<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Development of novel therapeutic strategies for specific targeting of liver and other solid cancers"^^ . "The emergence of molecular targeted therapies has marked a paradigm shift in the scope of anticancer therapy in recent decades. However, acquired resistance to treatment and severe side effects frequently limit the efficacy of current therapies. Additionally, targeting solid tumors therapeutically remains a significant challenge due to the intricate complexity of both the tumor and its surrounding microenvironment. With this concept in mind, I aimed to develop new therapeutic strategies to achieve highly specific targeting of tumor cells without damaging normal cells, ultimately improving outcomes with fewer adverse effects. To this end, I explored approaches in the fields of cancer nanomedicine, genetics, and immunotherapy.\r\n\r\nIn the first approach, I examined the anti-tumor efficacy of indocyanine nanoparticles (INPs) encapsulating proteasome inhibitors that have not yet been used for the treatment of solid tumors. Carfilzomib (CFZ) INPs exhibited improved growth inhibition of murine primary liver cells in vitro compared to CFZ diluted in DMSO, driving cells into G2/M-phase cell cycle arrest and subsequent caspase-mediated apoptosis. Moreover, CFZ INPs were well-tolerated in vivo and showed specific accumulation in murine autochthonous liver tumors. However, these INPs did not demonstrate an improved therapeutic effect against such tumors compared to the experimental controls. Other strategies, such as combined INPs encapsulating CFZ and the tyrosine kinase inhibitor sorafenib, did not provide a therapeutic advantage either. Thus, further investigations employing other in vivo models are required to ascertain the reason underlying the lack of anti-tumor activity of these newly developed INPs.\r\n\r\nIn the second approach, I investigated how passenger or bystander events in genomic amplifications could be therapeutically exploited by providing targetable molecules on the cell surface. For this, I screened the genomic status and expression levels of cell surface protein- coding genes (CSPs) in hepatocellular carcinoma (HCC) using publicly available multi-omics data. This screen identified MPZL1 gene (Myelin protein zero-like 1), located in chromosome 1q, as a CSP-coding gene amplified in 75% of HCCs, with elevated mRNA levels in tumors compared to healthy livers. I further assessed MPZL1 protein expression in different human tissues of cancerous (n=2244) and normal (n=90) origin by immunohistochemistry, assigning expression scores equivalent to the HER2-score employed in the clinics. A high percentage of tumors received scores 2 or 3, such as 48% of HCCs or 89% of TNBCs, compared to healthy tissues, which mostly got scores 0 or 1. Next, a highly specific monoclonal antibody against the extracellular domain of human MPZL1 protein was developed to target MPZL1-expressing cells, and its scFv sequence was subsequently utilized to generate a chimeric antigen receptor (CAR) construct against MPZL1. T cells expressing this CAR construct showed specific killing of several human cancer cell lines in vitro, along with enhanced cytotoxic cytokine production (TNFα, IFNγ, GZMB, IL-2) when encountering the specific antigen. Importantly, MPZL1-28ζ CAR-T cells induced regression of human MPZL1+ tumors in liver and breast cancer cell line- derived xenograft mouse models, as well as complete eradication of murine autochthonous liver tumors with human MPZL1 overexpression. In summary, my results revealed MPZL1 as a novel therapeutic target for tumors harboring amplification of chromosome 1q, a recurrent phenomenon across cancer genomes, and provided proof of concept highlighting the potential of passenger events within large chromosomal amplifications as potent therapeutic targets."^^ . "2025" . . . . . . . "Sonia"^^ . "Jiménez Vázquez"^^ . "Sonia Jiménez Vázquez"^^ . . . . . . "Development of novel therapeutic strategies for specific targeting of liver and other solid cancers (PDF)"^^ . . . "Development of novel therapeutic strategies for specific targeting of liver and other solid cancers (Other)"^^ . . . . . . "Development of novel therapeutic strategies for specific targeting of liver and other solid cancers (Other)"^^ . . . . . . "Development of novel therapeutic strategies for specific targeting of liver and other solid cancers (Other)"^^ . . . . . . "Development of novel therapeutic strategies for specific targeting of liver and other solid cancers (Other)"^^ . . . . . . "Development of novel therapeutic strategies for specific targeting of liver and other solid cancers (Other)"^^ . . . . . "HTML Summary of #35492 \n\nDevelopment of novel therapeutic strategies for specific targeting of liver and other solid cancers\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .