Mapping Long Interspersed Element-1 interactomes in human disease and characterising the response to drugs

LINE-1 retrotransposons are newly emerging targets in cancer. This public private partnership between the Prof. Dr. John LaCava (The Laboratory of Macromolecules and Interactomes at ERIBA/UMCG) and ROME Therapeutics Inc. (Boston, MA) will explore the potential of drugs that target LINE-1 to disrupt its molecular interactions, and e.g., potentially lessen the severity of some cancers.

Over half of all cancers express LINE-1 and those that do expression LINE-1 are more severe and less treatable. Several drugs developed by ROME Therapeutics will be tested for their molecular-level effects by Dr. LaCava. Both parties will work together to maximally integrate the information into a comprehensive understanding of the role of LINE-1 interactomes in disease.

Many pharmaceuticals target individual proteins to modulate their functions, yet experience shows that only 1-2% of these are susceptible to existing pharmacochemical libraries (typically e.g. receptors and enzymes); drugging the LINE-1 ORF2p enzyme falls within this paradigm. Contrastingly, protein interactions encompass promising new targets to drastically expand the ‘druggable universe’. This project holds promise in both the traditional and the emerging druggability contexts: it was previously showed that LINE-1 interactomes change in response to mutations in the enzymatic domains – supporting the possibility that similar effects can be achieved with small molecules. This approach may also reveal alternative efficacious targets among LINE-1 interacting partners.

In this project they will conduct a comprehensive survey of the responses of proteins that interact with LINE-1 in the presence of drugs that inhibit the activity of the ORF2p protein. For this, Dr. LaCava’s lab will apply a cutting-edge protein interactions screening approach to comprehensively explore the effects of the drug treatments on LINE-1 macromolecules at the molecular-level.