A synthetic lethal approach to treating hereditary diffuse gastric cancer
Abstract: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome, characterised by loss of function in the CDH1 gene. Affected individuals suffer a 70 per cent lifetime risk of developing stomach cancer.
Loss of function mutations are difficult to exploit therapeutically, due to the lack of protein expression, and thus an obvious druggable target. However, synthetic lethality can be used to address this. Synthetic lethality describes vulnerable pathways that emerge following the loss of function in a gene, and these can be further disrupted through drug treatment to induce selective death in the target cells.
We have used a drug screening approach in isogenic cell lines to identify compounds that can selectively kill CDH1-/- cells, while leaving CDH1+/+ cells relatively unharmed. However, there is a need to apply these findings in more sophisticated preclinical models. To address this, a gastric organoid model of CDH1 loss has been established to better represent the stomach of an HDGC patient. A selection of promising compounds were validated in this gastric organoid model, and may lead to the development of new therapies for HDGC.
|Date||Tuesday, 24 November 2020|
|Time||12:00pm - 1:00pm|
|Location||Microbiology Seminar Room 208|
|Contact Name||Department of Biochemistry|