TS-000856 — Alveolar Rhabdomyosarcoma is a malignancy that forms in a muscle, stemming from a soft tissue and residing in the lungs. A team of researchers led by Dr. Benjamin Stanton have developed an initial characterization of PAX3-FOXO1 that is localized across the genome associated with this disease. PAX3-FOXO1 localizes to both repressed and active regions of the tumor genome and is initially targeted as a driver oncogene. Additionally, the immediate-early targets of localization encode metabolic genes and cell cycle genes. By understanding this rare tumor oncogene, caregivers will be able to identify target genes and implement FDA-approved therapies.

TS-000506 — 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.