Projekt 3

LIQUID BIOPSY METHODS FOR DETERMINING TUMOR CELL HEEROGENICITY IN ADVANCED PROSTATE CANCER: RESISTANCE DEVELOPMENT, TRANS- AND DE-DIFFERENTIATION.

The use of new drugs has significantly improved the treatment of prostate cancer in recent years. However, the consequence of androgen receptor (AR)-directed therapy is an increasing treatment pressure on the prostate cancer cells. The tumor cell attempts to counteract this by activating alternative signaling pathways. Consequently, aggressive variants of prostate cancer (AVPC) develop, characterized by a more rapid progression of the disease with a frequently unusual metastatic pattern. In addition, a proportion of AVPC also shows features of neuroendocrine transdifferentiation. Because AVPC produce little prostate-specific antigen (PSA), which is commonly used as a progression parameter to estimate treatment success or disease progression, transition to AVPC is often not detected, especially in the early stages.

Liquid biopsy techniques are based on the detection of circulating tumor cells and tumor cell products, such as nucleic acids, present in body fluids. For example, analysis of circulating tumor cells and tumor DNA in blood can provide information about genomic aberrations in tumor tissue. Liquid biopsies are also better at detecting tumor heterogeneity than conventional biopsies. In addition, the disease can be better tracked in its progression by continuous measurements.

The aim of this project is to identify new blood-based biomarkers for the diagnosis of AVPC. For this purpose, circulating tumor cells from the blood of participating patients will be examined with the CellSearch system on the one hand and on the other hand the gene expression of neuroendocrine genes in circulating tumor cells will be specifically analyzed. From the same patients, cell-free tumor DNA is additionally enriched and isolated from the blood. Subsequently, genomic aberrations of some key tumor suppressor genes will be investigated by next-generation sequencing.

The development of biomarkers for the blood-based diagnosis of AVPC will serve as a basis for clinical studies and the optimization of treatment concepts for affected patients.