PROJECTS USING SYNTHETIC LETHALITY CONCEPT
One of the challenges in the development of new drugs is the limited number of actionable protein targets that are at the same time closely related to the etiology of the disease and susceptible to targeting with small molecule compounds.
Novel protein targets and mechanisms of cancer cell sensitivity that can be used therapeutically are identified within the framework of the Targeted Therapeutics Platform. One of the main strategies is to use the phenomenon of synthetic lethality. Synthetically lethal compounds selectively kill tumor cells characterized by a precisely defined genetic, epigenetic or metabolic characteristic, sparing unchanged cells.
Bioinformatics tools are intensively used in this strategy, which allow to identify often unobvious and unanticipated relations between the sensitivity of cells and their unique features. Because dependencies may also apply to changes that only coincident with driving oncogenic processes as well as changes that cannot be targeted directly, this approach expands our treatment options to new patient groups.
One of the most advanced projects within the platform is focused on SMARCA2/BRM protein in cancer cells with damaging mutations in the function of SMARCA4, which encodes protein BRG1, part of the chromatin remodeling complex SWI/SNF. More than 6% of patients with non-small cell lung cancer (NSCLC), which accounts for about 80% of all lung cancer cases, have SMARCA4 mutations. The project develops molecules that selectively target cells that carry SMARCA4 mutations by inhibiting helicase/ATPase activity of the SMARCA2/BRM protein.
The project has been initiated by the EPTHERON consortium led by Selvita S.A. with the support of National Center of Research and Development (NCBiR) under the STRATEGMED program. The Consortium includes renowned scientific institutions such as: Institute of Experimental Biology PAN with headquarters in Warsaw, Institute of Hematology and Transfusiology with its headquarters in Warsaw, Institute of Oncology – Institute of Maria Sklodowska Curie with headquarters in Warsaw, Malopolska Center of Biotechnology (MCB) with headquarters in Krakow, Wroclaw University of Technology and the Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University (WBBiB UJ) based in Krakow.