TumoR microEnvIronment Normalization FOR enhanCed photodynamic thErapy

The progression of cancer is closely associated with alterations in the mechano-cellular phenotype and in the structure and mechanical properties of the tumor microenvironment (TME) in a complex and not well-understood manner. Desmoplasia, a tumour-associated fibrotic reaction, is responsible for tumor stiffening, poses a major barrier to effective drug delivery. Although novel therapeutic strategies that target cancer cells are emerging, their efficacy varies due to intra- and inter-patient variability as well as tumor heterogeneity. Notably, photodynamic therapy (PDT) is gaining prominence as a compelling alternative. This two-stage treatment harnesses both light energy and a specialized drug (photosensitizer, PS) to target cancer cells upon activation by a specific wavelength of light. However, the effectiveness of PDT is greatly compromised by various resistance factors originating from the complex TME. These factors can present several biological barriers, including desmoplasia. In this project, we propose the use of TME normalization treatment with approved anti-fibrotic drugs in combination with PDT. We aim to test the hypothesis that the combination of anti-fibrotic drugs that remodel and normalize the TME with PDT can increase the PDT efficiency. The specific research objectives are focused on breast cancer (BC) and includes in vitro study of the effect of different components of PDT treatment on BC cells, in vivo study of the effectiveness of the combination of PDT with anti-fibrotic treatment in murine BC models and mathematic modelling to optimize the combination therapies. In the proposed project, the fellow will acquire scientific and complementary skills according to his personalized career development plan and through advanced training, international and inter-sectoral mobility will reach a position of professional maturity in research.