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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 for nominating new E3 ligase-fusion oncoprotein pairs and structures for "molecular glue" or PROTAC design, pushing the development of new therapeutic for the "undruggable" sarcoma fusion oncoproteins.

Landscape of immunotherapeutic targets in sarcoma


Immunotherapy has emerged as a promising modality for the treatment of cancer and is designed to tip the balance from tumor immune evasion to an effective anti-tumor immune response. Major immunotherapeutic approaches are immune checkpoint inhibition, neoantigen-based peptide vaccination as well as adoptive cell transfer (ACT) based on T-cell receptors (TCRs; MHC-restricted) or chimeric antigen receptors (CARs; non-MHC-restricted) that target tumor-associated antigens (TAA) derived from cancer testis antigens (CTA), neoantigens or cancer germline antigens. Studying tumor-intrinsic pathways and immunoregulatory proteins expressed on tumors and their interactions with tumor immune microenvironment can unveil disease mechanisms and inform the choice of effective immunotherapeutic strategy. Our group is combining multi-omics-based immune profiling of tumors with multiplex immunohistochemistry, mass spectrometry and in vitro immune-assays to uncover the immune evasion strategies of tumors and enable systematic discovery of immunotherapeutic targets.

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