Targeted protein degradation for sarcoma drivers

One third of sarcomas are characterized by recurrent genetic changes known as chromosomal translocations created by breakpoints within two cellular genes that result in generation of a chimeric fusion gene. In majority of cases, fusion genes in sarcoma involve chromatin remodeling factors or transcription factors. Gene fusion results in alteration in pattern of gene expression regulation, which results in – in majority of cases – enhanced proliferation, resistance to apoptosis, increased migration and invasion. As the fusion genes are the oncogenic drivers that are expressed only in tumor cells, they represent attractive molecular targets. However, fusion genes derived from transcription factors do not exhibit enzymatic activity and are hence not amenable to small-molecule inhibition. A promising approach towards that end is small molecules which induce proximity between E3 ubiquitin ligases and oncogenic substrates thereby targeting the substrates for degradation by the ubiquitin proteasome system (UPS). Success of this approach is exemplified by of compounds such as lenalidomide analogs, also known as immunomodulatory drugs (IMiDs) and proteolysis-targeting chimeras (PROTACs). By means of reporter-based functional genomic screens coupled with protein biochemistry and structural biology approaches, we are investigating protein degradation pathways of sarcoma fusion genes to lay groundwork for IMiD and/PROTAC design, pushing the development of new therapeutic for the "undruggable" sarcoma fusion oncoproteins.

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