International Workshops Prioritize Drug Targets for Childhood Medulloblastoma and Rhabdoid Tumours
International expert workshops have identified priority therapeutic targets for medulloblastoma and rhabdoid tumours, two rare childhood cancers. For medulloblastoma, key priorities include SRC degradation, c-MYC/MYCN inhibition, and B7-H3 targeted approaches. For rhabdoid tumours, DCAF5 and MDM2 were highlighted, with EZH2 degraders showing potential.
International multi-disciplinary workshops have established priority therapeutic targets and development strategies for two rare childhood cancers: medulloblastoma and rhabdoid tumours. Both tumour types are associated with poor survival in high-risk groups and significant long-term treatment toxicities, driving the need for more effective, less-toxic therapies.
Medulloblastoma is the second most common malignant brain tumour in children, with an annual incidence of 4–5 cases per million. Although 60–70% of patients survive with current surgery, radiotherapy and chemotherapy combinations, survivors often experience life-long neurological, cognitive and endocrine side effects, and those in the highest-risk groups face a probability of survival below 10%. The second LifeArc Paediatric Therapeutic Development Workshop focused on this cancer and concluded that targeting SRC using a degrader is a high priority. For poor-prognosis groups, such as SHH-medulloblastoma with MYCN amplification or TP53 mutation, and Group 3 medulloblastoma with c-MYC amplification, inhibition of c-MYC and MYCN tumour-relevant functions was prioritized. For good-prognosis WNT-medulloblastoma, a radiolabelled theranostic antibody approach was considered an innovative strategy to further reduce treatment toxicity. Additionally, the cell surface protein B7-H3 was identified as having advantages for both CAR T-cell and antibody-drug conjugate (ADC)-based therapies. The workshop also discussed combination strategies, noting that central nervous system-penetrant selective PARP-1, CHK1/2 or CDK9 inhibitors combined with an ATR inhibitor could be evaluated in early-phase clinical trials for high-risk patients, after robust pre-clinical testing. Early-phase studies should be international, employ novel designs to accommodate small patient numbers, and incorporate correlative biological studies.
Rhabdoid tumours are malignancies of the central nervous system, kidneys, liver and soft tissues that primarily affect infants and young children, with average five-year overall survival rates of 30–40%. Treatment typically includes surgery, intensive chemotherapy and radiotherapy, causing substantial short- and long-term toxicities, particularly to the developing brain in children with intracranial tumours. The first LifeArc Paediatric Therapeutic Development Workshop on these tumours recognized that a common biology—biallelic inactivation of SMARCB1 (or rarely SMARCA4)—suggests a similar therapeutic approach for both intra- and extra-cranial disease. The workshop prioritized DDB1–CUL4-associated factor 5 (DCAF5) as a promising target, with development of small molecule binders and degraders a key goal. EZH2 degraders were considered to potentially have greater therapeutic benefit than EZH2 inhibitors. In certain subgroups, inhibitors of fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) may be valuable. Mouse double minute 2 homologue (MDM2) was designated a top priority for novel therapeutic development and combination trials. Preclinical evaluation of EZH2 inhibitors, MDM2 inhibitors and selective inhibitors of nuclear export (SINE) in combination should drive early-stage clinical studies.
Both workshops underscored the need for coordinated global development, international trials, and early regulatory dialogue to accelerate approval of new therapies for these rare childhood cancers.