Necrotic cell death pathways & immunemodulation: identification of predictive markers in central nervous system tumors

• Grant number: 19/23151-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: February 01, 2021
• End date: January 31, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Ricardo Weinlich
• Grantee: Guilherme Afonso Vergara
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

Central Nervous System (CNS) Cancers, despite their low incidence rates, are highly lethal and clinically heterogeneous tumors. The vast majority of primary CNS tumors are diagnosed as gliomas, followed by Meningiomas and other less common types such as Craniopharyngiomas, Hemangiomas and Gangliogliomas. To date, the available biomarkers are not enough to underscore the characteristics that lead to the very different patient's outcomes, which hampers better patient management and more effective and personalized treatments. Thus, improving and expanding the search for molecular markers is needed to refine current diagnostic techniques leading to a more reproducible and decisive system for clinical use. Resistance to cell death is one of the key hallmarks of malignant transformation. For a long time, apoptosis was the sole subject of study in this field, as it was the only known pathway with an identified biochemical machinery; and with great success. However, in the last decade several other cell death routines have been identified, with a phenotype quite distinct from apoptosis and similar to necrotic death. Among them, necroptosis, pyroptosis and ferroptosis have a high pro-inflammatory profile and the potential to induce neo-angiogenesis, tissue remodeling and elicit robust immune responses. Little is known about the role of these new targets as prognostic markers, but published evidence indicates that increased expression of molecules of these pathways are usually associated with a better prognosis. However, our hypothesis is that regarding tumors in immunoprivileged sites, such as the CNS, activation of these death pathways is associated with a poorer prognosis due to increased inflammation induction with little or no concomitant immune infiltration. Preliminary data from our group support this idea, given that in patients with low-grade gliomas, increased expression of RIPK3 (one of the necroptosis genes) is associated with an altered inflammatory profile and increased risk of death. Thus, the present project aims to identify candidates to compose a minimal signature list of genes involved in cell death pathways that can predict the prognosis of patients diagnosed with different CNS cancers, and to help understand the relationship between immunomodulation, cell death and cancer progression at immunoprivileged sites. (AU)