EXTH-79. TRIAL WORKING GROUPS TO EXPEDITE PRECLINICAL TRANSLATION FOR PAEDIATRIC BRAIN TUMOURS

INTRODUCTION Children's brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children, including intra-CSF chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate these. The science and technology underlying these developments is not traditionally embedded within the paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures, and the testing and licensing of implantable devices, add difficulty at the regulatory level. METHODS In early 2021, we launched the ‘Clinical Trials Working Group for Central Nervous System Drug Delivery’. This aims to accelerate clinical trials to assess the safety and effectiveness of drug delivery devices for treating paediatric brain tumours. On March 1st, we hosted the first virtual meeting of this group, involving 38 leading brain tumour scientists and clinicians from the UK, EU and US. RESULTS A pre-meeting survey identified the main challenges to acceleration of this preclinical to clinical research pathway as: (1) a lack of specific funding for prototype development and/or scale up for clinical trials; (2) difficulties in navigation of the regulatory landscape; (3) lack of accurate preclinical models; and (4) increased need for multicentric working. Discussion at the meeting echoed the survey responses, and there was agreed consensus that a ‘Roadmap’ document for preclinical to clinical translation should be created. Following the meeting, we launched a pump prime funding call for projects that will address challenges along the preclinical to clinical pathway to move trial proposals into an ‘advanced state of readiness’. CONCLUSION The ideas generated during the initial meeting will help form the basis of a ‘Clinical Trials’ workshop in the autumn of 2021.

The role of diffusion tensor imaging metrics in machine learning-based characterisation of paediatric brain tumors and their practicality for multicentre clinical assessment

Aims Magnetic resonance imaging (MRI) is a valuable tool for non-invasive diagnosis of paediatric brain tumours. The rarity of the disease dictates multi-centre studies and imaging biomarkers that are robust to protocol variability. We investigated diffusion tensor MRI (DT-MRI), combined with machine learning, as an aid to diagnosis and evaluated the robustness of the imaging metrics. Method A multi-centre cohort of 52 clinical DT-MRI scans (20 medulloblastomas (MB), 21 pilocytic astrocytomas (PA), 11 ependymomas (EP)) were analysed retrospectively. Histograms for regions of solid tumour for fractional anisotropy (FA), mean diffusivity (MD), pure anisotropic diffusion (q) and pure isotropic diffusion (p) were compared to assess diagnostic capability. Linear discriminate analysis (LDA) was used for classification and validated using leave-one-out-cross-validation (LOOCV). Results Histogram medians for FA, MD, q and p were all different between tumor groups (P<.0001, Kruskal Wallis test). Median MD, p and q values were highest in PA, then EP and lowest in MB (P<.0001, Pairwise Wilcox test). FA median was higher for EP than PA (P=.004) with no significant difference between EP and MB (P=.591). ROC analysis showed that median MD, q and p perform best as a diagnostic marker (AUC= 0.92 to 0.99). LOOCV showed an overall accuracy of the LDA classification, ranging between 67% - 87%. FA values were highly dependent on protocol parameters, whereas pure anisotropic diffusion, q, was not. Conclusion DT-MRI metrics from multi-centre acquisitions can classify paediatric brain tumours. FA is the least robust metric to protocol variability and q provides the most robust quantification of anisotropic behaviour.

Trial working groups for paediatric brain tumours

Aims Children's brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children. These include intra-CSF chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate any of these. The science and technology underlying these developments is not traditionally embedded within the standard paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures and, in some cases, the testing and licensing of implantable devices, add difficulty at the regulatory level. Method The authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this workshop and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) in 2018 and 2020, the CBTDDC and the recently developed ITCC (Innovative Therapies for Children with Cancer) brain tumour group started working together to set up a new initiative. Called the ‘Clinical Trials Working Group for Central Nervous System Drug Delivery’, this aims to accelerate clinical trials to assess the safety and effectiveness of drug delivery devices for the treatment of paediatric brain tumours. On March 1st, 2021, CBTDDC with guest chair, Mr Kristian Aquilina (Consultant Paediatric Neurosurgeon at Great Ormond Street Hospital), hosted the first virtual meeting of this group. Results We have assembled a prestigious steering group, comprising international researchers and clinicians with expertise in diverse aspects of translational and clinical research in CNS drug delivery. At our first group meeting on March 1st, 2021, 38 leading brain tumour research scientists and clinicians from the UK, EU and US tackled the challenges head-on, with commitment and a driving passion to identify and move forwards with the most effective ways of translating drug delivery modalities into clinical trials. Attendees were split into three break-out sessions based on distinct drug delivery systems, and lots of insightful comments were collated. Conclusion The ideas generated during the 1st March meeting will help form the basis of a CBTDDC ‘Clinical Trials’ workshop in the autumn of 2021. In particular, there was an agreed consensus that a key objective will be the creation of a ‘Roadmap’ document for pre-clinical to clinical translation which would be shared with the paediatric neuro-oncology research community. CBTDDC look forward to working with steering group as we act on their recommendations to address the current challenges faced by translational drug delivery research. We present this abstract to the BNOS Annual 2021 Meeting to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.

