Research Report 2010 - MDC

Graduate StudentsJana RolffAnnika Wulf-GoldenbergMarlen KeilJane WenzelAndrea OrthmannMaria Rivera MarkelovaMaria StecklumTechnical AssistantsMonika BeckerMargit LemmLars KonkelSecretariatSylvia SchulzFigure 1. One dimensional hirarchical clustering of primary lung carcinomas and their derived xenografts (Affymetrix profiling).these, 155 probe sets mainly belonging to cell adhesion,immune response and extracellular pathways weredown regulated. These data confirm the observationthat during early xenotransplantation, human normalaccessory cells are replaced by murine tissue while thetumors themselves maintain their identity. Some ofthe NSCLC xenografts were used as intracranialgrowing models to show the potential of a novelepothilone derivative, Sagopilone, to inhibit brainmetastases in a very efficient way. Further analysesconcerning the relevance of EGFR related signalingfor response of tumors to anti-EGFR therapies areongoing.Inhibition of metastasis by nanoparticlesThe formation of metastases is not completely understoodand is the main reason for a failure in cancertherapy. We used the human MT3 breast cancer in amouse xenograft model to gain a deeper insight intothe mechanisms of metastasis. We found that thedevelopment of lung metastases is essentially dependenton the formation of fibrin clots in the vasculature asa precondition for a pulmonary arrest of tumor cells.Subsequently, intravascular micro-metastases are generatedwhich finally invade into the surrounding tissue.We could further demonstrate a prevention of fibrinclot formation in vivo by the use of dual liposomes,simultaneously encapsulating the anticancer drug,Perifosine, and the haemostatic inhibitor, Dipyridamole.These dual liposomes are potent inhibitors ofmetastasis and caused a significant reduction in thenumber of lung metastases both in an experimental(MT3) (Figure 2 a) and in a spontaneous murine 4T7breast carcinoma model. Our data suggest that thesedual liposomes may display a new principle to preventmetastasis.Cancer Research 137