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Targeting ferroptosis to treat high-risk neuroblastoma

Smyrilli, Kyriaki (2022) MOBN02 20212
Degree Projects in Molecular Biology
Popular Abstract
Inducing iron-dependent death to treat high-risk childhood cancer

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor and one of the deadliest, accounting for 15% of pediatric cancer deaths. In Europe there are 10.5 cases per million, with the median age at diagnosis being 17 months. In some cases, tumors regress spontaneously but in others they relapse and become resistant to treatment. Regardless of the intense treatment, survival rate for high-risk NB is still less than 50%. Hence, there is a high need for improved treatments which will not lead to resistance. This study aimed to test the potential of three drugs which induce an iron-dependent cell death, known as ferroptosis, to treat high-risk NB. These drugs... (More)
Inducing iron-dependent death to treat high-risk childhood cancer

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor and one of the deadliest, accounting for 15% of pediatric cancer deaths. In Europe there are 10.5 cases per million, with the median age at diagnosis being 17 months. In some cases, tumors regress spontaneously but in others they relapse and become resistant to treatment. Regardless of the intense treatment, survival rate for high-risk NB is still less than 50%. Hence, there is a high need for improved treatments which will not lead to resistance. This study aimed to test the potential of three drugs which induce an iron-dependent cell death, known as ferroptosis, to treat high-risk NB. These drugs were also combined with the currently used chemotherapeutic protocol to test for potential enhanced sensitivity against aggressive resistant NB.

Background, aims and significance of this study
NB cells have a higher metabolic need for iron. This enhanced metabolism promotes aggressive growth but can also produce damaging byproducts called reactive oxygen species (ROS). To deal with ROS, cancer cells also have enhanced compensatory antioxidant systems to prevent damage and cell death. We can take advantage of this dependency from a therapeutic standpoint, as the inhibition of these antioxidant systems would potentially sensitize NB cells to ferroptosis, an iron-dependent type of cell death. In this study we have tested three drugs that inhibit different stages of these systems and we have used patient-derived models called organoids, which are 3D cultured spheres of cancer cells. These models derived from high-risk NB patients and are known to be highly resistant to normal chemotherapy, making them perfect to test novel therapeutics.

Main results
The ferroptosis-inducing drugs were more efficient in inhibiting the cell growth of the resistant models, compared to the current standard-of-care. Two of the drugs seemed more promising and were each combined with the current standard-of-care to test for possible enhanced sensitivity. One combination led to a decreased sensitivity in both models, known as an antagonistic effect. The other combination moderately increased the inhibition of cell growth caused by each of the drugs individually, known as an additive effect. RNA analysis of the later combination showed an upregulation of mechanisms which lead to increased intracellular iron levels and a downregulation of a drug efflux pump. This drug efflux pump has been associated with NB chemoresistance. Hence, this data suggests that this drug combination promotes ferroptosis and increases the sensitivity of resistant NB tumours by decreasing drug efflux.

Conclusions
This study revealed the potential of ferroptosis-inducing drugs to treat high-risk resistant NB. Combination of the current standard-of-care with one of the ferroptosis-inducing drugs tested, led to enhanced sensitivity, providing an alternative approach to treat this complex disease.

Master’s Degree Project in Molecular Biology 45 credits 2022
Department of Biology, Lund University


Advisors: Adriana Mañas Nuñez and Daniel Bexell
Advisors Unit/Department: Division of Translational Cancer Research, Medicon Village, Building 404 (Less)
Please use this url to cite or link to this publication:
author
Smyrilli, Kyriaki
supervisor
organization
course
MOBN02 20212
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9103305
date added to LUP
2022-11-17 12:05:53
date last changed
2022-11-17 12:05:53
@misc{9103305,
  author       = {{Smyrilli, Kyriaki}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Targeting ferroptosis to treat high-risk neuroblastoma}},
  year         = {{2022}},
}