Cell based miRNA Expression as a Marker of Response to Bevacizumab (Avastin) Therapy of Patients with Colorectal Cancer

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The use of anti-angiogenic therapies, such as Bevacizumab (Avastin), which disrupt vascular endothelial growth factor (VEGF) signalling, has significantly extended the treatment options for patients with metastatic colorectal cancer (CRC). Nevertheless, a significant number of patients does not respond to this high-cost therapy; while others suffer from severe side effects such as impaired wound healing and an increased risk of stroke. These problems are compounded by the fact that there is as yet no clear marker for selecting patients that may benefit from anti-VEGF-therapy.Circulating tumor cells (CTCs), shed from the tumor, and circulating endothelial progenitor cells (CEPs), mobilized from the bone marrow (BM), are detected in the blood from cancer patients. Both populations of cells have been shown to be associated with tumor progression and resistance to a range of treatments, including anti-angiogenesis therapy. However, first studies investigating the predictive value of these cells in patients receiving Bevacizumab treatment have revealed controversial results. CTCs/CEPs as they are currently defined describe a complex cell population of cells with genetic and phenotypic heterogeneity. Currently, it is still unknown which properties enable individual CTCs to grow out to solid metastasis. Additionally, a subpopulation of CEPs that plays a crucial role in the development of therapy resistance has not yet been identified.Thus, the objective of my project is (i) to investigate the heterogeneity of CTCs/CEPs using miRNA expression profiling and (ii) to develop a panel of miRNAs that will be used in combination with single cell analysis of CTCs/CEPs to determine patients´ response to Bevacizumab treatment. The expression of miRNAs that are pathologically relevant in malignancy/tumor angiogenesis will be analyzed on single CEPs/CTCs using a combination of In Situ hybridization (ISH) and immunocytochemistry (ICC). Furthermore, CRC patients receiving Bevacizumab will be analyzed for CTCs/CEPs and cell based miRNA-expression at six different time points of treatment. The correlation to clinical data will lead to the identification of miRNAs expressed in CTCs/EPCs that are predictive of disease progression. These miRNAs and their function will be further studied using cell transfection experiments the results of which I believe will contribute to the development of novel strategies to overcome therapy resistance.