Rhabdoymosarcoma is a pediatric tumor associated with poor survival in high-risk cases. While initiatives such as ITCC (www.itcc-consortium.org) explore novel therapies in sarcoma patients through phase 1 clinical (basket) trials, parallel intensive research programs to identify novel therapeutic vulnerabilities and drug targeting strategies are of utmost importance to fuel these initiatives with novel ideas for more potent drugs and combinations thereof with ideally limited toxicity. Recent studies indicate that AURKA is emerging as key drug target in rhabdomyosarcoma through destabilization of the PAX3-FOXO1 fusion protein and MYCN. We recently achieved to develop novel AURKA targeting PROTACs with excellent selectivity and AURKA degrading potential that block both kinase dependent and independent functions. In this project, we aim to follow-up on these achievements, including (1) in-depth phenotypic and molecular evaluation of AURKA inhibition vs degradation in vitro and in vivo, (2) profound chemical optimization of our lead AURKA PROTAC SK2188 for in vivo application and further exploitation as tool compound to evaluate the importance of AURKA kinase-independent functions in rhabdomyosarcoma tumorigenesis and (3)scrutinize the power of pharmacological inhibition or degradation of AURKA as entry point for combination therapy and evaluate immunomodulatory characteristics to ‘heat up’ rhabdomyosarcoma tumors that are renown to be intrinsically immunologically ‘cold’.