Paediatric therapeutic development workshop on osteosarcoma.

The fourth Paediatric Therapeutic Development Workshop focused on osteosarcoma, the most common primary bone cancer in children and young adults. Current treatment of osteosarcoma comprises surgery and chemotherapy. Outcome has shown very little improvement over the last four decades and there are substantial unmet needs including improving survival, especially in metastatic or relapsed disease, and reducing treatment toxicity. There is a lack of new therapeutics in osteosarcoma, with the evaluation of new treatments challenged by complex biology and variation in chemotherapy standard of care regimens. An antibody-drug conjugate (ADC) targeting LRRC15 with an osteosarcoma-relevant payload is a promising therapeutic approach. Small molecule inhibitors and degraders targeting SMARCAL1 should be considered as a very high priority, as it is a target applicable to several high unmet need malignancies. Preclinical evaluation of KIF18A in osteosarcoma models is required. An early phase study of an eIF4A1 inhibitor is warranted. Further preclinical validation of RUNX2 using PROTACs or ADCs is required. Targeting MYC, either indirectly or directly is a high priority. Osteosarcomas have significant genomic instability and impaired DNA repair mechanisms and efforts are ongoing to exploit this vulnerability therapeutically. The goal is that these therapeutic developments will improve survival for patients with osteosarcoma.