Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy

Nazha, Bassel; Inal, Cengiz; Owonikoko, Taofeek K.

doi:10.3389/fonc.2020.01000

Cited by 184 publications

(184 citation statements)

References 116 publications

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“…4A ). In postnatal tissues, however, expression of key genes encoding GD2 synthases is most confined to the central and peripheral nervous systems ( 20 ). Therapeutic antibodies targeting GD2 are deployed in most treatment protocols of high-risk neuroblastoma.…”

Section: Resultsmentioning

confidence: 99%

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

et al. 2021

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Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

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Section: Resultsmentioning

confidence: 99%

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

et al. 2021

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“…GD2 has limited expression in normal tissues but is overexpressed across a wide range of tumors particularly of neuroectodermal origins such as neuroblastoma melanoma and small-cell lung cancer [ 2 , 3 ]. Due to its restricted expression in normal tissue, GD2 has long been recognized as an important target for cancer immunotherapy [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Wingerter

Malki

Sandhoff

et al. 2021

Cancers

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The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing’s sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood–brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher’s disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.

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“… 82 The disialoganglioside GD2 is another interesting oncofetal surface antigen expressed by several solid tumors. 83 A preclinical study exploring hu3F8-BsAb (a GD2xCD3 BiTE in which the IgG backbone was aglycosylated to prevent Fcγ receptor-mediated toxicity) showed high tumor killing potency, absence of neurotoxicity and ability to drive circulating T cells into solid tumors. 84 These encouraging preclinical results warranted the initiation of a clinical trial in patients with relapsed/refractory neuroblastoma, osteosarcoma and other solid tumors ( NCT03860207 ).…”

Section: Going Back From Bed To Benchside: Improving Icesmentioning

confidence: 99%

Immune cell engagers in solid tumors: promises and challenges of the next generation immunotherapy

et al. 2021

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In the landscape of cancer immunotherapy, immune cell engagers (ICEs) are rapidly emerging as a feasible and easy-to-deliver alternative to adoptive cell therapy for the antitumor redirection of immune effector cells. Even if in hematological malignancies this class of new therapeutics already hit the clinic, the development of ICEs in solid tumors still represents a challenge. Considering that ICEs are a rapidly expanding biotechnology in cancer therapy, we designed this review as a primer for clinicians, focusing on the major obstacles for the clinical implementation and the most translatable approaches proposed to overcome the limitations in solid tumors.

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Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy

Cited by 184 publications

References 116 publications

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Immune cell engagers in solid tumors: promises and challenges of the next generation immunotherapy

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