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Enhancing the effect of Tumour necrosis factor - Related Apoptosis Inducing Ligand (TRAIL) in malignant pleural mesothelioma

Alrifai, Doraid; (2020) Enhancing the effect of Tumour necrosis factor - Related Apoptosis Inducing Ligand (TRAIL) in malignant pleural mesothelioma. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Malignant pleural mesothelioma (MPM) is a cancer which originates from the pleura, a layer lining the lungs. The prognosis is bleak as patients who receive standard of care chemotherapy have a median overall survival of approximately 12 months. Tumour necrosis factor - Related Apoptosis Inducing Ligand (TRAIL) is a protein involved in activating the extrinsic apoptosis pathway via engagement with death receptors located on the surface of cells. Following activation of this intracellular cascade, cells undergo apoptosis. We have previously shown that when MPM cells have loss of function mutations in BRCA-1 associated protein 1 (BAP1) they sensitise to TRAIL. BAP1 is involved in several other key cellular functions such as DNA damage response, cell cycle regulation, cell growth and differentiation. Moreover, TRAIL selectively seeks out transformed cells and activates apoptosis making this a therapy of great interest. Methods of utilising TRAIL include recombinant TRAIL (rTRAIL) or through lentiviral transduction of mesenchymal stromal cells expressing TRAIL on their surface (MSCTRAIL). The work I present in this thesis attempts to amplify the effect of TRAIL exploiting key areas that govern its function. I show in vitro that BAP1 plays a non-critical role in homologous recombination and by attempting to exploit this through synthetic lethality using PARP inhibition, a marginal differential response is seen between mutant and wild type cell lines. In addition, I explore the relationship between TRAIL and the immune system. I go on to show that a strong anti-tumour synergistic relationship exists between host immune cells and TRAIL, validated through the development of a syngeneic platform using pleural effusion derived cell lines and matched immune cells from the same patient. Finally, I present work evaluating the role of heat shock protein 90 (HSP90) inhibition and TRAIL confirming a synergistic relationship between the two.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Enhancing the effect of Tumour necrosis factor - Related Apoptosis Inducing Ligand (TRAIL) in malignant pleural mesothelioma
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
Keywords: mesothelioma, trail
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10113766
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