Project: The identification of new drugs for the treatment and prevention of diffuse gastric cancer using high throughput compound screening approach
By Bryony J. Telford
Many tumours can be treated with drugs that specifically target the cancer cells. These drugs target specific proteins overexpressed in the malignant tissue. Hereditary Diffuse Gastric Cancer however is characterised by loss of E-cadherin, meaning that the protein is not present to be targeted using this conventional therapy. To circumvent this problem, we have utilised ‘synthetic lethality’. This describes a situation where loss of two specific proteins causes cells to die, but loss of only one is survivable. In this research we searched for proteins with a synthetic lethal relationship to E-cadherin, that is, proteins that caused only E-cadherin negative cells to die when they were inactivated. This is an exciting approach to cancer therapy and may provide a way to specifically destroy E-cadherin negative diffuse gastric cancer cells without harming normal tissue.
To find these proteins, we inactivated each of 18,000 proteins in two human cell lines that were identical except for one difference – one had E-cadherin and the other didn’t. We then measured cell viability to determine which proteins killed the E-cadherin negative cells and not the normal cells. Our screen revealed a class of cell surface receptors, the G-protein coupled receptors, which were often synthetic lethal to E-cadherin negative cells. We now plan to develop drugs to target these proteins to prevent the development of advanced cancer in HDGC patients, providing an alternative to prophylactic gastrectomy.
To take advantage of drugs currently used to treat human disease we also tested 4,000 FDA approved drugs in our E-cadherin positive and negative cell lines. Again, we searched for drugs that killed the E-cadherin negative cells without harming the normal cells. Five different drugs targeting similar proteins – the histone deacetylases – all caused a synthetic lethal effect. We are now testing these in combination with other clinically used treatments to identify the most effective drugs to continue development in more complex experimental systems. Our goal is to start human trials in 3-5 years.