- PhD project, may also be considered for an Honours project
Uveal melanoma is the most common ocular cancer. Metastatic spread occurs in approximately 50% of cases, despite intervention at the primary disease stage. There are currently no effective treatments available for metastatic disease. The common genetic alterations that occur in uveal melanoma are different from those in cutaneous melanoma and targeted therapies developed for cutaneous melanoma are ineffective in uveal melanoma. A better understanding of the functional consequence of common uveal melanoma genetic alterations is required in order to identify potential therapeutic targets for its’ treatment. Monosomy of chromosome 3 is a common genetic alteration that is strongly associated with poor prognosis, however, the underlying mechanism of this and how chromosome 3 monosomy may influence therapeutic responses is poorly understood.
- To develop cell lines models representing different uveal melanoma genetic states associated with chromosome 3 monosomy
- Determine the biological consequences of chromosome 3 monosomy-associated alterations on cellular signalling and tumourgenicity
- Determine if chromosome 3 monosomy-associated changes impact therapeutic response to treatments currently being trailed or novel therapeutic targeting strategies identified through modelling and functional work.
This project will involve genetic engineering of cell lines through plasmid, siRNA and CRISPR/Cas9 based approaches. An array of molecular biology techniques including FACS analysis, proliferation/migration assays, qRT-PCR, western blotting and reverse-phase protein arrays will be used to characterise the functional consequences of these alterations. Drug screening in generated models and existing cell lines will also form part of this project. Basic bioinformatic analysis and immunohistochemical analysis of patient samples will also be utilised to confirm/translate results in the patient setting. Depending on the timeline of progress, there is also the possibility of testing cell line models in mice xenograft models to assess consequences on tumourigencity, metastasis and therapeutic response.
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