We have targeted core catalytic subunits of ATP-dependent chromatin remodeling complexes in each major subtype of rhabdomyosarcoma with PROTAC degraders (SMARCA4-31, DL-dS2-4) to enable concomitant degradation of (1) the driver oncogene in the alveolar subtype, PAX3-FOXO1, and (2) the FOXO1 transcription factor in the embryonal subtype. These effects are accompanied by defects in rhabdomyosarcoma cell proliferation. The degradation of PAX3-FOXO1 is only partially rescued with removal of the PROTACS. To our knowledge, FOXO1 or PAX3-FOXO1 fusions have not been targeted for rapid degradation previously.
This is a (1) new process of BAF-proximity degradation, and (2) a new process of PAX3-FOXO1 degradation.
We are not aware of other methods of targeted degradation of FOXO1 or PAX3-FOXO1 in rhabdomyosarcoma, or other tumors.