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Synergistic treatment of lung cancer with genetically modified cell therapy and chemotherapy

Kolluri, KK; (2016) Synergistic treatment of lung cancer with genetically modified cell therapy and chemotherapy. Doctoral thesis , UCL (University College London).

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Synergistic treatment of lung cancer with genetically modified cell therapy and chemotherapy-KOLLURI.pdf
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Abstract

Lung cancer and malignant pleural mesothelioma (MPM) carry a high mortality. Conventional therapies are ineffective in their treatment and there is a need to develop novel therapies. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic agent that triggers the extrinsic death pathway selectively in cancer cells. Mesenchymal stem cells (MSCs) are a type of bone marrow-derived stem cell that have been widely shown to home to and to infiltrate areas of the tumour microenvironment. This homing capacity can be exploited to deliver pro-apoptotic agents, including TRAIL, straight into the tumour micro-environment. Earlier studies show cancers can be treated with TRAIL-expressing MSCs (MSC-flT cells). However, some cell lines are resistant to MSC-flT cells. This study aimed to increase the efficiency of tumour cell killing using MSCs that are engineered to express TRAIL. This study investigates if cancer cell-killing by MSC-flT cells could be enhanced for the treatment of TRAIL-resistant cancers. The aims of this study were to increase the tumour cell-killing efficiency of MSCs engineered to express TRAIL by identifying whether the full-length or soluble form of TRAIL expressed by MSCs is superior in tumour cell killing, whether cancer cell-killing by MSC-flT cells can be increased by combining them with novel chemotherapeutic agents and to identify a biomarker to predict sensitivity to TRAIL. Cancer cell-killing by MSCs expressing full-length TRAIL was superior to that of MSCs expressing the shortened soluble form of TRAIL. MSC-flT cells showed a synergistic cancer killing affect when combined with novel chemotherapeutic agents. In collaboration with McDermott’s laboratory in the Wellcome Trust Sanger Institute, it was found that BAP1-mutated MPM cells are sensitive to TRAIL. This was validated by knock-in and knockdown experiments. It was shown that BAP1-mutated tumours are sensitive to TRAIL in vivo. Further work was done to delineate the mechanism of BAP1-induced TRAIL resistance. The deubiquitinating function of BAP1 and its nuclear localization were shown to be required for TRAIL resistance. This indicates that loss of function of BAP1 is a biomarker for TRAIL sensitivity.

Type: Thesis (Doctoral)
Title: Synergistic treatment of lung cancer with genetically modified cell therapy and chemotherapy
Event: UCL
Language: English
Keywords: Mesenchymal stem cells, TRAIL, Cell therapy, Cancer, BAP1
UCL classification: 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 > Div of Medicine > Respiratory Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/1485809
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