Download The Chemoprevention and Treatment of Hereditary Diffuse Gastric

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.