Abstract The Paediatric Bespoke Therapeutic Development Workshop (PBTDW) initiative is a multistakeholder effort to landscape the unmet need in childhood cancer indications. The second PBTDW focused on medulloblastoma, with a global panel of experts invited to participate in a virtual meeting discussing promising therapeutic targets and drug combination strategies. The principal objective was to enable the development of targeted therapeutics in poor prognosis subgroups (SHH-MYCN amplified, TP53 mutated and Group 3 MYC amplified) and developing less toxic therapies for subgroups with better prognosis disease (WNT). A high priority was identified for the inhibition of MYC and MYCN tumor-relevant functions for poor prognosis subsets. Alternative degrader-based therapies may also be effective. Reducing toxicity when targeting WNT subgroup tumors is important. For immunotherapy targets, B7-H3 has many advantages for the development of CAR T-cell and ADC-based approaches and GPC2 shows promise but requires clinical validation. Early-phase clinical studies should be designed based on a deep understanding of biology and have integrated correlative studies. These will require international cooperation and novel designs to address critical groups with small patient numbers. Based on currently available evidence, combinations of either a CDK transcriptional inhibitor and an ATR inhibitor, or a PARP1-selective CNS-penetrant inhibitor and an ATR inhibitor could be tested in early phase trials for high-risk patients; however, these potential combinations require robust evaluation in preclinical models first.
Equihua et al. (Fri,) studied this question.