CLRM-08. TRIAL WORKING GROUPS FOR PAEDIATRIC BRAIN TUMOURS

INTRODUCTION Brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the outlook for these children, including intra-CSF chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems, electric field therapy, and intra-arterial and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate these. In addition, custom-built hardware, novel surgical procedures and the testing and licensing of implantable devices add difficulty at the regulatory level. METHODS The authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium), the CBTDDC and the ITCC (Innovative Therapies for Children with Cancer) brain tumour group launched the ‘Clinical Trials Working Group for Central Nervous System Drug Delivery’. This aims to accelerate clinical trials to assess the safety and effectiveness of drug delivery devices for the treatment of paediatric brain tumours. RESULTS On 1 March, 2021, CBTDDC and Mr Kristian Aquilina (Consultant Paediatric Neurosurgeon at Great Ormond Street Hospital) hosted the first steering group meeting, comprising 38 leading brain tumour research scientists and clinicians from the UK, EU and US. CONCLUSION The ideas generated during the March meeting are driving the agenda for a Clinical Trials Workshop that will be held in the autumn of 2021. In particular, there was agreed consensus that a ‘Roadmap’ document for pre-clinical to clinical translation needs to be created and shared with the paediatric neuro-oncology research community. We present this abstract to the CNS Clinical Trials Meeting to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.

EPCT-08. TRIAL WORKING GROUPS FOR PAEDIATRIC BRAIN TUMOURS

Introduction Brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children. These include ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial, intra-CSF and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate any of these. The science and technology underlying these developments is not traditionally embedded within the standard paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures and, in some cases, the testing and licensing of implantable devices, add difficulty at the regulatory level. Methods The authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this workshop and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) in 2018 and 2020, the CBTDDC and the recently developed ITCC (Innovative Therapies for Children with Cancer) brain tumour group started working together to set up a new initiative. This aims to develop CNS-delivery-focused trial working groups for paediatric brain tumours. Results We have assembled a prestigious steering group, comprising international researchers and clinicians with expertise in diverse aspects of translational and clinical research in CNS drug delivery. At our first group meeting in March, participants will discuss the most effective ways of translating the emerging drug delivery modalities into clinical trials. Prioritised actions will be taken forward and the group will reconvene to discuss developments and next steps at a workshop in the Autumn. Conclusion We present this abstract to the SNO Paediatric conference to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.

Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma

Diffuse Intrinsic Pontine Gliomas (DIPGs) are highly aggressive paediatric brain tumours. Currently, irradiation is the only standard treatment, but is palliative in nature and most patients die within 12 months of diagnosis. Novel therapeutic approaches are urgently needed for the treatment of this devastating disease. We have developed non-persistent gold nano-architectures (NAs) functionalised with human serum albumin (HSA) for the delivery of doxorubicin. Doxorubicin has been previously reported to be cytotoxic in DIPG cells. In this study, we have preclinically evaluated the cytotoxic efficacy of doxorubicin delivered through gold nanoarchitectures (NAs-HSA-Dox). We found that DIPG neurospheres were equally sensitive to doxorubicin and doxorubicin-loaded NAs. Colony formation assays demonstrated greater potency of NAs-HSA-Dox on colony formation compared to doxorubicin. Western blot analysis indicated increased apoptotic markers cleaved Parp, cleaved caspase 3 and phosphorylated H2AX in NAs-HSA-Dox treated DIPG neurospheres. Live cell content and confocal imaging demonstrated significantly higher uptake of NAs-HSA-Dox into DIPG neurospheres compared to doxorubicin alone. Despite the potency of the NAs in vitro, treatment of an orthotopic model of DIPG showed no antitumour effect. This disparate outcome may be due to the integrity of the blood-brain barrier and highlights the need to develop therapies to enhance penetration of drugs into DIPG.

Recent Advances in Understanding the Role of Autophagy in Paediatric Brain Tumours

Autophagy is a degradative process occurring in eukaryotic cells to maintain homeostasis and cell survival. After stressful conditions including nutrient deprivation, hypoxia or drugs administration, autophagy is induced to counteract pathways that could lead to cell death. In cancer, autophagy plays a paradoxical role, acting both as tumour suppressor—by cleaning cells from damaged organelles and inhibiting inflammation or, alternatively, by promoting genomic stability and tumour adaptive response—or as a pro-survival mechanism to protect cells from stresses such as chemotherapy. Neural-derived paediatric solid tumours represent a variety of childhood cancers with unique anatomical location, cellular origins, and clinical presentation. These tumours are a leading cause of morbidity and mortality among children and new molecular diagnostics and therapies are necessary for longer survival and reduced morbidity. Here, we review advances in our understanding of how autophagy modulation exhibits antitumor properties in experimental models of paediatric brain tumours, i.e., medulloblastoma (MB), ependymoma (EPN), paediatric low-grade and high-grade gliomas (LGGs, HGGs), atypical teratoid/rhabdoid tumours (ATRTs), and retinoblastoma (RB). We also discuss clinical perspectives to consider how targeting autophagy may be relevant in these specific paediatric tumours.

Classification of paediatric brain tumours by diffusion weighted imaging and machine learning

To determine if apparent diffusion coefficients (ADC) can discriminate between posterior fossa brain tumours on a multicentre basis. A total of 124 paediatric patients with posterior fossa tumours (including 55 Medulloblastomas, 36 Pilocytic Astrocytomas and 26 Ependymomas) were scanned using diffusion weighted imaging across 12 different hospitals using a total of 18 different scanners. Apparent diffusion coefficient maps were produced and histogram data was extracted from tumour regions of interest. Total histograms and histogram metrics (mean, variance, skew, kurtosis and 10th, 20th and 50th quantiles) were used as data input for classifiers with accuracy determined by tenfold cross validation. Mean ADC values from the tumour regions of interest differed between tumour types, (ANOVA P < 0.001). A cut off value for mean ADC between Ependymomas and Medulloblastomas was found to be of 0.984 × 10−3 mm2 s−1 with sensitivity 80.8% and specificity 80.0%. Overall classification for the ADC histogram metrics were 85% using Naïve Bayes and 84% for Random Forest classifiers. The most commonly occurring posterior fossa paediatric brain tumours can be classified using Apparent Diffusion Coefficient histogram values to a high accuracy on a multicentre basis.