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

Cancer is a disease that develops as a consequence of changes in genes that control cell growth and tissue organization so that some cells gain a growth advantage. The development of a cancerous tumor, tumor evolution, can take many years and the cells will during this time accumulate new genetic changes at a high pace. This process also accelerates the emergence of treatment resistance. The goal of this EUROSTARS project is to develop a new type of medicine that can inhibit tumor evolution and thus prevent the emergence of treatment-resistant clones.

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.