Cancer is a major health burden affecting 12-million people each year world-wide. Tumor growth is not only determined by tumor cell malignancy but also by the tumor microenvironment. Cancer-associated fibroblasts (CAF) are key cell type in the tumor microenvironment influencing tumor initiation, angiogenesis, metastasis and tumor drug response. CAF strongly express platelet-derived growth factor receptors (PDGFR). The applicant has recently developed a novel drug delivery technology to target CAF using a PDGFR-binding carrier (HPC) which is composed of a PDGFR-binding cyclic peptide conjugated to albumin. Targeting of doxorubicin using HPC induced anticancer effects by depleting tumor stromal tissue in-vivo.
This proposal aims to further exploit this technology to investigate the therapeutic potential of CAF in tumor. In the first part of the project, we will study the impact of CAF on tumor initiation, metastasis and tumor drug uptake. To carry out this, we will use doxo-HPC in order to kill CAF selectively in tumors and examine the effect on latter parameters. Of note, these experiments will be performed in the state-of-the-art genetically-modified tumor models specifically developed to study these tumor mechanisms.
In the second part, we will study the relative importance of different signaling pathways (PDGF, TGF-beta and hedgehog) in CAF. Different inhibitors of these pathways will be conjugated to HPC. Treatment with these conjugates will induce blockade of these pathways in CAF through which we can study their importance in CAF-inducing effects. This project thus brings together the expertise of the applicant in targeted drug delivery with the experimental therapy expertise of the host group. Surely, this project will help the researcher in long-term integration and to explore his knowledge and skills to develop novel anti-CAF therapies. The project will also yield new scientific excellence with the potential of benefiting human health and European economy.
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