GPC2 as an Immunotherapeutic Target in Medulloblastoma and other Pediatric Brain Tumors

Medulloblastoma and other pediatric brain cancers could be candidates for immunotherapy, a therapy that utilizes a patient’s own immune system to attack a tumor. Immunotherapy requires molecular targets and medulloblastomas and other brain tumors differentially express cell surface molecules that could act as targets. The recently FDA-approved chimeric antigen receptor (CAR) T cell therapy (a type of immunotherapy) for acute lymphoblastic leukemia, pioneered at the Children's Hospital of Philadelphia, provides proof that immunotherapies can combat pediatric cancers. Challenges remain in identifying molecules that meet optimal immunotherapeutic safety and efficacy criteria for use in the pediatric patient population. Researchers have recently discovered that the signaling co-receptor glypican-2 (GPC2) meets these criteria in both medulloblastomas and neuroblastomas. GPC2 is a highly expressed medulloblastoma and neuroblastoma cell surface molecule that is not detectable at significant levels on normal pediatric tissues. The group has developed a GPC2-directed antibody-drug conjugate (ADC) that potently inhibits the growth of neuroblastoma in animal models. However, the efficacy of this ADC in medulloblastoma models remains undefined. Researchers have also found that GPC2 may be overexpressed in other lethal pediatric brain tumors, such as high-grade gliomas (HGGs), peripheral neuroectodermal tumors (PNETs) (including the universally lethal embryonal tumors with multilayered rosettes [ETMRs]), and atypical teratoid rhabdoid tumors (ATRTs). The central hypothesis of this project is that targeting GPC2 with the identified ADC in medulloblastoma and other GPC2-expressing pediatric brain tumors will lead to better outcomes for patients. The Children's Brain Tumor Network contributed cell lines and tissue in freezing media necessary to develop the models needed for this line of research.