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Projekt Druckansicht

"Liquid Biopsy" im Leberzellkrebs

Antragsteller Dr. Johann von Felden
Fachliche Zuordnung Gastroenterologie
Hämatologie, Onkologie
Förderung Förderung von 2017 bis 2019
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 386082919
 
Erstellungsjahr 2019

Zusammenfassung der Projektergebnisse

Liver cancer is among the deadliest cancers worldwide. Despite a broad knowledge on molecular alterations in early stage hepatocellular carcinoma (HCC), the most frequent form of liver cancer, biomarkers for early detection or prediction of response to systemic therapies are lacking. The objective of this project was to investigate the role of liquid biopsy in HCC, particularly in the setting of the aforementioned clinical needs. Over the recent years, liquid biopsy has emerged as a novel technology to assess tumor components that are released to the bloodstream, such as circulating tumor DNA (ctDNA), circulating tumor cells (CTC), or extracellular vesicles (EVs). During my stay at the laboratory of Dr. Villanueva at the Tisch Cancer Institute at Mount Sinai in New York, USA, we have successfully carried out several liquid biopsy projects in HCC. In a pilot study, we were able to detect tissue mutations with ultra-deep next generation sequencing of ctDNA in paired plasma samples from the same patients. We have further refined this technology and applied it in a large cohort of patients with advanced HCC. Mutational profiling of ctDNA of advanced stage patients revealed similar mutation frequencies compared to tissue sequencing of early stage patients and was able to identify patients with primary resistance to systemic therapies. Sequential profiling of ctDNA throughout the treatment correlated with treatment response, including the detection of new mutations at the time of progressive disease. These findings underscore the potential of liquid biopsy in personalized medicine and provide the rationale for biomarker enriched clinical trials that might change decision-making in advanced stage HCC, specifically in the context of treatment allocation. In a different project, we isolated plasma EVs from HCC patients and controls at risk for HCC. EVs are small, nanosized vesicles that are released by their host cell and contain bioactive cargo, such as nucleic acids and proteins. By genome-wide RNA sequencing of plasma EVs, we identified differentially expressed transcripts between HCC patients and controls. In an independent phase 2 biomarker stud, we found our signature was able to discriminate patients with early stage HCC from controls at risk for HCC. Our test provides a non-invasive, operator independent tool for HCC risk stratification and might improve the performance and implementation of HCC surveillance. In a small study on single-cell whole transcriptome sequencing of CTCs, we identified heterogeneity of CTCs within the same patient and further identified potentially druggable alterations, suggesting that liquid biopsy is capable to capture tumor heterogeneity and infer clinically meaningful conclusions. In summary, our findings underscore the potential impact of liquid biopsy on decision making in HCC and suggest potential clinical implications.

Projektbezogene Publikationen (Auswahl)

 
 

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