Ganglioside GD2: a novel therapeutic target in triple‐negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by lack of hormone receptor expression and is known for high rates of recurrence, distant metastases, and poor clinical outcomes. TNBC cells lack targetable receptors; hence, there is an urgent need for targetable markers for the disease. Breast cancer stem-like cells (BCSCs) are a fraction of cells in primary tumors that are associated with tumorigenesis, metastasis, and resistance to chemotherapy. Targeting BCSCs is thus an effective strategy for preventing cancer metastatic spread and sensitizing tumors to chemotherapy. The CD44 hi CD24 lo phenotype is a well-established phenotype for identification of BCSCs, but CD44 and CD24 are not targetable markers owing to their expression in normal tissues. The ganglioside GD2 has been shown to be upregulated in primary TNBC tumors compared with normal breast tissue and has been shown to identify BCSCs. In this review, we discuss GD2 as a BCSC-and tumor-specific marker in TNBC; epithelial-to-mesenchymal transition and the signaling pathways that are upstream and downstream of GD2 and the role of these pathways in tumorigenesis and metastasis in TNBC; direct and indirect approaches for targeting GD2; and ongoing clinical trials and treatments directed against GD2 as well as future directions for these strategies.

Therapeutic efficacy of antibody-drug conjugates targeting GD2-positive tumors

“… 8 Additionally, it has recently been shown that GD2 can serve as a marker of breast cancer. 28 In light of the clinical success of ADCs in breast cancer and a limited number of available markers, specifically in TNBC, it seemed important to assess the activity of the conjugates in breast cancer cell lines. We show that regardless of the type of cancer, anti-GD2 ADCs are able to induce the death of tumor cells expressing GD2, which suggests the potential of ADC applicability for the entire wide spectrum of GD2-positive tumors.…”

Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins

“…GD2 has been used as a target of antibody therapy [ 31 , 32 ] towards neuroblastomas [ 33 ], gliomas [ 34 ], and breast cancers [ 26 ], and also of CAR-T therapy of various cancers [ 19 , 20 ]. Furthermore, the biological function of GD2 has been reported, i.e., in EMT [ 35 , 36 ], tumor invasion [ 37 ], and cancer metastasis [ 38 ], though it had been expected based on the clinical samples with different disease stages [ 16 ]. Thus, they have attracted interest from medical and biological science fields.…”

GD2+ cancer stem cells in triple-negative breast cancer: mechanisms of resistance to breast cancer therapies

“…GD2 has been identified as a breast cancer stem cell marker and is a promising target for breast cancer therapy [ 44 ] . Furthermore, dinutuximab is a GD2-specific monoclonal antibody that is FDA approved for neuroblastoma.…”

“…Anti-GD2 antibodies, however, do confer toxicity and are associated with adverse side effects including neuropathy, fever, significant pain, and allergies [42] . Neuropathic pain is likely due to GD2 expression in neural cells; however, O-acetyl-GD2 (OAcGD2), a GD2 derivative, is expressed on GD2+ solid tumor cells but not on neural fibers, and specific targeting OAcGD2 may reduce the aforementioned side effects [43] . Overall, these compounds may be beneficial for the treatment of TNBC, in combination with other therapies, by targeting the CSC subpopulation.…”