Pharmacological Inhibition of polysialyltransferase ST8SiaII Modulates Tumour Cell Migration

YesPolysialic acid (polySia), an α-2,8-glycosidically linked polymer of sialic acid, is a developmentally regulated posttranslational modification predominantly found on NCAM (neuronal cell adhesion molecule). Whilst high levels are expressed during development, peripheral adult organs do not express polySia-NCAM. However, tumours of neural crest-origin re-express polySia-NCAM: its occurrence correlates with aggressive and invasive disease and poor clinical prognosis in different cancer types, notably including small cell lung cancer (SCLC), pancreatic cancer and neuroblastoma. In neuronal development, polySia-NCAM biosynthesis is catalysed by two polysialyltransferases, ST8SiaII and ST8SiaIV, but it is ST8SiaII that is the prominent enzyme in tumours. The aim of this study was to determine the effect of ST8SiaII inhibition by a small molecule on tumour cell migration, utilising cytidine monophosphate (CMP) as a tool compound. Using immunoblotting we showed that CMP reduced ST8iaII-mediated polysialylation of NCAM. Utilizing a novel HPLC-based assay to quantify polysialylation of a fluorescent acceptor (DMB-DP3), we demonstrated that CMP is a competitive inhibitor of ST8SiaII (Ki = 10 μM). Importantly, we have shown that CMP causes a concentration-dependent reduction in tumour cell-surface polySia expression, with an absence of toxicity. When ST8SiaII-expressing tumour cells (SH-SY5Y and C6-STX) were evaluated in 2D cell migration assays, ST8SiaII inhibition led to significant reductions in migration, while CMP had no effect on cells not expressing ST8SiaII (DLD-1 and C6-WT). The study demonstrates for the first time that a polysialyltransferase inhibitor can modulate migration in ST8SiaII-expressing tumour cells. We conclude that ST8SiaII can be considered a druggable target with the potential for interfering with a critical mechanism in tumour cell dissemination in metastatic cancers.Yorkshire Cancer Research; EPSRC; Association for International Cancer Research; Jordanian Government PhD scholarshi

Synthesis of Recommendations From 25 Countries and 31 Oncology Societies: How to Navigate Through Covid-19 Labyrinth

Introduction: Pandemic COVID-19 is an unexpected challenge for the oncological community, indicating potential detrimental effects on cancer patients. Our aim was to summarize the converging key points providing a general guidance in order to support decision making, pertaining to the oncologic care in the middle of a global outbreak. Methods: We did an international online search in twenty five countries that have managed a surge in cancer patient numbers. We collected the recommendations from thirty one medical oncology societies. Results: By synthesizing guidelines for a) oncology service delivery adjustments, b) general and specific treatment adaptations, and c) discrepancies from guidelines comparison, we present a clinical synopsis with the forty more crucial statements. A Covid-19 risk stratification base was also created in order to obtain a quick, objective patient assessment and a risk-benefit evaluation on a case-by-case basis. Conclusions: In an attempt to face these complex needs and due to limited understanding of COVID-19, a variability of recommendations based on general epidemiological and infectious disease principles rather than definite cancer-related evidence has evolved. Additionally, the absence of an effective treatment or vaccine requires the development of cancer management guidance, capitalizing on comprehensive COVID-19 oncology experience globally

Polysialic acid sustains cancer cell survival and migratory capacity in a hypoxic environment

Polysialic acid (polySia) is a unique carbohydrate polymer expressed on the surface of NCAM (neuronal cell adhesion molecule) in a number of cancers where it modulates cell-cell and cell-matrix adhesion, migration, invasion and metastasis and is strongly associated with poor clinical prognosis. We have carried out the first investigation into the effect of polySia expression on the behaviour of cancer cells in hypoxia, a key source of chemoresistance in tumours. The role of polysialylation and associated tumour cell migration and cell adhesion were studied in hypoxia, along with effects on cell survival and the potential role of HIF-1. Our findings provide the first evidence that polySia expression sustains migratory capacity and is associated with tumour cell survival in hypoxia. Initial mechanistic studies indicate a potential role for HIF-1 in sustaining polySia-mediated migratory capacity, but not cell survival. These data add to the growing body of evidence pointing to a crucial role for the polysialyltransferases (polySTs) in neuroendocrine tumour progression and provide the first evidence to suggest that polySia is associated with an aggressive phenotype in tumour hypoxia. These results have significant potential implications for polyST inhibition as an anti-metastatic therapeutic strategy and for targeting hypoxic cancer cells

Evaluation of quality of life outcomes following palliative radiotherapy in bone metastases: A literature review

