Children with brain tumors such as medulloblastoma continue to have poor outcomes despite maximal intensification of existing radiation and chemotherapeutic regimens. Consistent with their embryonal origins, medulloblastomas and other brain tumors differentially express lineage-specific cell surface molecules, raising the possibility that immunotherapeutic approaches can be developed. The recently FDA-approved chimeric antigen receptor (CAR) T cell therapy for acute lymphoblastic leukemia that was pioneered at the Children's Hospital of Phildadelphia provides proof that immunotherapies can combat otherwise fatal childhood cancers. However, challenges remain in identifying molecules that meet optimal immunotherapeutic safety and efficacy criteria in most childhood cancers, including pediatric brain tumors. An ideal immunotherapeutic target should be cell surface localized and robustly differentially expressed between tumor and normal tissues. We have recently discovered that the signaling co-receptor glypican-2 (GPC2) meets these criteria in both medulloblastomas and neuroblastomas (Bosse et al., Cancer Cell, 2017). GPC2 is a highly expressed medulloblastoma and neuroblastoma cell surface molecule that is not detectable at significant levels on normal pediatric tissues. To therapeutically leverage GPC2’s differential expression, we have developed a GPC2-directed antibody-drug conjugate ADC; D3-GPC2-PBD), that links a GPC2-specific antibody (D3) with DNA damaging pyrrolobenzodiazepine (PBD) dimers.
This ADC potently inhibits the growth of neuroblastoma patient-derived xenografts (PDXs). However, the efficacy of this ADC in medulloblastoma models remains undefined. Furthermore, in additional preliminary work, we have also found that GPC2 may be overexpressed in other lethal pediatric brain tumors, such as high-grade gliomas (HGGs), CNS peripheral neuroectodermal tumors (PNETs) including the universally lethal embryonal tumors with multilayered rosettes (ETMRs), and atypical teratoid rhabdoid tumors (ATRTs). Our central hypothesis is that targeting GPC2 with the D3-GPC2-PBD ADC in medulloblastoma and other GPC2-expressing pediatric brain tumors will evoke potent tumor cytotoxicity.
What are the goals of this project?
The goals of this project are to perform a pan-pediatric brain tumor assessment for high GPC2 expression and to define the efficacy of the GPC2 ADC D3-GPC2-PBD in medulloblastoma, HGG and AT/RT preclinical models.
What is the impact of this project?
Medulloblastoma and other high-risk pediatric brain tumors remain lethal to children despite intense multimodal therapy. Recent immunotherapy advances have resulted in enthusiasm for the use of this type of treatment in otherwise incurable childhood cancers. This proposal focuses on GPC2, a differentially expressed cell surface oncoprotein we recently identified and validated in neuroblastoma and have also found to be highly expressed in pediatric brain tumors such as medulloblastomas and possibly HGGs, CNS PNETs, and ATRTs. Considering GPC2’s cell surface location and limited expression in normal tissues, taken together with its critical role in sustaining tumorigenesis, GPC2 appears to be an ideal molecule to target with an ADC or other immunotherapeutic approaches. This proposal is both innovative and impactful. This work may directly lead to a novel GPC2-targeted ADC for children with brain tumors. Finally, although here we focus on a GPC2 ADC we are also engineering GPC2 RNA (in collaboration with Dr. Jessica Foster in the Resnick Lab at CHOP) and DNA chimeric antigen receptor T cells and will plan to test these immunotherapeutics in the above identified GPC2 expressing preclinical brain tumor models in parallel.
Why the CBTN request is important to this project?
CBTN cell lines are important to this project to provide newly developed cellular brain tumor models to characterize for GPC2 expression and to test the efficacy of this GPC2 directed ADC.
The Children's Brain Tumor Network contributed cell lines and tissue in freezing media for in vitro studies.
Kristopher Bosse, MD
Despite the use of intensive multimodal therapy for neuroblastoma, approximately one-half of children still die from this disease. Dr. Bosse's laboratory focuses on the development of new immune-based therapies for this embryonal malignancy of the developing nervous system. Through these stu
Jessica B. Foster, MD
Dr. Foster’s current research focuses on immunotherapy for pediatric solid and brain tumors. Specifically she is investigating chimeric antigen receptor (CAR) T cell therapy for neuroblastoma, high-grade gliomas, medulloblastomas, diffuse intrinsic pontine gliomas, and other brain tumors. The goa
Medulloblastomas comprise the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa, where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.The clinica
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective
Atypical teratoid/rhabdoid tumor (AT/RT)
Atypical teratoid/rhabdoid tumor (AT/RT)
Central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) is a very rare, fast-growing tumor of the brain and spinal cord. It usually occurs in children aged three years and younger, although it can occur in older children and adults. About half of these tumors form in the cerebellum