Discover novel therapies for human Uveal Melanoma

Abstract

Uveal melanoma (UM) is the most common intraocular malignancy in adults, with a high propensity for metastasis, particularly to the liver. Non-pharmacological approaches remain the gold standard for treating the primary tumour. While these treatments have improved tumour control and may preserve the eye and vision, they are still largely ineffective in preventing or managing UM metastasis, which occurs in over 50% of patients. Consequently, the prognosis for metastatic UM remains poor.

Common cancer receptor targets such as EGFR, VEGF and HDAC, as well as UM-specific targets such as GNAQ/11 and BAP1 have all been extensively studied and trialled in UM both in in vitro and in vivo studies. However, their effects have not been proven to improve patient outcomes causing concern for patient prognosis. In this thesis, I re-examine the well-known EGFR receptor family – specifically the HER2 isoform to shed light on its effect in UM.

Different modes of cell death can offer valuable insights into potential treatment strategies for UM. A literature review was conducted to further explore the relationship between autophagy and key cellular components, such as mitochondria and the endoplasmic reticulum (ER), focusing on processes like ER stress and the unfolded protein response (UPR), and their potential impact on cancer treatment strategies.

The novel compound UC2288 is also tested in UM primary, metastatic and patient tumour-derived ex vivo cell lines to assess its anti-cancer effect. UC2288 was proven to cause potent cell viability reduction, ROS production, mitochondria health disruption and ER stress production in a tumour-specific manner. UC2288 also extend its effect to prevent cell invasion and disrupt reproduction to prevent metastatic tumour formation. It is hypothesised UC2288 induces anti-UM effect partly through inducing significant amount of ER stress resulting in the unfolded protein response and causing autophagic cell death.