A GPC2-targeting antibody–drug conjugate promotes tumor regression in a high-risk neuroblastoma PDX.

  • Major finding: A GPC2-targeting antibody–drug conjugate promotes tumor regression in a high-risk neuroblastoma PDX.

  • Approach: An RNA-seq pipeline identifies candidate cell-surface targets specifically expressed in neuroblastoma.

  • Impact: Immunotherapeutic GPC2 targeting may be beneficial in high-risk neuroblastoma and other embryonal tumors.

Activating mutations in druggable targets are rare in neuroblastoma, supporting investigation of other therapeutic strategies. Neuroblastoma arises from neural crest progenitor cells in the developing sympathetic nervous system, and thus expresses targets not found on mature cells, suggesting the possibility for the development of immunotherapies. Using an RNA-sequencing (RNA-seq)–based pipeline to analyze 126 primary high-risk neuroblastomas, Bosse and colleagues identified candidate genes for optimal immunotherapeutic targeting. The putative targets were cell-surface proteins (or proteins with extracellular epitopes) highly expressed in neuroblastoma compared with normal tissues, and expressed in the majority of tumors. The extracellular glycosylphosphatidylinositol anchored signaling co-receptor glypican 2 (GPC2) was selected as a top hit. MYCN bound to the GPC2 promoter to increase its expression in neuroblastoma, thereby upregulating GPC2 in MYCN-amplified tumors. Further, in approximately 40% of high-risk neuroblastomas somatic gain of chromosome 7q, which harbors the GPC2 locus, promoted enhanced GPC2 expression. GPC2 was highly expressed on the plasma membrane of the majority of neuroblastoma tumors, and its expression was limited in normal tissues, suggesting the possibility for therapeutic targeting with minimal toxicity. Moreover, GPC2 was required for neuroblastoma cell proliferation, and its depletion resulted in apoptosis. The dependency of neuroblastoma cells on GPC2 expression may prevent the emergence of immune escape mechanisms in response to therapeutic targeting. A GPC2-targeting antibody–drug conjugate was developed and was cytotoxic to neuroblastoma cells expressing GPC2 in vitro. Further, the antibody–drug conjugate promoted durable tumor regression in a patient-derived xenograft (PDX) model of MYCN-amplified neuroblastoma, extending survival with minimal toxicity. Additionally, GPC2 is expressed in other pediatric embryonal malignancies including medulloblastoma and retinoblastoma, suggesting that GPC2 may be an immunotherapy target in other tumor types. Collectively, these findings suggest that GPC2 may be an optimal target for immunotherapy in high-risk neuroblastoma and other embryonal tumors, supporting further development of GPC2-directed immunotherapeutics.

Bosse KR, Raman P, Zhu Z, Lane M, Martinez D, Heitzeneder S, et al. Identification of GPC2 as an oncoprotein and candidate immunotherapeutic target in high-risk neuroblastoma. Cancer Cell 2017;32:295–309.e12.

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