The Vanden Berghe Lab is a multidisciplinary team performing basic as well as applied research on mechanisms, treatment and prevention of cell death-driven diseases, with focus on ferroptosis (kind of biological rust). We follow an integrated approach from knowledge building and discovery to (pre)clinical research, along support and consultancy.
30% of global deaths occur in intensive care units due to multiple organ dysfunction syndrome (MODS). Excess iron is known to cause cell death/ferroptosis and (multi) organ damage in critical illness. In collaboration with Augustyns lab, we developed, characterised and patented ferrostatin-analogues with improved efficacy, solubility and stability. Out of >160 ferrostatin-analogues, two lead candidates with increased solubility were found substantially more stable than Fer1. We have proven the in vivo superior protective action of both lead candidates, over benchmark Fer1 in several ferroptosis-driven experimental disease models. Moreover, one of our lead candidates is lifesaving against acute liver injury, which is unprecedented. We are analysing critical illness patients with MODS for signs of ferroptosis. Novel diagnostic tools are developed to detect ferroptosis and cell death.
The success of transplantation is hampered by a shortage in suitable organ grafts and the adverse effects of ischemia reperfusion injury (IRI). Inflammation and cell death in the transplanted organ, caused by the activation of the innate immune system as part of the IRI process, lead to primary graft dysfunction (PGD). Transplant recipients that suffer from severe PGD have an increased risk for early and late morbidity and mortality.
The ex-vivo organ perfusion strategy was developed to increase the number of available grafts. During the ex-situ phase between organ retrieval and transplantation, machine perfusion offers a unique window of opportunity for organ graft modulation to target ferroptosis due to IRI. Our in-house developed and patented third generation ferroptosis inhibitors show superior protection in preclinical models of organ injury and are therefore good drug candidates to block injury during transplantation.
Neuroblastoma is the most common solid tumor outside the brain of infants and very young children. The aggressive form or high-risk neuroblastoma is characterized by a poor clinical outcome, therapy resistance or even relapse. 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. We are developing novel pharmacological and nanomedicinal approaches to improve the therapeutic applicability of ferroptosis in neuroblastoma.
Multiple sclerosis (MS) is an autoimmune disease characterised by central nervous inflammation and demyelination driven by an auto-amplifying mechanism of inflammation and cell death. MS lesions and cerebrospinal fluid of MS patients revealed several signs of ferroptosis. Treatment with our lead ferroptosis inhibitor strongly delays relapse and ameliorates disease progression in a preclinical model of relapsing-remitting MS. Stroke is a devastating neurological condition, representing a leading cause of disability and death worldwide. Although stroke is a global health priority, there are still no highly effective acute therapies available. There are quite some indications that ferroptosis also contributes to stroke, therefore the aim of this research project is to explore the therapeutic potential of ferroptosis targeting in stroke.
In patients with sepsis or multi-organ failure syndrome (MODS), plasma labile iron and excessive inflammasome signalling are key detrimental factors associating with mortality. Excess iron is known to cause ferroptosis and organ damage. MODS and sepsis often show substantial individual variation due to genetic differences, co-morbidities, frailty and dynamic disease fluctuations. To deal with this form of heterogeneity, innovative biomarkers with predictive value are needed to allow determining subtypes of clinically similar patients. We use genetic models of ferroptosis-driven kidney or liver injury, along samples derived from critically ill patients to identify ferroptosis signatures in biofluids. We are developing immuno-based bead arrays to detect ferroptosis and factors released by dying cells, as well as (epi)sequencing cell free DNA in biofluids using Nanopore technology to detect tissue specific cell death. Precision medicine using innovative molecular diagnostics will bring intensive care into the 21st century.
Ferroptosis is increasingly recognized as a promising treatment option for cancer therapy. However, epigenetic changes have been reported as one of the mechanisms for anti-tumor drug resistance. The aim of this project is to understand how the epigenetic modifications affect ferroptosis resistance and how to revert them. In addition, diagnostic tools that predict tumor’s sensitivity for ferroptosis are still lacking. Therefore, we are also developing a Nanopore-seq based epi-ferroptosis biomarker assay (‘nFERROCATCH’) to systematically predict the sensitivity to ferroptosis-based cancer therapies.
A big thank you to…
