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Title: Preclinical testing of a targeted TRAIL therapeutic for bone sarcoma
Authors: Gamie, Zakareya Esame Khalil
Issue Date: 2020
Publisher: Newcastle University
Abstract: Background: TNF-related apoptosis-inducing ligand (TRAIL) can induce cell death in cancer cells after binding to its TRAIL receptors [TRAILR, Death Receptor 4 (DR4) and Death Receptor 5 (DR5)] while sparing non-malignant cells. The application of TRAIL provides an approach that can potentially overcome drug resistance and toxicity associated with high doses of conventional therapies. It could be administered alone or in combination with conventional therapies and, therefore, may offer a promising new approach to bone sarcoma treatment. Enhancing the cytotoxic effect of TRAIL involves targeting a tumour associated antigen (TAA). Here, the aim was to characterise bone sarcoma cells for TRAILR expression and to assess the effectiveness, both in vitro and in vivo of a novel TRAIL construct, neural/glial antigen 2 (NG2) targeted TRAIL (ScFvNG2-Fc-scTRAIL). Methods: Bone sarcoma cell lines were characterised for TRAILR and NG2 expression on RNA and protein level. Together with non-malignant cell lines, they were exposed to the novel TRAIL therapeutic (ScFvNG2-Fc-scTRAIL) in vitro and then tested in vivo in a newly developed xenograft model of dedifferentiated chondrosarcoma. Results: Surface DR5 was expressed in all cell lines examined (very high: HT1080, MG63; moderate: SW153, U2OS, TC71). NG2 was also expressed (very high: SW1353, MG63; moderate: U2OS, HT1080). ScFvNG2-Fc-scTRAIL demonstrated enhanced cytotoxicity in DR5- and NG2-expressing cell lines (MG63>HT1080>U2OS), which increased with doxorubicin and was also found in vivo when engrafting a luciferase expressing HT1080 cell line in a dedifferentiated chondrosarcoma mouse model. Conclusion: I demonstrate that a novel targeted TRAIL therapeutic, ScFvNG2-FcscTRAIL, has a selective and significant cytotoxic effect on cell lines expressing both cell surface DR5 and NG2, and these cytotoxic effects can be enhanced further with doxorubicin. Such combinations could minimise the risk of treatment failure due to drug resistance, a common problem of single agent approaches. Furthermore, these findings provide a framework for the clinical development of ScFvNG2-Fc-scTRAIL and could potentially be used in the neoadjuvant setting, which would be a shift from the usual convention of prioritising excision of the sarcoma.
Description: PhD Thesis
Appears in Collections:Northern Institute for Cancer Research

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