Dr Braun on Protein Glycosylation as a Potential Biomarker of Response in RCC

“Altered protein glycosylation could be considered a hallmark of cancer. This process is essential to oncogenesis and maintaining oncogenic function, and [it has the] potential to be immunomodulatory. [Based on that], we asked the question of whether this might be relevant for predicting [response to] nivolumab plus cabozantinib [in RCC].”

David A. Braun, MD, PhD, assistant professor, medical oncology, Louis Goodman and Alfred Gilman Yale Scholar, member, Center of Molecular and Cellular Oncology, Yale Cancer Center, discusses the potential use of protein glycosylation as a biomarker of response in renal cell carcinoma (RCC) and how this provided the rationale for conducting an exploratory biomarker analysis of the phase 3 CheckMate 9ER study (NCT03141177).

Research efforts in RCC are increasingly focused on understanding the genomic and transcriptomic underpinnings of the disease to characterize gene expression signatures and identify therapeutic targets, Braun begins. Beyond these approaches, the role of post-translational protein modifications, particularly glycosylation, has emerged as a critical area of study, he adds. Altered protein glycosylation is now recognized as a hallmark of cancer, with significant implications for tumor biology and immune modulation, Braun states.

One example of altered glycosylation is sialylation, a process that is frequently upregulated in cancer and is immunomodulatory, Braun continues. Elevated levels of sialylation can engage cyclic molecules, ultimately driving immune suppression and contributing to resistance mechanisms, such as reduced efficacy of PD-1 blockade, he explains. This underscores the relevance of glycosylation in oncogenesis, tumor progression, and immune evasion, Braun emphasizes.

Given this biological context, the research group explored whether altered glycosylation patterns, particularly sialylation, could serve as a biomarker for predicting responses to combination therapy with nivolumab (Opdivo) plus cabozantinib (Cabometyx), he states. This investigation builds on the hypothesis that the interplay between glycosylation-driven immune modulation and therapeutic mechanisms of action might provide insights into patient stratification and treatment optimization, he concludes.