Project Details
Projekt
Exploring selenocysteine metabolism as a targeted therapy approach in cancer
Applicant
Hamed Alborzinia, Ph.D.
Subject Area
Cell Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 549677598
Ferroptosis is a distinct form of cell death mediated by iron. Glutathione Peroxidase 4 (GPX4) serves as a key regulator and inhibitor of ferroptosis through its ability to eliminate phospholipid hydroperoxides. Our recent findings indicate that targeting components of ferroptosis, particularly GPX4, along with cysteine uptake and its metabolic enzymes, represents a promising approach for addressing high-risk neuroblastoma with MYCN amplification. GPX4 is among the 25 selenoproteins in the human selenoproteome that incorporate the unique amino acid selenocysteine (Sec). Selenium obtained from the diet is predominantly metabolized in the liver, where it is integrated into selenoprotein P (SELENOP). SELENOP is subsequently released into circulation from the liver and primarily internalized into all cells via LRP8, thereby providing cells with intracellular Sec. We recently demonstrated that genetic deletion of LRP8 in MYCN-amplified neuroblastoma cells triggers ferroptosis in cultured cells and significantly impacts neuroblastoma tumor growth in orthotopic mouse models. The overarching objective of our SPP2306 second-phase proposal is to leverage insights gained from the first phase and target cancer cells based on their susceptibility to Sec metabolism and ferroptosis. Drawing on our own data, our focus will be on neuroblastoma and AML as cancer types dependent on Sec metabolism and thus vulnerable to ferroptosis induction. We will systematically integrate standard-of-care (SoC) cancer treatments with targeted inhibition of Sec uptake and downstream pathway components. We propose the following aims for the second phase of this Priority Programme: 1. Identifying the most effective combination of SoC treatment with Sec pathway interference to eradicate neuroblastoma and AML cells. 2. Exploring the potential of targeting Sec metabolism to overcome drug-tolerant persister (DTP) cells. Additionally, we will build upon our recent findings of significant tumor growth inhibition achieved with a selenium-restricted diet in a lymphoma preclinical model. We plan to integrate this approach with SoC treatment and extend our initial findings to neuroblastoma and AML. Finally, as demonstrated in our collaborative publications during the first phase of this consortium, we anticipate that our findings, coupled with our capacity to conduct in vivo studies including pre-clinical treatment trials, will be invaluable to the members of the SPP2306. Likewise, the data and insights from other teams will be essential for collectively developing novel ferroptosis-based strategies to target hard-to-treat cancers, such as high-risk neuroblastoma and AML. Collaborative efforts in this direction will enable us to explore a broader range of therapeutic options and enhance our understanding of ferroptosis mechanisms, thus paving the way for more precise and effective treatments for these aggressive malignancies.
DFG Programme
Priority Programmes
Co-Investigator
Professor Andreas Trumpp, Ph.D.
