Research Amber Driesen

Abstract

Iron plays a major role in cell homeostasis by regulating metabolism, respiration and DNA synthesis. Moreover, various cancer cells, such as multiple myeloma (MM), are addicted to increased iron levels as compared to their healthy counterparts to maintain rapid growth and proliferation. MM is a B-cell malignancy of malignant plasma cells in the bone marrow. Besides, iron plays an important role in the regulation of ferroptotic cell death, which makes iron metabolism an attractive therapeutic cancer target. We recently demonstrated that therapy resistant MM cells are highly sensitive to ferroptosis. Remarkably, we found that ferroptosis treatment triggers unique epigenetic changes in iron-specific histone modifications and chromatin remodeling proteins FOXA1 and NR4A1-3 which target genes involved in metal detoxification, cell cycle progression and DNA damage regulation. In this respect, I want to further elucidate iron-chromatin dependent epigenetic regulation ferroptosis therapy sensitivity in MM in vitro and ex vivo (blood, bone marrow) by i) demonstrating in vitro iron binding to recombinant histones, ii) assessing iron-histone binding-dependent ferroptosis therapy sensitivity, iii) assessing iron-histone-ferroptosis-dependent changes in chromatin accessibility and gene expression and iv) assessing single cell iron-histone-ferroptosis gene expression and antitumor immunity signatures in MM patient samples.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Fellow: Driesen Amber

Research team(s)

• Cell death signaling (CDS)

Project type(s)

• Research Project

Abstract

Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of a clone of malignant plasma cells in the bone marrow. Despite the progress in therapy, MM remains largely incurable. Conventional therapies with proteasome inhibitors (bortezomib), immunomodulatory drugs (thalidomide, lenalidomide), epigenetic drugs (Velcade), corticosteroids, and alkylating agents (melphalan) are associated with low remission rates, limited survival times (approx. 5 years) and the development of drug resistance. In the current project, pharmacological and biophysical (plasma) ferroptosis strategies will be optimized for MM chemosensitisation and/or immunogenic therapeutic approaches in MM cell lines (in vitro), MM patient samples (ex vivo) and preclinical MM mouse models (in vivo). In addition, a novel phospho-catalytic kinome activity mapping approach will be developed using biological peptide targets as phospho-sensors which allow kinome level quantification of redox specific changes in tyrosine kinase activities following ferroptosis chemosensitisation and/or immunisation in the different experimental therapeutic setups. Moreover, this phosphopeptide fingerprint can be applied as a diagnostic and/or predictive biomarker for personalized medicine applications for improved therapeutic outcome in MM patients

Researcher(s)

• Promoter: Vanden Berghe Wim
• Fellow: Driesen Amber

Research team(s)

• Cell death signaling (CDS)

Project type(s)

• Research Project