes required for survival, suggesting differing tumorigenesis mechanisms and the potential for therapeutically targeting genotype specific pathways. Correlation of parallel drug screen and RNA-seq data will potentially reveal H3-dependent pathways for therapeutic exploitation. Collectively, we show a functional genomics approach is able to identify genotype-specific pathway dependencies in DIPG, paving the way for molecularly informed personalized therapies for patients.
DIPG-27. TARGETING FACILITATES CHROMATIN TRANSCRIPTION (FACT) AS A NOVEL STRATEGY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) THAT ENHANCES RESPONSE TO HISTONE DEACETYLASE (HDAC) INHIBITION
Authors: Ehteda Anahid , Franshaw Laura , Liu Jie , Joshi Swapna , Simon Sandy , Pang Chi Nam Ignatius , Giorgi Federico , Pandher Ruby , Ung Caitlin , Tolhurst Ornella , Mayoh Chelsea , Khan Aaminah , Hayden Elisha , Gopalakrishnan Anjana , Trebilcock Peter , Upton Dannielle , Lehmann Rebecca , George Sandra , Vittorio Orazio , Tsoli Maria , Gurova Katerina , Gudkov Andrei Gudkov , Norris Murray D , Haber Michelle , Ziegler David S 
Published: December 2020

Abstract
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumour for which new treatments are needed. A high throughput drug screen of 3500 pharmaceutical compounds identified anti-malarials, including quinacrine as having potent activity against DIPG neurospheres. CBL0137, a compound modelled on quinacrine, is an anti-cancer compound which targets Facilitates Chromatin Transcription (FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. CBL0137 effectively crosses the blood-brain barrier and is currently in Phase I trials in adult cancer. CBL0137 induced apoptosis in DIPG neurospheres in vitro and had profound cytotoxic activity against a panel of DIPG cultures. In a DIPG orthotopic model, treatment with CBL0137 significantly improved survival. We found that treatment with CBL0137 up-regulated TP53 and increased histone H3.3 acetylation and tri-methylation in DIPG cells. We therefore examined the interaction between CBL0137 and the HDAC inhibitor, panobinostat. In vitro experiments showed that the two agents had profound synergistic activity against DIPG neurospheres in clonogenic assays and enhanced apoptosis. Transcriptomic analysis and immunoblotting indicated that combination treatment activated signalling pathways controlled by Retinoblastoma (RB)/E2F1 and subsequently increased phosphorylation and enzymatic activity of enhancer of zeste homolog 2 (EZH2). Consistent with the in vitro results, the combination of CBL0137 and panobinostat significantly prolonged the survival of two orthotopic models of DIPG, while histological analysis showed increased H3K27me3 and decreased Ki67 positive cells. Given these promising results, a paediatric trial of CBL0137 is planned to open through the Children’s Oncology Group with an expansion cohort for DIPG patients.
DIPG-28. REPEATED LOW DOSE RT FOR PEDIATRIC DIPG – LESS DISEASE BURDEN WITH COMPARABLE OUTCOMES
Authors: Wu Yao Yu , Tseng Chen Kan 
Published: December 2020

Abstract

PURPOSE
Pediatric diffuse intrinsic pontine glioma (DIPG) is the most dismal prognosis pediatric brain tumor. Six weeks radiation therapy (RT) remains the mainstay of treatment. The aim of the current study was to compare the results of firstly reported repeated low dose RT (rLRT) with conventional RT (CRT). METHODS AND MATERIALS: This retrospective review included 24 children with DIPG, aged 3 -18 years, underwent CRT (52- 60.0 Gy in 1.8- 2.0 Gy, n = 16) or rLRT (18 - 30 Gy in 1.5–2.0 Gy per cycle for 1–3 cycles, n = 8). All children had typical symptoms and MRI features of DIPG, or biopsy-proven DIPG.

RESULTS
The median overall survival (OS) was 12.6 months in rLRT group and 11.4 months in CRT group (p =0.347), progression-free survival (PFS) was 3.6 months in rLRT group and 6.5 months in CRT group (p = 0.821), no significant survival difference was observed between two groups. Temporary discontinuation or tapering of steroids rate was significantly higher in rLRT group (100% vs 60%, p = 0.028). Although not statistically significant, mean non-hospitalized days were longer in the rLRT group, 403 days versus 305 days in the CRT group, as were mean cumulative progression-free days, 276 days versus 163 days and 1-year free from CSF diversion rate was higher, 100% versus 64.9%.

CONCLUSIONS
For patients with newly diagnosed DIPG, repeated low dose RT, given over 3 to 4 weeks per cycle for 1 to 3 cycles, offers comparable survival outcome with less disease burden compared with conventional RT.
DIPG-32. AKT SIGNALING DRIVES RESISTANCE TO ONC201 IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Jackson Evangeline R , Duchatel Ryan J , Mannan Abdul , Hulleman Esther , Carcaboso Angel M , Monje Michelle , McCowage Geoff B , Alvaro Frank , Dun Matthew D 
Published: December 2020

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive, childhood brainstem cancer with a median overall survival of 10 months post diagnosis. Remarkably, 80–90% of patients harbor recurring point mutation in histone H3, which induces a lysine for methionine substitution at amino acid 27 (H3K27M) in either H3.1 (HIST1H3B ~25%) or H3.3 (H3F3A ~65%) variants. Using the blood-brain barrier (BBB) permeable DRD2 antagonist, ONC201 (in clinical trials for DIPG and H3K27M-mutant gliomas – NCT03416530), we hypothesized that DRD2 antagonism would induce TRAIL expression via indirect inhibition of AKT and ERK signaling, to drive apoptosis in both H3.1K27M and H3.3K27M patient-derived DIPG cell lines alike. For the first time, we reveal that ONC201 shows efficacy in 100% of WT-H3 and H3.1K27M mutant DIPG cell lines (n=5), compared to 50% of H3.3K27M mutant DIPGs (n=6). Investigations to identify the mechanisms of resistance to ONC201, revealed that cell lines with decreased sensitivity upregulated the PI3K/AKT/MTOR signaling axis to drive phosphorylation of AKT and increase metabolic activity. Combined administration of ONC201 and the BBB-permeable PI3K/AKT inhibitor, paxalisib (previously GDC-0084, in clinical trials for newly diagnosed DIPG – NCT03696355), showed synergistic cytotoxicity, reduced PI3K/AKT signaling and metabolic reprogramming to drive apoptosis in all DIPG cell lines tested. This combination was used to treat a 3-year-old DIPG patient, commencing 14 weeks post disease progression, completing 40 weeks of therapy prior to her passing, December 2019. These studies highlight the potential of combined administration of two safe, BBB penetrant, oral targeted therapies and supports testing under clinical trial conditions.