Aldehyde dehydrogenases (ALDHs) catalyse the oxidation and detoxification of reactive endogenous and exogenous aldehydes into carboxylic acids via NAD+ coupled reduction. ALDH1 has been widely studied and is considered a marker of cancer stem cells (CSCs) and has been shown to be predictive of poor clinical outcome. Increased expression of cytosolic ALDH has been implicated as a mechanism whereby tumour cells may escape the lethality of cytotoxic anticancer alkylating agents, such as cyclophosphamide and related congeners. An improved understanding the role ALDHs play within the tumour microenvironment and stem cell niche is crucial for unravelling their potential for biomarker and drug discovery strategies.
The aims of the PhD project are: (i) To synthesise and biologically evaluate ALDH agonists and antagonists with potential to treat ocular, cancer and other diseases (ii) To probe and/or investigate the expression of ALDHs in mono-layered and multilayered (spheroids) cancer cell lines, co-culture systems (e.g. cancer-associated fibroblasts), and clinical samples derived from cancer patients. (iii) To investigate ALDH expression in (cancer) stem cells (iv) To investigate the effect of ALDH-targeting inhibitors as single agents or in combination with targeted cancer therapies