Speaker
Description
The dynamics of malignant neoplasms of the central nervous system, such as malignant gliomas and brain metastases, are strongly shaped by the blood–brain barrier and by interactions between tumor cells and immune populations within the tumor microenvironment. In particular, tumor-associated myeloid populations—including microglia and macrophages—can promote tumor growth through immunosuppressive and pro-tumoral signaling pathways. Among the molecular regulators involved in these interactions, the receptor for advanced glycation end-products (RAGE) has emerged as a key mediator linking inflammation, immune dysfunction, and tumor progression.
Azeliragon (AZG), a small-molecule RAGE inhibitor, has recently shown promising preclinical results in combination with radiotherapy (RT), and clinical trials are currently underway to evaluate its therapeutic potential (e.g., NCT05635734 and NCT05789589). Motivated by these findings, we developed an ordinary differential equation model of malignant gliomas that explicitly incorporates tumor–immune interactions and the combined effects of RT and AZG. This framework enables the quantitative exploration of treatment schedules through in silico trials and provides a mechanistic tool to investigate how RAGE inhibition may reshape the tumor immune microenvironment and enhance radiotherapy efficacy. The proposed framework also provides a quantitative basis to investigate similar immune-mediated treatment strategies in other intracranial malignancies, where activation of the S100A9–RAGE signaling axis has been identified as a driver of radiotherapy resistance. I will discuss the theoretical foundations of the model, and its validation with clinical data as well as the extension of the concepts to brain metastases, a more frequent malignancy where similar biological processes are also present.
