Speaker
Description
Prostate cancer (PCa) has been widely studied, yet new strategies are needed to mitigate resistance and recurrence. Ferroptosis, an iron-dependent form of regulated cell death, is emerging as a promising therapeutic strategy, yet its mathematical modelling in PCa remains limited \cite{Maccarinelli2023}. This is especially relevant for castration-resistant prostate cancer (CRPC), where hormonal control fails and new therapies are needed. In this work, we developed a hybrid multi-scale framework to investigate the response of PCa to iron-supplemented, RSL3-induced ferroptosis. We use an ABM to represent the growth and treatment response dynamics of normal and cancer cells (e.g. proliferation, necrosis, phenotypic switching, and ferroptotic death), PDE reaction-diffusion equations for nutrients and drugs in the tumour microenvironment, and ODEs for the intracellular dynamics of key ferroptosis factors (e.g. iron, lipid hydroperoxides, and GPX4). Simulations of this hybrid ABM-PDE-ODE system calibrated to in vivo experiments reasonably capture tumour progression, treatment response, spatial patterns of the cellular species and drug-combination effects. Thus, by coupling intracellular biochemistry with spatial tumour dynamics, our framework enables investigation of how iron availability and GPX4 inhibition govern ferroptotic sensitivity, and how treatment scheduling and dosing can be optimised to maximise tumour elimination and prevent progression to CRPC.
Bibliography
@article{Maccarinelli2023,
abstract = {
Prostate cancer (PCa) is a leading cause of death in the male population commonly treated with androgen deprivation therapy that often relapses as androgen-independent and aggressive castration-resistant prostate cancer (CRPC). Ferroptosis is a recently described form of cell death that requires abundant cytosolic labile iron to promote membrane lipid peroxidation and which can be induced by agents that inhibit the glutathione peroxidase-4 activity such as RSL3. Exploiting in vitro and in vivo human and murine PCa models and the multistage transgenic TRAMP model of PCa we show that RSL3 induces ferroptosis in PCa cells and demonstrate for the first time that iron supplementation significantly increases the effect of RSL3 triggering lipid peroxidation, enhanced intracellular stress and leading to cancer cell death. Moreover, the combination with the second generation anti-androgen drug enzalutamide potentiates the effect of the RSL3 + iron combination leading to superior inhibition of PCa and preventing the onset of CRPC in the TRAMP mouse model. These data open new perspectives in the use of pro-ferroptotic approaches alone or in combination with enzalutamide for the treatment of PCa.
},author = {Federica Maccarinelli and Daniela Coltrini and Silvia Mussi and Mattia Bugatti and Marta Turati and Paola Chiodelli and Arianna Giacomini and Floriana De Cillis and Nadia Cattane and Annamaria Cattaneo and Alessia Ligresti and Michela Asperti and Maura Poli and William Vermi and Marco Presta and Roberto Ronca},
doi = {10.1038/s41420-023-01383-4},
issn = {2058-7716},
issue = {1},
journal = {Cell Death Discovery},
month = {3},
pages = {81},
title = {Iron supplementation enhances RSL3-induced ferroptosis to treat naïve and prevent castration-resistant prostate cancer},
volume = {9},
year = {2023}
}
