Abstract A024: Insights across indications from the Pediatric Bespoke Therapeutic Development Workshop initiative

Abstract The Pediatric Bespoke Therapeutic Development Workshop (PBTDW) initiative is a collaborative multi-stakeholder effort aimed at mapping unmet needs across childhood cancer indications. Each workshop convenes a global panel of experts, including researchers, patient advocates, and representatives from charitable organizations, for a virtual discussion focused on emerging therapeutic targets, combination drug strategies, as well as other clinical challenges and opportunities. To support prioritisation of targets for novel therapeutic development, detailed diligence is prepared and shared prior to the meeting, considering biological rationale, strength of target validation, tractability, and existing commercial development of each target. To date, six workshops have been conducted, addressing rhabdoid tumors, medulloblastoma, rhabdomyosarcoma, osteosarcoma, acute myeloid leukemia, and desmoplastic small round cell tumors. A seventh workshop, focused on high-grade glioma, is scheduled for early September. Despite the biological and clinical diversity of these indications, several recurring themes have emerged. Most targets require some level of further validation. For a target where the ideal therapeutic would modulate target activity, such as small molecule inhibitors, it is critical to show a strong functional and mechanistic association with the tumor type. For antigen-directed therapies independent of functional modulation, such as cell therapies or antibody-drug conjugates, expression studies should show sufficiently high and homogeneous expression (ideally at the protein level) to stimulate on-tumor activity. Many prominent targets are involved in early stages of childhood development and require rigorous evaluation for potential toxicity and safety concerns. However, the limited availability of developmental gene expression and functional datasets in paediatric populations remains a significant barrier to progress. Notably, targets once deemed "undruggable", such as transcription factors and fusion genes, are increasingly viewed favorably, with ongoing efforts to develop targeted degraders and cell-based therapies. From a clinical perspective, paediatric oncology shares many of the challenges inherent to rare diseases. Small patient populations require innovative trial designs and international collaborative efforts to coordinate and enable effective recruitment. Access to promising therapies remains constrained, often due to industry challenges around return on investment and the complexities of extending adult indications to pediatric populations, despite existing regulatory incentives. The Pediatric Bespoke Therapeutic Development Workshops aim to identify approaches with promise and accelerate therapeutics to clinical development. Citation Format: Joseph S Baxter, Claudia Montiel Equihua, Jan Molenaar, Sheena Patel, Siwan Oldham, Andrew DJ Pearson, David Jenkinson. Insights across indications from the Pediatric Bespoke Therapeutic Development Workshop initiative [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A024.