Alteration of cellular phenotype by therapeutic modulation of epigenetic gene regulation to induce synthetic lethality in prostate cancer

• Antragsteller: Professor Dr. Philipp Nuhn
• Fachliche Zuordnung: Reproduktionsmedizin, Urologie
• Förderung: Förderung von 2010 bis 2012
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 181096137

Epigenetics refers to heritable variations in gene expression that occur without alteration in DNA sequence. Disruption of epigenetic processes, which affect chromatin structure and function, can lead to altered gene function and malignant cellular transformation. Unlike genetic deletions and mutations, epigenetic aberrations are potentially reversible. Somatic epigenetic defects are present in all human prostate cancers, leading to silencing of critical genes and pathways. These genome changes can provide a selective advantage for growth and survival during cancer pathogenesis. Therapeutic modulation of the epigenome using drugs that affect dynamic chromatin function, reactivate epigenetically-silenced genes or silence others, offers a rational approach to prostate cancer treatment. Small molecule inhibitors of DNA methyltransferases and histone deacetylases are already used as single agents for myelodysplasia and cutaneous T-cell lymphoma respectively, and several other epigenetic drugs are under active preclinical and clinical development. Moreover, epigenetic drugs may expose new and unexpected vulnerabilities of prostate cancer cells by alteration of the cellular phenotype. Thus, combination of epigenome-modifying agents with drugs targeted at the products of reactivated genes and pathways may provide effective therapeutic opportunities.Aims of this proposal are to test combinations of epigenetic drugs and existing targeted drugs for cytotoxicity of prostate cancer cells and to perform genome-wide RNAi screens to identify functional vulnerabilities or synthetic lethal interactions with epigenetic drugs. Furthermore, the new phenotypes induced by reactivation of epigenetically-silenced genes will be explored using transcriptome and epigenome profiling technologies and molecular targets will be evaluated in human prostate cancer xenografts.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: USA
• Gastgeber: Professor Dr. William G. Nelson