Predictive biomarker for immunotherapy of cancer targeting a ganglioside – PREDIGANG

O-acetyl GD2 (OAcGD2): Towards a more targeted, safer and personalized anticancer immunotherapy

This project aims to characterize the expression and functional role of the ganglioside OAcGD2 in different tumor models and to assess its relevance as a predictive biomarker for the monitoring of the targeted immunotherapies, optimization of patient selection and improvement of benefit–risk ratio of treatments.

Scientific and medical challenges of targeting OAcGD2 for the development of a predictive biomarker in immunotherapy

Glycosphingolipids are now recognized as major players in tumor progression and represent diagnostic biomarkers as well as potential targets for immunotherapy. However, for certain gangliosides, their high expression level in healthy tissues (for example in the nervous system), where they play essential roles in membrane organization and signaling, limits their therapeutic use because of the high risk of toxicity. The ganglioside GD2 illustrates this issue. Although it is a validated therapeutic target in some cancers, particularly neuroblastoma, its expression in nerve fibers is associated with significant adverse effects (notably frequent neuropathic pain), which limits its clinical use and its extension to other cancer types. In this context, O-acetylated forms of gangliosides, such as OAcGD2 and OAcGD3, have emerged as promising therapeutic targets because of their more specific expression in tumor cells and their limited presence in healthy tissues. These features suggest a better safety profile while preserving strong potential for specific targeting and therapeutic efficacy. Biologically, gangliosides are involved in key processes of carcinogenesis, including proliferation, migration, adaptation to the tumor microenvironment and resistance to treatment. Their expression is also associated with specific cellular subpopulations that contribute to tumor aggressiveness and relapse. In this context, identifying predictive biomarkers for immunotherapy response monitoring is a major challenge in order to optimize patient selection, improve the benefit–risk ratio of treatments and support the development of more targeted therapeutic strategies. The PREDIGANG project aims to develop an integrated approach to better characterize OAcGD2 expression in different tumor models and to assess its relevance in immunotherapy strategies. The objectives are: • To map OAcGD2 expression across various tumor models using complementary approaches. • To assess the impact of targeted therapeutic strategies, alone or in combination with standard treatments. • To identify potential mechanisms of resistance. This project aims to contribute to the development of new precision medicine approaches by improving our understanding of immunotherapy response mechanisms and by facilitating their translation into clinical practice.