OS03.5.A Corelation between longitudinal t2 MRI radiomic primary texture feature values and radiation dose in non-tumoral regions of the brain in paediatric brain tumours

BACKGROUND Paediatric brain tumour survivors may have treatment toxicity associated with signal change on follow-up MRI. Quantitative MRI texture features can potentially be used as surrogates of the underlying tissue changes following radiation therapy. MATERIAL AND METHODS Longitudinal retrospective study in 51 paediatric primary brain tumours treated with photon (N=30) and proton (N=21) radiotherapy (RT). T2 MRI scans at baseline and multiple time point from the date of surgery to 2 years following radiotherapy were selected for the textural analysis. Scans were bias corrected, registered with the CT dose maps and with baseline scan for each patient using 3Dslicer. Regions of interest (ROI) of fixed diameter were drawn in 11 predetermined non-tumoral regions of brain including in peri-tumoural region (PTV). ROIs were placed in homogenous white/grey matter. Radiation dose was calculated in each of these 11 ROIs and texture features were extracted using pyradiomics. Data were analysed using machine learning and statistical analysis. General linear multivariate model was used to corelate primary texture features over period of 24 months and radiation dose, time, effect of dose*time together at each ROI separately. RESULTS There were Brainstem 4, Cerebellar19, Hemispheric cerebral 7 and Supratentorial midline 10 tumours. Median age at diagnosis was 8.26 years (range: 0–20). Median RT treatment dose was 28.52Gy (0-60Gy). Multivariate analysis shows significant corelation (p < 0.001) between radiation dose and longitudinal primary texture features in all 11ROIs. Time showed corelation with feature values only in 3 ROIs and dose* time showed corelation in 5ROIs. Primary (statistical) feature values showing consistent correlation with dose in all 11 ROIs over 24 months are total energy, 10%, 90%, energy, entropy, mean, median, and minimum. CONCLUSION Radiomic texture analysis is a promising modality to understand dose related textural changes in the normal part of brain in paediatric brain tumour patients treated with radiation therapy. Radiomic changes need to be related to neurological outcomes in future research.

T-type Calcium Channel Inhibitors Induce Apoptosis in Medulloblastoma Cells Associated With Altered Metabolic Activity

Medulloblastoma (MB) is the most common malignant paediatric brain tumour. In our previous studies, we developed a novel 3D assay for MB cells and screened of plasma membrane calcium channel modulators. These studies identified T-type (CaV3) channel inhibitors, mibefradil and NNC-55-0396 (NNC) as selective inhibitors of MB cell growth. Mibefradil was originally approved for treatment of hypertension and angina pectoris, and recently successfully completed a Phase I trial for recurrent high-grade glioma. NNC is an analogue of mibefradil with multiple advantages compared to mibefradil that makes it attractive for potential future clinical trials. In this study, we aimed to characterise the effect of mibefradil and NNC on MB cells and elucidate their mechanism of action. This study demonstrates that the induction of toxicity in MB cells is selective to T-type but not to L-type Ca2+ channel inhibitors. Addition of CaV3 inhibitors to vincristine sensitised MB cells to this MB chemotherapeutic agent, suggesting a synergistic effect. Furthermore, CaV3 inhibitors induced cell death in MB cells via apoptosis. Supported by proteomics data and cellular assays, apoptotic cell death was associated with reduced mitochondrial membrane potential and reduced ATP levels, which suggests that both compounds alter the metabolism of MB cells. This study offers new insights into the action of mibefradil and NNC and will pave the way to test these molecules or their analogues in pre-clinical MB models alone and in combination with vincristine to assess their suitability as a potential MB therapy.

MOMC-5. Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma

Background Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Clearly, there is an urgent need for improved, targeted therapies that minimize these harmful side effects. Methods We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB. Results Our analyses identified drugs targeting CDK4, CDK6, and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing Sonic Hedgehog and Group 3 patient-derived xenograft tumours, providing the first demonstration of its efficacy in MB. Conclusions Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.

Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma

Background Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects. Methods We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB. Results Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB. Conclusions Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.

Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead

The constitutive and dysregulated expression of the transcription factor MYCN has a central role in the pathogenesis of the paediatric brain tumour medulloblastoma, with an increased expression of this oncogene correlating with a worse prognosis. Consequently, the genomic and functional alterations of MYCN represent a major therapeutic target to attenuate tumour growth in medulloblastoma. This review will provide a comprehensive synopsis of the biological role of MYCN and its family components, their interaction with distinct signalling pathways, and the implications of this network in medulloblastoma development. We will then summarise the current toolbox for targeting MYCN and highlight novel therapeutic avenues that have the potential to results in better-tailored clinical treatments.

