Research Behrouz Hassannia

Abstract

Neuroblastoma is the most common solid tumor outside the brain of infants and very young children. A substantial part of neuroblastoma patients presents with high-risk neuroblastoma disease. In fact, these children have a poor prognosis, do not respond to therapy or even relapse. Therefore, there is an urgent need to find novel treatment strategies. Recently, our research group discovered a new approach to kill aggressive therapy-resistant neuroblastoma cells in mice by inducing a sort of biological rusting in cancer cells, called ferroptosis. Ferroptosis is a type of cell death that rusts away the cellular membrane, which quickly kills the cells. By using nanoparticles, the lab was able to minimize side effects of treatment and enhance tumor targeting. However, to get full tumor regression without relapse using a nanomedicinal approach, it is needed to further improve the efficacy of targeting ferroptosis in neuroblastoma. The aim of this project is to recondition high-risk neuroblastoma to a ferroptosis sensitive state, by acting on anti-ferroptosis mechanisms in cancer cells. In addition, ferroptosis-sensitizing compounds will be encapsulated in lipid nanoparticles, currently used for the Covid-19 RNA vaccines. These ferroptosis-sensitizing nanomedicines will be tested and validated in cell- and patient-derived high-risk neuroblastoma mouse models and provide a steppingstone to clinical investigation of ferroptosis targeting as anti-cancer therapy.

Researcher(s)

• Promoter: Vanden Berghe Tom
• Co-promoter: Hassannia Behrouz
• Fellow: Koeken Ine

Research team(s)

• Cell death signaling (CDS)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder resulting from aggregation of the Tau protein and amyloid-β (Aβ) plaques in the brain. Iron dysbiosis appears to be the common theme prevalent across neurodegenerative diseases by promoting aggregation and pathogenicity of the characteristic aberrant proteins, β-amyloid, Tau, α-synuclein, and TDP43, in these diseases. Studies have demonstrated that iron can regulate Tau phosphorylation by inducing the activity of multiple kinases. The involvement of iron and free radical mediated lipid peroxidation injuries in AD pathogenesis is further supported by the recent discovery of ferroptosis, as a mode of necrotic cell death executed by an iron-catalyzed lipid peroxidation process. Preliminary data in the lab suggest that targeting Tau phosphorylation for example via ferroptosis-kinase pathways could represent a valid therapeutic approach to reduce Tau aggregation and associated neuronal death in AD and other neurodegenerative 'Tauopathies'. Our lab conceptualized ferroptosis induced by an excess in labile iron as non-canonical ferroptosis. In collaboration with the medicinal chemistry lab (Prof. K. Augustijns, UA), we also developed and characterized a novel generation of ferroptosis inhibitors. A lead candidate is superior over the benchmarks ferroptosis inhibitors in protecting against several ferroptosis-driven experimental disease models, including neurodegeneration in experimental multiple sclerosis. These novel class of inhibitors allows to determine the crosstalk of iron dependent lipid peroxidation with kinome signaling changes towards Tau phosphorylation and ferroptosis induced neurodegeneration. Within the current grant application, we want to identify ferroptosis dependent inhibition of Tau kinases by blocking ferroptosis in two cellular models of Alzheimer's disease using innovative phospho-peptidome kinome activity profiling, followed by kinobead-phosphoproteomic validation.

Researcher(s)

• Promoter: Hassannia Behrouz

Research team(s)

Project type(s)

• Research Project

Abstract

Neuroblastoma (NB) is the most common solid tumor outside the brain of infants and very young children. The aggressive forms of neuroblastoma are often accompanied by an increased resistance to current chemotherapies due to defects in the molecular mechanisms that normally leads to the death of cancer cells. Therefore, the challenge is to find new molecular mechanisms to kill the cancer cells. Recently, we discovered a new approach to kill aggressive therapy-resistant neuroblastoma in mice by triggering a sort of biological rusting in cancer cells called ferroptosis. Ferroptosis rusts away the membranes of cells, which quickly kills the cells. By using nanoparticles, we were able to minimize the side effects of treatment and enhanced tumor targeting. However, to get full tumor regression without relapse using a nanomedicinal approach, it is needed to further improve the efficacy of ferroptosis targeting in neuroblastoma. In this project, we will use different genetic and pharmacological approaches to improve the therapeutic applicability of ferroptosis in neuroblastoma. We will identify potent ferroptosis triggers and nanoparticles, which could effectively suppress the tumor growth and relapse in cell- and patient-derived mouse cancer models as a stepping stone to clinical investigation.

Researcher(s)

• Promoter: Vanden Berghe Tom
• Fellow: Hassannia Behrouz

Research team(s)

Project type(s)

• Research Project