Unmet Treatment Needs for Triple Negative Breast Cancer  

Breast cancer is the second-leading cause of death in women worldwide.¹ Triple-negative breast cancer (TNBC) is an especially aggressive form of breast cancer that accounts for 10-15% of cases. 

Unlike most other types of breast cancer, TNBC cells do not express: 

• estrogen receptors (ERs) 
• progesterone receptor (PRs)
• human epidermal growth factor receptor 2 (HER2)

 

Hence, conventional therapies targeting these receptors are not effective in patients with TNBC, and there are fewer targeted treatment options available for patients with this form of breast cancer. Accordingly, TNBC is associated with worse prognosis compared to other forms of breast cancer, and novel therapies are urgently needed.

Ganglioside G_D2 is a Tumor-Specific Antigen

Ganglioside G_D2 is emerging as a marker of and therapeutic target for breast cancer, including TNBC.^2,3 Ganglioside G_D2 is a glycosphingolipid that contains a ceramide base and two sialic acid residues linked to an inner galactose unit.⁴ Ganglioside G_D2 expression is limited to neurons, peripheral nerves, and skin melanocytes in healthy tissues.^4,5 However, ganglioside G_D2 is abundantly expressed in several cancers, where it has roles in cell signaling, cell proliferation and survival, invasiveness, and metastasis.⁶ Almost all neuroblastomas express ganglioside G_D2, and it is also highly expressed by bone and soft tissue sarcomas, melanoma, and small cell lung and breast cancer.⁷Elucidating the ganglioside G_D2 expression pattern in cancer may help predict responses to ganglioside G_D2-based therapies. 

Ganglioside G_D2 is Associated with Breast Cancer Aggressiveness 

Ganglioside G_D2 expression has been associated with aggressive traits in breast cancer, including the TNBC phenotype, where it is correlated with reduced survival.³ Published studies report that the percent of TNBC expressing ganglioside G_D2 ranges from 45 to 67%.^3,8 Other studies have indicated that ganglioside G_D2 is a marker for breast cancer stem-like cells, which are associated with tumorigenesis, chemotherapy resistance, and metastasis, and ganglioside G_D2 expression may also be associated with activation of the epithelial-mesenchymal transition.^2,7,9

Antibody-Based Approaches for Ganglioside G_D2-Based Therapies 

Because ganglioside G_D2 is extensively expressed in many tumor cells and is absent in most healthy tissues, ganglioside G_D2 is an intriguing target for novel cancer therapies. Indeed, dinutuximab, an anti-ganglioside G_D2 monoclonal antibody, is approved for the treatment of neuroblastoma in children. Recent studies have shown that dinutuximab may have utility in the treatment of TNBC.¹⁰ Dinutuximab reduces tumor growth in a patient-derived xenograft (PDX) mouse model of TNBC, and it has synergistic effects when used in combination with activated NK cells.

Ganglioside G_D2 is also an attractive candidate for anti-cancer vaccines. In a phase II clinical trial, a bivalent ganglioside G_D2/G_D3 vaccine in combination with β-glucan adjuvant was investigated in patients with high-risk neuroblastoma and prior history of disease progression.¹¹Anti-ganglioside G_D2-IgG1 titers ≥ 150 ng/ml at eight weeks after adjuvant administration were associated with improved survival in this patient cohort. Given the significance of ganglioside G_D2 in cancer, phase III studies for neuroblastoma and additional studies for other cancers, such as breast cancer, are urgently awaited. 

Despite the potential of ganglioside G_D2-based therapies in cancer, there are challenges to overcome to move the field forward. Gangliosides are often mixtures derived from natural sources, which presents two obstacles. One, gangliosides from natural sources contain ganglioside species with fatty acyl chains of variable lengths, and there may also be variations in the sphingoid backbone. This can result in different immunogenicity of the gangliosides, and variability of the final preparations. Also, most ganglioside G_D2 products are isolated from bovine brain, which raises concerns over prion-transmissible infections like spongiform encephalopathy, also known as mad cow disease.

Available from Cayman

As one of the top suppliers of bioactive lipids worldwide, Cayman has built an industry-leading portfolio of research tools and services that support ganglioside research.  

Gangliosides from Natural Sources

Cayman is a leading supplier of high-purity gangliosides for the lipid research community. We offer purified gangliosides that have been extracted from a variety of natural sources. 

Synthetic Gangliosides

Our chemists have pioneered a method that yield single molecule gangliosides. These products are fully synthetic, eliminating the variability seen in gangliosides from natural sources. Our chemoenzymatic platform is flexible and allows for modifications to both the sphingoid base and fatty acid chains on the final ganglioside. 

Semisynthetic Gangliosides

Cayman can also produce semisynthetic forms of gangliosides derived from natural sources. Hence, this product is free from potential contamination with transmissible spongiform encephalopathies (TSE). 

Ganglioside Lipid Analysis 

With Cayman Services, your lipid analysis study is in the hands of scientists with several decards of collective experience in lipid synthesis, purification, and characterization. Cayman's lipid analysis laboratories are equipped with state-of-the-art chromatography/mass spectrometry systems and data analysis software, enabling us to offer lipid analysis services to meet your specific project needs. 

References

et alMol. Cancer22

2. Shao, C., Anand, V., Andreeff, M., et al. Ganglioside GD2: a novel therapeutic target in triple-negative breast cancer. Ann. N.Y. Acad. Sci., 1508(1), 35-53 (2022).
3. Higashi, C., Saito, K., Kozuka, Y., et al. Ganglioside GD2 expression is associated with unfavorable prognosis in early triple-negative breast cancer. Anticancer Res. 43(9) 4045-4053 (2023).
  
4. Nazha, B., Inal, C., and Owonikoko, T.K. Disialoganglioside GD2 expression in solid tumors and role as a target for cancer therapy. Front. Oncol. 10, 1000 (2020).
  
5. Doronin, I.I., Vishnyakova, P.A., Kholodenko, I.V., et al. Ganglioside GD2 in reception and transduction of cell death signal in tumor cells. BMC Cancer 14, 295 (2014).
  
6. Suzuki, M. and Cheung, N.K. Disialoganglioside GD2 as a therapeutic target for human diseases. Expert Opin. Ther. Targets. 19(3), 349-362 (2015).
7. Machy, P., Mortier, E., and Birklé, S. Biology of GD2 ganglioside: implications for cancer immunotherapy. Front. Pharmacol. 14, 1249929 (2023).
  
8. Orsi, G., Barbolini, M., Ficarra, G., et al. GD2 expression in breast cancer. Oncotarget 8(19), 31592-31600.  
9. Battula, V.L., Shi, Y., Evans, K.W. et al. Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis. J. Clin. Invest. 122(6), 2066-2078 (2012).
  
10. Ly, S., Anand, V., El-Dana, F., et al. Anti-GD2 antibody dinutuximab inhibits triple-negative breast tumor growth by targeting GD2⁺ breast cancer stem-like cells. J. Immunother. Cancer 9, e001197 (2021).
11. Cheung, I.Y., Cheung, N.K., Modak, S., et al. Survival impact of anti-GD2 antibody response in a phase II ganglioside vaccine trial among patients with high-risk neuroblastoma with prior disease progression. J. Clin. Oncol. 39(3), 215-226 (2021).