Periodic Reporting for period 4 - TarMyc (Targeting the Oncogenic Function of Myc in vivo)
Reporting period: 2022-09-01 to 2023-08-31
In ageing Western societies tumors are becoming the most relevant medical problem. Transcription factors of the Myc oncoprotein family are key players in the development of most human tumors. The central goal of TarMyc was to elucidate the critical oncogenic mechanism of MYC and to develop strategies to target MYC function for cancer therapy. By identifying critical target genes and binding partners of MYC as novel targets for cancer therapy.
First, we developed systems to deplete MYC and MYC-associated proteins in cells and mice using both inducible shRNAs and targeted protein degradation systems. We observed that MYC regulates unique sets of genes when expressed at low, physiological, versus high, oncogenic levels. Oncogenic processes induced by MYC include angiogenesis, specific metabolic adaptations and, most importantly, immune evasion. Second, we identified and characterized MYC binding partners that are critical for the establishment of these oncogenic gene expression signatures. Third, we developed proteolysis targeting chimeras (PROTACs) for the most promising candidates and characterized their impact on tumor growth in vivo.
Overall, the TarMyc project has laid the foundation for potential new anti-MYC-based cancer therapies.