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Wilde, Megan (2023) The identification of targeting peptides and tumour associated antigens for the treatment and early detection of triple negative breast cancer. PhD thesis, University of Nottingham.

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Abstract

Breast cancer (BCa) is the most common type of non-cutaneous cancer globally. Despite advances in screening methods and treatment regimens, the malignancy leads to the most female cancer-related deaths each year. An aggressive subtype of breast cancer which often presents at a high histological grade is triple negative breast cancer (TNBC). TNBC is characterised by the absence of estrogen and progesterone receptor expression, as well as a lack of HER2 over-expression. TNBC currently has the worse prognosis among the molecular subtypes. However, early diagnosis and the development of targeted treatment may improve patient outcome.

Peptide-drug conjugates are an emerging class of targeted therapies that are increasing the efficacy of anticancer agents through tumour-specific delivery. This work focused on identifying small peptides which target TNBC cells for the subsequent development of a peptide-based drug delivery system. To identify small peptides which specifically target TNBC, next generation phage display was employed for the high throughput screening of a diverse, small peptide library against non-tumourigenic and TNBC cell lines. Next generation sequencing analysis led to the identification of 44 potential TNBC targeting peptide candidates. In vitro cellular uptake studies with the peptide candidates resulted in the prioritisation of two TNBC targeting small peptides for in vivo biodistribution studies and the subsequent development of TNBC targeted therapeutics.

Recent studies have highlighted the diagnostic potential of serum autoantibodies, which are produced in early carcinogenesis in response to tumour associated antigens. In this study, the presence of cancer-specific autoantibodies in TNBC patient serum samples was confirmed by flow cytometry and potential TNBC autoantibody antigens were identified using a serological proteome analysis approach. Following on from the identification of TNBC neoantigens, western blot analyses with overexpression lysate confirmed the presence of a novel TNBC autoantibody in patient sera. This highlighted the value of autoantibodies in early diagnostic screening, but also their potential use for targeted therapies when combined with novel delivery systems.

Overall, the work in this study has led to the discovery of TNBC associated antigens, their corresponding autoantibodies, and targeting small peptides for the development of early diagnostic tools and peptide-based targeted treatments with the potential to improve the prognosis and subsequent outcome for women with TNBC.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Allegrucci, Cinzia Gough, Kevin Dixon, James
Keywords:	Breast cancer; Tumour associated antigens; Peptides; Autoantibodies
Subjects:	R Medicine > RC Internal medicine > RC 254 Neoplasms. Tumors. Oncology (including Cancer)
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID:	73855
Depositing User:	Wilde, Megan
Date Deposited:	19 Jul 2023 04:40
Last Modified:	19 Jul 2023 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/73855

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