A new take on cancer therapy: Developing inhibitors of activation induced cytidine deaminase (AID)

Kreft er sykdommer som utvikler som en konsekvens av endringer i genererer som kontrollerer cellevekst og vevsorganiseringen slik at enkelte celler får en vekstfordel. Utvikling av en kreftsvulst, tumor evolusjon, kan ta mange år og cellene vil gjennom denne tiden akkumulere nye genforandringer i et rasende tempo. Denne prosessen fremskynder også fremvekst av behandlingsresitens. Målet med dette EUROSTARS-prosjektet er å utvikle en ny type medisin som kan hemme tumoruevolusjon og dermed hindre fremvekst av behandlingsresistente kloner.

OUTCOMES: • (CYTURA) Cellular models established. Lead compunds are identified and tested in cell culture experiments and toc performed in the mouse model at INNOS. • (INNOS) 3D organoid lymphoma model established. • (INNOS) P53-knockout/AID-overexpressing transgenic lymphoma mouse model established. • (UIO) UNG//MSH2-knockout-AID overexpressing transgenic lymphoma mouse model established. • (INNOS) transplant AID-overexpression mouse model established.

LEMONAID will deliver AIDIs, a new class of drugs that address cancer through prevention, by preventing cancer recurrence after treatment, and by preventing its initial occurrence from a healthy state. The drugs will be inhibitors of AID (activation induced cytidine deaminase), and in the first instance will be developed as an add-on drug to prevent cancer relapse in Diffuse Large B-Cell Lymphoma (DLBCL). At the end of LEMONAID, lead candidates will be ready to enter GLP-toxicity evaluation. The main aim of the Norwegian contribution is to develop novel in vitro and in vivo AID overexpression and lymphoma models. These models will be used in WP2, WP3 and WP4 for compound screening, efficacy testing and for biomarker development. OUTCOMES: Outcomes of this WP will be the following selection of in vitro and in vivo mouse models: 1. In vitro – AID activated mouse- and human-derived B-cell and models 2. In vitro - 3D patient-derived lymphoma organoid models 3. In vivo - transgenic AID-overexpressing TP53-knock out mouse model 4. In vivo – transgenic AID-overexpressing UNG/SMUG/MSH2-knock out mouse model. 5. In vivo – autologous lymphoma transplant mouse model The outcomes of this WP will be used to carry out the activities specified in WP2, 3 and 4 (efficiency and proof of concept testing; biomarker identification; mechanistic studies). These new models will not only benefit the LEMONAID project, but will also facilitate further research in lymphoma drug development, cancer mutation and drug resistance.