Targeting PI3-kinase signalling in genetically engineered mouse models of intestinal cancer

Zeiger, Lucas (2022) Targeting PI3-kinase signalling in genetically engineered mouse models of intestinal cancer. PhD thesis, University of Glasgow.

Abstract

PI3-Kinase signalling is frequently dysregulated in human colorectal cancer (CRC), but its role in cancer initiation, progression to malignant disease, and subsequent impact upon response to treatment are not fully understood.

In order to address these ongoing clinical concerns, I have developed and characterised a novel collection of genetically engineered mouse models of intestinal cancer, driven by hyperactivation of the PI3-Kinase signalling pathway. Targeted expression of oncogenic Pik3caH1047R or deletion of the negative regulator Pten in the intestinal epithelium result in rampant acceleration of tumourigenesis in models driven by loss of the tumour suppressor Apc. Moreover, PI3-Kinase and Kras mutations, which co-occur in human CRC, strongly synergise to drive intestinal tumour initiation and alter the transcriptional landscape.

Using these advanced preclinical models as a platform, I have now interrogated the therapeutic impact of targeted inhibition of key PI3-Kinase/MAPK/mTOR signalling nodes. From these studies, a number of key observations were made, in particular, oncogenic Kras mutations drives resistance to PI3-Kinase alpha inhibition, irrespective of concomitant PI3-Kinase mutation. Moreover, models which were driven by activation of PI3-Kinase signalling in the absence of Kras mutation were acutely sensitive to mTORC1 inhibition, with Kras mutation again seen to drive resistance. The therapeutic approaches tested here indicate that combination approaches may be the most effective means of driving therapeutic benefit in CRC, particularly in the context of KRAS mutation.

Through the research described here, I have developed a set of mouse models which will hopefully aid the development of novel therapeutic approaches for a large proportion of CRC patients, particularly those for whom current therapeutic options are limited.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Sansom, Professor Owen
• Date of Award: 2022
• Depositing User: Theses Team
• Unique ID: glathesis:2022-83180
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 11 Oct 2022 12:22
• Last Modified: 11 Oct 2022 12:23
• Thesis DOI: 10.5525/gla.thesis.83180
• URI: https://theses.gla.ac.uk/id/eprint/83180