Purpose: To assess the quality of life (QoL) following palliative radiotherapy (RT) in patients with painful bone metastases. Methods: A literature search limited to English-written publications was carried out, through the Cochrane Central Register of Controlled Trials (November 2018), OvidSP and PubMedCentral (1940-November 2018) databases. Subject headings and keywords included “quality of life”(QoL), “bone metastases”, “palliative therapy”, “pain” and “radiotherapy”. Original articles, literature reviews, trials and meta-analyses revealing alterations in QoL post-RT using ratified measuring tools were examined. Studies referring to other types of metastases (e.g. brain metastases), or to other types of palliative therapy (e.g. the use of bisphosphonates alone), or focusing only on pain, or even reporting QoL only before or only after the use of RT were excluded. Results: Twenty four articles were selected from a total of 1360 articles. Seven trials proceeded to patients’ randomization. The most commonly used tool to evaluate QoL was EORTC, followed by Brief Pain Inventory (BPI) and Edmonton Symptom Assessment System (ESAS) questionnaires. All studies showed improvement in symptoms and functional interference scores after RT. The QoL between responders (Rs) and non-responders (NRs) has been juxtaposed in 10 studies. Rs had a significant benefit in QoL in comparison with the NRs. Conclusion: Palliative radiotherapy in painful bone metastases improves responders’ (Rs) QoL. © This work by JBUON is licensed under a Creative Commons Attribution 4.0 International License

Benign intracranial lesions-radiotherapy: An overview of treatment options, indications and therapeutic results

Background: Radiation Therapy (RT) is an established treatment option for benign intracranial lesions. The aim of this study is to display an update on the role of RT concerning the most frequent benign brain lesions and tumors.Methods: Published articles about RT and meningiomas, Vestibular Schwannomas (VSs), Pituitary Adenomas (PAs), Arteriovenous Malformations (AVMs) and craniopharyngiomas were reviewed and extracted data were used.Results: In meningiomas RT is applied as an adjuvant therapy, in case of patientrefusing surgery or in unresectable tumors. The available techniques are External Beam RT (EBRT) and stereotactic ones such as Stereotactic Radiosurgery (SRS), Fractionated Stereotactic RT (FSRT), Intensity Modulated RT (IMRT) and proton-beam therapy. The same indications are considered in PAs, in which SRS and FSRT achieve excellent tumor control rate (92-100%), acceptable hormone remission rates (>50%) and decreased Adverse Radiation Effects (AREs). Upon tumor growth or neurological dete-rioration, RT emerges as alone or adjuvant treatment against VSs, with SRS, FSRT, EBRT or proton-beam therapy presenting excellent tumor control growth (>90%), facial nerve (84-100%), trigeminal nerve (74-99%) and hearing (>50%) preservation. SRS poses an effective treatment modality of cer-tain AVMs, demonstrating a 3-year obliteration rate of 80%. Lastly, a combination of microsurgery and RT presents equal local control and 5-year survival rate (>90%) but improved toxicity profile compared to total resection in case of craniopharyngiomas.Conclusion: RT comprises an effective treatment modality of benign brain and intracranial lesions. By minimizing its AREs with optimal use, RT projects as a potent tool against such diseases. © 2020 Bentham Science Publishers

Radiation-induced oral mucositis in head and neck cancer patients. Five years literature review

Backround: Radiation-induced oral mucositis consists of a series of relatively frequent side effects after head and neck cancer radiotherapy and has an adverse impact on both regular treatment process and the quality of life of patients. Objective: The purpose of the present review is to optimize the current management of radiation-in-duced oral mucositis in head and neck cancer patients. Methods: PubMed database research was performed on articles published since 2015 that demons-trated efficacy in the management of radiation-induced oral mucositis in head and neck cancer pa-tients.The study selection included observational, prospective, comparative, randomized, dou-ble-blind, placebo-controlled or uncontrolled, and retrospective studies, as well as systematic reviews and metanalyses. Results: From the 931 citations obtained from the search, only 94 articles met the inclusion crite-ria, including mucosal protectants, anti-inflammatory agents, growth factors, and various miscellaneous and natural agents. Several methods, including both pharmacological and natural agents, have been proposed for the management of oral mucositis. In addition to the already known interventions with strong evidence, according to the Multinational Association of Supportive Care in Cancer and he International Society of Oral Oncology guidelines, further agents have been used. However, a great number of them lack clear evidence, which surely requires the design of more controlled clinical trials for a better assessment of the ideal methods. Conclusion: The management of oral mucositis constitutes an active area of research. In light of these results, it is aimed to illustrate those treatment strategies that are most effective regarding the treatment approach of oral mucositis. © 2021 Bentham Science Publishers