Pre-clinical cancer studies: mTOR signalling mechanisms as a therapeutic target

Hunt, David K. 2014. Pre-clinical cancer studies: mTOR signalling mechanisms as a therapeutic target. MPhil Thesis, Cardiff University. Item availability restricted.

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Abstract

Defects in mechanistic Target of Rapamycin Complex 1 (mTORC1) signalling are the cause of a number of heritable human diseases such as Tuberous Sclerosis Complex, Neurofibromatosis and Birt-Hogg-Dubé syndrome. Mutations in signalling components in the mTORC1 signalling pathway are also present in a significant number of sporadic cancers, such as bladder and renal cancer. A number of mTORC1-driven features arise as a result of these mutations that offer opportunities to develop selective therapeutic strategies that exploit such differences. One such variation that has been suggested is that cells with upregulated mTORC1 activity have elevated levels of Endoplasmic Reticulum (ER) stress. The clinically approved HIV protease inhibitor, Nelfinavir, has been suggested to exacerbate ER stress. The aim of this project was to examine whether Nelfinavir could be used to exploit existing basal elevations in ER stress in cells with aberrant mTORC1 signalling to selectively induce cell death. In addition to assessing the therapeutic potential of this drug treatment strategy, this project sought to further examine interactions between mTORC1 signalling and autophagy, a major survival component of the ER stress response. The results of experimentation demonstrated the increased susceptibility of TSC deficient cells to ER stress and increased levels of cell death following Nelfinavir treatment. Research also identified a complex signalling pathway in which mTORC1 both regulates, and is regulated by the autophagy protein ULK1. Following observations of increased autophagy after treatment with Nelfinavir, a novel combinatorial therapeutic strategy was formulated that sought to exacerbate ER stress in conjunction with autophagy inhibition. Of clinical relevance, this novel strategy (using Food and Drug administration (FDA)-approved drugs) significantly and selectively induced cell death in TSC2-deficient cell lines and thus offers a promising avenue for future trials and research.

Item Type:	Thesis (MPhil)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Funders:	AICR
Date of First Compliant Deposit:	30 March 2016
Last Modified:	24 Oct 2023 12:55
URI:	https://orca.cardiff.ac.uk/id/eprint/59221

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