Pharmacodynamic and pharmacogenomic research of new drugs in the treatment of solid tumors

Subproject 1. In the first part of the project new complexes based on various metals, such are trans-PT, Cd(II), Zn(II), Ru (II and III) with different ligands, will be screened for antiproliferative activity against several cancer cell lines, especially Pt-resistant cells. The mechanism of their action will be compared to cisplatin, the cell cycle perturbation and mode of cell death, type and level of DNA breaks and role of PARP enzyme and PARP-inhibitors, antimetastatic and antiinvasive potential, the role of some signal transduction molecules will be examined as well as antiangiogenic potential. Combinational treatment of our metal complexes with some conventional anticancer drug will be used. Selected compounds will be tested for their antitumor activity in in vivo animal model and offered for further preclinical and clinical development. Subproject 2. The focus of the second part of the project will be on continuation of analysis of already established predictive biomarkers in our lab as well as on introduction of new biomarkers for solid tumors. We will analyze several biomarkers in prospectively collected tumor samples of some rare clinical entities; such are inflammatory and locally advanced breast cancer, rectal cancer, hepatocellular carcinoma. Patients will be treated by radiotherapy, combined chemo-radiotherapy or targeted agents and clinical outcome will be associated with the expression of several molecular biomarkers.