Kurzfassung

Prostate carcinoma (PCa) is one of the leading causes of tumor-related deaths in men. With respect to the genomic profile and biological characteristics, PCa is a very heterogeneous type of cancer which can be clinically characterized from indolent to vastly aggressive. Treatment of patients with radiation and/or anti-androgen therapy quite often results in a recurrence of the tumor, which is then resistant to therapy. This is frequently accompanied by a neuroendocrine differentiation and an...Prostate carcinoma (PCa) is one of the leading causes of tumor-related deaths in men. With respect to the genomic profile and biological characteristics, PCa is a very heterogeneous type of cancer which can be clinically characterized from indolent to vastly aggressive. Treatment of patients with radiation and/or anti-androgen therapy quite often results in a recurrence of the tumor, which is then resistant to therapy. This is frequently accompanied by a neuroendocrine differentiation and an increased apoptosis resistance of the recurrent tumor. Therefore, the evaluation of novel combination therapies for the treatment of PCa is  of particular importance. Within this context there is also a lack of diagnostic markers for a more precise prediction of therapy response. Therefore, the identification of novel biomarkers for an improved diagnostic stratification of patients for the therapy of PCa is an urgent need. In our preliminary experiments we found that the increased expression of Cyclin K (CycK) protein in PCa was associated with a shorter biochemical recurrence-free survival of the patients. Furthermore, our functional analyses revealed that a decreased expression of CycK in PCa cells resulted in a delayed proliferation, aberrant mitosis and in the induction of apoptosis. In this regard, the CycK-mediated regulation of Aurora kinase B and DNA repair pathways represent a crucial mechanism. In the proposed project we will investigate the eligibility of CycK as therapeutic target in combination with standard radio- or hormone therapy. We assume that inhibition of CycK might impede DNA repair resulting in a more pronounced sensitivity to radio- and hormone therapy of PCa cells. We will further focus on the role of CycK during the development of PCa. Since CycK is involved in the transcription of DNA repair genes, we suppose, that low expression levels might enhance PCa development and aggressiveness. Hence CycK expression might serve as a prognostic marker for PCa. Finally, we will analyze the role of CycK in neuroendocrine differentiated PCa cells. Our preliminary data showed that a decreased expression of CycK resulted in a loss of neuroendocrine differentiated PCa cells. Based on this, we suppose that neuroendocrine differentiated PCa might be especially sensitive to a CycK-targeting therapy.» weiterlesen» einklappen