Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
The Chemoprevention and Treatment of Hereditary Diffuse Gastric Cancer Parry Guilford, Augustine Chen, Bryony Telford, Henry Beetham, Chris Hakkaart, Andrew Single, Tom Brew and Tanis Godwin. Cancer Genetics Laboratory, Centre for Translational Cancer Research, University of Otago, Dunedin, New Zealand Hereditary Diffuse Gastric Cancer (HDGC) is caused by germline mutation of the gene (CDH1) that encodes the cell-to-cell adhesion protein E-cadherin. Although a rare disease, its early age of onset, over-representation in M , and the realistic potential to largely eliminate HDGC-associated death, āori increases its clinical significance and importance. Current clinical guidelines recommend prophylactic gastrectomy for mutation carriers from the age of about 20yrs upwards. Although most people who have undergone this procedure are satisfied with their choice, there is the expectation that future generations will be able to consider additional safe, non-surgical options. To this end, and to develop targeted treatments for advanced diffuse gastric cancer and lobular breast cancer, we are taking a synthetic lethal approach to identify and develop drugs that target E-cadherin-deficient cells. To identify the vulnerabilities created by E-cadherin loss, we have conducted a genome-wide siRNA knockdown screen, a 4000 compound known drug screen and a screen of the WEHI’s 114,000 compound WECC library in isogenic MCF10a cell lines with and without E-cadherin expression. The functional screen has shown that GPCR signalling proteins are highly enriched amongst the candidate synthetic lethal proteins, as well as many protein classes associated with microtubule and cystoskeletal function. Drug classes that show increased activity against the E-cadherin-deficient cells include the JAK inhibitor LY2784544, the tyrosine kinase inhibitor Crizotinib and several HDAC inhibitors. The WECC library screen has identified a further 88 novel compounds that show synthetic lethality. This finding paves the way for targeted use of several existing cancer drugs as well as the development of novel drugs and drug combinations for the chemoprevention and treatment of Ecadherin-negative cancers.