Longterm cognitive dysfunction in paediatric brain tumour survivors - the need for multifactorial risk screening

AimsIdentify common risk factors for longterm cognitive dysfunction in PBTS (paediatric brain tumour survivors) Examine how various paediatric cancer treatment modalities affect cognitive outcomes Consider baseline features which may increase the risk of cognitive dysfunction in PBTSMethodCurrent research into the neuropsychiatric sequelae of childhood brain tumours is limited, therefore review of the literature was conducted to identify research within this field.DatabasesGoogle Scholar - papers accessed via the University of Brighton or Sussex online libraryNICE HDAS - HMIC, AMED, MEDLINE, BNI, PsycINFO, CINAHL, Pubmed, EMBASE & EMCAREMendeley reference manager - papers for background readingSearch termsPICO(T) method - Population (Cancer Survivors), Intervention (Cancer Treatment), Comparison (Brain tumour), Outcome (Cognitive dysfunction) & Time (Childhood & adolescence) Boolean operators (AND/OR), truncation and wildcard search functions were also utilised.Inclusion criteria; no limits on date, study type or gender, however, study results were limited by age - as the research focus was restricted to children and adolescents.Excluded results; papers which did not meet inclusion criteria, duplicate studies, studies measuring non-cognitive cancer outcomes or investigating non-cortical tumours, non-English language studies with no available English translations.ResultCommon risk factors - certain tumour types (glioneuronal tumours or gliomas) or inner cortical tumour sites e.g. were more vulnerable to epileptogenesis. In particular, seizures which were prolonged and treatment-resistant were associated with a greater degree of cognitive dysfunction.Impact of various cancer treatment modalities - overall results understandably suggested that patients are more likely to develop cognitive deficits following brain tumour treatment. In particular, partial tumour resection (especially if epileptogenic), whole-brain irradiation, cranial radiotherapy and chemotherapy were more likely to impact cognitive function.Baseline features that may increase likelihood of cognitive dysfunction e.g. intellectual disability or education level were not noted in the reviewed literature.ConclusionCancer is one of the leading causes of global child mortality, and younger populations often present to paediatric oncology services with brain tumour involvement. Current childhood brain tumour research has begun to recognise that many young survivors develop into adulthood with cognitive sequelae impacting quality of life measures. However, existing evidence is also limited and requires further research to produce a standardised clinical tool for screening various risk factors which may increase longterm risk of cognitive dysfunction and subsequent difficulties with daily life.

Exploring evidence of fatigue in survivors of paediatric brain tumours: a systematic review

AimsAs the number of survivors of childhood brain tumor grows, fatigue is being increasingly recorded as a long-term consequence of both the cancer itself and the treatment received. Survivors of childhood brain tumour report more significant fatigue than children with other cancers, often impacting all aspects of life, including academic attainment, self-concept and social relationships with peers, leading to reduced health-related quality of life.This study aimed to systematically evaluate the evidence for fatigue in paediatric brain tumour survivors.MethodA systematic search using EMBASE, MEDLINE and PsycINFO identified 20 papers meeting the inclusion criteria. Scientific rigor was used throughout by following Scottish Intercollegiate Guidelines Network (2015) guidance for systematic reviews. Quality Assessment of Evidence Rating tool - Fatigue (QAERT) was developed with substantial inter-rater agreement found.Result19 of the 20 studies reviewed showed conclusive evidence of fatigue in survivors of paediatric brain tumour. One study offered adequate evidence that there was no difference in levels of fatigue in paediatric cancer survivors, including survivors of paediatric brain tumour, when compared to healthy controls. Three studies found that fatigue was worse in survivors of paediatric brain tumour when compared to survivors of other paediatric cancersConclusionThis review provides evidence for the presence of fatigue in survivors of paediatric brain tumour. However, the construct of fatigue was poorly defined throughout, with fatigue associated with physical effects of treatment and fatigue associated with long-term cognitive impairment not distinguished. This poor construct validity, coupled with a lack of comparison groups in 12 of the 20 studies, reduces the generalizability of the data and its usefulness for developing effective psychological interventions. Further research is needed, built on a clear fatigue construct definition, and including well defined exclusion criteria, to provide a sound basis for improving the quality of life of these children.