The Use of Biomaterials in Internal Radiation Therapy

Radiotherapy has become one of the most prominent and effective modalities for cancer treatment and care. Ionising radiation, delivered either from external or internal sources, can be targeted to cancerous cells causing damage to DNA that can induce apoptosis. External beam radiotherapy delivers either photon radiation (x-rays or gamma rays) or particle radiation (neutrons or protons) in a targeted manner to specific tumour locations. Internal radiotherapy involves placing radioactive sources within the body to deliver localised doses of therapeutic radiation to tumours using short range radionuclides. Biomaterials have been developed to allow more precise targeting of radiotherapy in order to reduce toxicity to surrounding healthy tissues and increase treatment efficacy. These unique biomaterials have been developed from polymers, glasses and ceramics. Polymeric materials have been used to both displace healthy tissue from tumours receiving radiation, and to deliver radioactive sources into the body. These polymers can respond to various stimuli, such as radiation or reactive oxygen species, to deliver therapeutic payloads to target tissue during or post radiotherapy. Glass-based biomaterials doped with radionuclides have also been developed to provide in situ radiotherapy. Novel biomaterials that can enhance the synergistic effect of other treatment modalities, such as chemotherapy and immunotherapy, continue to be developed. Theranostic materials that are capable of providing diagnostic information whilst simultaneously delivering a therapeutic effect to enhance radiotherapy are also briefly reviewed

Chemical modulation of autophagy as an adjunct to chemotherapy in childhood and adolescent brain tumors

Brain tumors are the leading cause of cancer-related death in children and are the most challenging childhood cancer in relation to diagnosis, treatment, and outcome. One potential novel strategy to improve outcomes in cancer involves the manipulation of autophagy, a fundamental process in all cells. In cancer, autophagy can be thought of as having a “Janus”-like duality. On one face, especially in the early phases of cancer formation, autophagy can act as a cellular housekeeper to eliminate damaged organelles and recycle macromolecules, thus acting as tumor suppressor. On the other face, at later stages of tumor progression, autophagy can function as a pro-survival pathway in response to metabolic stresses such as nutrient depravation, hypoxia and indeed to chemotherapy itself, and can support cell growth by supplying much needed energy. In the context of chemotherapy, autophagy may, in some cases, mediate resistance to treatment. We present an overview of the relevance of autophagy in central nervous system tumors including how its chemical modulation can serve as a useful adjunct to chemotherapy, and use this knowledge to consider how targeting of autophagy may be relevant in pediatric brain tumors

Preservation of whole antibodies within ancient teeth

Archaeological remains can preserve some proteins into deep time, offering remarkable opportunities for probing past events in human history. Recovering functional proteins from skeletal tissues could uncover a molecular memory related to the life-history of the associated remains. We demonstrate affinity purification of whole antibody molecules from medieval human teeth, dating to the 13th – 15th centuries, from skeletons with different putative pathologies. Purified antibodies are intact retaining disulphide-linkages, are amenable to primary sequences analysis, and demonstrate apparent immunoreactivity against contemporary EBV antigen on western blot. Our observations highlight the potential of ancient antibodies to provide insights into the long-term association between host immune factors and ancient microbes, and more broadly retain a molecular memory related to the natural history of human health and immunity

Molecular insights into an ancient form of Paget’s disease of bone

Paget’s disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals over 55 years of age. PDB like changes have been reported in archaeological remains as old as Roman, although accurate diagnosis and natural history of the disease is lacking. Six skeletons from a collection of 130 excavated at Norton Priory in the North West of England, which dates to medieval times, show atypical and extensive pathological changes resembling contemporary PDB affecting up to 75% of individual skeletons. Disease prevalence in the remaining collection is high, at least 16% of adults, with age at death estimations as low as 35 years. Despite these atypical features, paleoproteomic analysis identified sequestosome 1 (SQSTM1) or p62, a protein central to the pathological milieu of PDB, as one of the few non69 collagenous human sequences preserved in skeletal samples. Targeted proteomic analysis detected >60% of the ancient p62 primary sequence with western blotting indicating p62 abnormalities including in dentition. Direct sequencing of ancient DNA excluded contemporary PDB associated SQSTM1 mutations. Our observations indicate that the ancient p62 protein is likely modified within its C-terminal ubiquitin associated (UBA) domain. Ancient microRNAs were remarkably preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression consistent with that reported in contemporary PDB associated bone tumours. Our work displays the use of proteomics to inform diagnosis of ancient disease such as atypical PDB, which has unusual features presumably potentiated by as yet unidentified environmental or genetic factors

Identification of novel therapeutic targets for histone 3 mutated children’s brain tumour, using unique tumour cell surface proteomic signatures

Abstract Aims Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they continue to carry a very poor prognosis. These brain tumours are now defined by mutations affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome (cell membrane proteins) signature. Method We therefore analysed the cell surface proteomics of pHGG and DIPG, in order to identify novel targets for therapy. We have at first isolated the cell membrane fractions from a range of patient cells carrying different histone 3 mutations (G34R, G34V), relative to wild type histone 3. A comparative quantitative mass-spectrometry analyses of these cell surface membrane fractions is then performed. Results The results obtained to date demonstrated unique differential cell membrane expression patterns which correlated to specific mutation type. For example, increased expression of Ras-related proteins Rab-3, Rab-3D is detected only in histone H3.3-G34R mutated cell line in comparison. Conclusion Identification and analyses of these unique cell membrane proteins’ association with specific in H3.3 mutation in pHGG, will help to identify precise mutation specific therapeutic targets, benefiting the patients to receive therapy based on tumour’s molecular signature. </jats:sec

HGG-25. IDENTIFYING YB1 AND NPM1 AS PART OF THE MUTANT HISTONE 3 PROTEIN INTERACTOME IN H3 MUTATED PHGG

 Paediatric high-grade gliomas (pHGG) are the leading cause of childhood cancer deaths, accounting for over 40% of deaths in the UK. pHGG tumours harbour histone H3 mutations, defining 50% of pHGG cases.   We have focused on YB-1 and Nucleophosmin 1 (NPM1). YB-1, is multifunctional transcription factor  as interacting proteins.  Our aim is to analyse the role of YB-1 and NPM1 in H3 mutated pHGG, in order to identify targeted therapeutic options for these difficult to treat tumours.</p