Investigating potential therapeutic targets, biomarkers, and preclinical models in malignant solid tumors

Abstract

As malignant diseases remain to be associated with high morbidity and mortality, the search for more effective therapeutics and biomarkers is a critical medical need. Research efforts in the last decade have led to the development of a novel and more physiological <em>in vitro</em> cancer model called patient-derived organoids (PDOs), which are cultured 3-dimentional self-organizing multi-cell structures generated from cancer stem cells. This thesis aimed to investigate potential novel therapeutic targets, employing in-house established PDOs, and predictive biomarkers in solid malignant tumors. In the first publication, we revealed that the TROP2 protein is frequently expressed in cholangiocarcinoma and that cholangiocarcinoma PDOs are highly susceptible to sacituzumab govitecan, an antibody-drug conjugate targeting TROP2. Using TROP2-knockout cholangiocarcinoma cell lines, we also demonstrated the target-dependent and target-independent mechanisms of action. Given that sacituzumab govitecan is a clinically-approved medication, used for the treatment of breast cancer, with a known safety profile in humans, our data suggests that sacituzumab govitecan could be repurposed for the treatment of cholangiocarcinoma patients. In my second publication, we established a novel protocol for generating PDOs from melanoma brain metastases and demonstrated that their response to targeted therapy (BRAF and MEK inhibitors) <em>in vitro</em> matched the mutational profile of the original tumor samples, implying that they represent an accurate model for predicting patient responses as well as for efficient targeted drug screening. In my third publication, we demonstrated that the expression of the amino acid transporter <em>SLC7A5</em>/LAT1 in tumor cells and in intra-tumoral immune cells is associated with shorter overall survival in a cohort of biliary tract cancer. Moreover, we revealed that its expression in intra-tumoral immune cells is higher in primary-sclerosing cholangitis associated- biliary tract cancer (PSC-BTC) compared to sporadic biliary tract cancer. These results suggest that <em>SLC7A5</em>/LAT1 could represent a prognostic biomarker in BTC, and demonstrates differences in the immune cells' phenotype between sporadic and PSC-associated BTC. Taken together, the findings of these studies could potentially improve the therapy, management, and/or prognosis of cholangiocarcinoma patients. Moreover, the proposed PDO culture model of melanoma brain metastases could pave the way for novel drug development for this advanced disease.