FORRCE

Framework for outcomes of radionuclide radiation on cellular environment

Project objectives and goals

Targeted radionuclide therapy (TRNT) offers promising avenues for treating cancer, yet current approaches to model its biological effects are largely adapted from external beam radiotherapy and fail to account for the unique characteristics of TRNT, namely, low dose rates for extended periods, heterogeneous energy deposition and complex subcellular dynamics. This project aims to advance the fundamental understanding of dose-response relationships in TRNT by developing and validating a modular, mechanistic framework that bridges physical energy deposition with biological outcomes across multiple spatial and temporal scales.

We will integrate high-resolution track-structure simulations (Geant4-DNA) with mechanistic models of DNA repair and survival, enhanced by artificial intelligence (AI) to simulate cellular damage in realistic 2D and 3D cellular environments. The framework will be validated using radiobiological assays, including among others gammaH2AX/53BP1 foci analysis, survival/death balance, microdosimetry, and advanced imaging techniques such as secondary-ion mass spectrometry (SIMS) and expansion microscopy, using human prostate cancer cells (e.g. PC3-PIP and LNCaP) exposed to clinically applied prostate specific membrane antigen (PSMA)-targeting radiopharmaceuticals labelled with relevant radionuclides (e.g. Ac-225, Tb-161, Lu-177). Experimental data will support the generation of in silico dose–response curves and allow for comparative evaluation of biological effectiveness against external radiation references.

The project is fully aligned with the objectives of PIANOFORTE Topic 1 and will contribute to the understanding of how spatial and temporal variations in dose delivery affect health outcomes. It will deliver open-access datasets and validated tools for internal dosimetry and mechanistic modelling. In parallel, the project will support capacity building through interdisciplinary training, open science practices and integration with PIANOFORTE WP5 infrastructures. This work will lay the groundwork for biologically optimised, personalized radiopharmaceutical therapies and improved radiation protection strategies across Europe.

 

Project coordinator

Dr. Ana Vaniqui, STUDIECENTRUM VOOR KERNENERGIE/CENTRE D’ETUDE DE L’ENERGIE NUCLEAIRE – SCK CEN, Research on Dosimetric Applications, Belgium