Background/Objectives: Fusion-positive rhabdomyosarcoma (FP-RMS) is characterized by the presence of tumor-specific chromosomal translocation products, most commonly PAX3::FOXO1, and typically results in lower survival rates compared to fusion-negative RMS cases. PAX3::FOXO1 plays a critical role in FP-RMS oncogenesis in both tumor initiation and maintenance, making it an excellent target for therapeutic intervention in FP-RMS. Methods: We created Proteolysis Targeting Chimeras (PROTACs) by combining PAX3::FOXO1-binding small molecules with E3 ligase recruiters for cereblon (CRBN) or S-Phase Kinase Associated Protein 1 (SKP1). Results: The PROTACs achieved up to 70% degradation of the endogenous PAX3::FOXO1 protein in FP-RMS cell lines in a concentration-, time-, and proteasome-dependent manner. Moreover, the PROTAC-mediated targeted degradation of PAX3::FOXO1 in FP-RMS cells deregulated the endogenous PAX3::FOXO1 gene expression signature and induced myogenic differentiation. Importantly, treatment of FP-RMS cells with PAX3::FOXO1-PROTACs synergized with vincristine treatment and impaired >80% of anchorage-independent growth in soft agar. Conclusions: Taken together, we demonstrate the proof of principle of PROTACs targeting the oncogenic fusion protein PAX3::FOXO1 in FP-RMS cells. The PROTACs created in this study will not only be useful tools in studying PAX3::FOXO1 biology in laboratory models but could also serve as molecular scaffolds for designing clinical-grade molecules to assess the therapeutic potential of PAX3::FOXO1-targeting PROTACs in FP-RMS patients.

Immune dysregulation in Down syndrome (DS) is a highly clinically relevant yet underrecognized feature of this common genetic syndrome. Infection is the leading cause of mortality in DS. This infectious risk likely stems from underlying immunodeficiency compounded by their unique intrinsic anatomy. Furthermore, individuals with DS display a broad range of autoinflammatory and autoimmune diseases, spanning dermatologic, neurologic, and metabolic features, which are often difficult to treat with immunomodulators. Through real clinical vignettes of our patients, we will describe how we treat immune dysregulation in DS.