"Identifying novel epigenome-targeted anticancer agents by high-throughput drug screening"
Genome instability is a cancer hallmark that leads to a wide spectrum of genetic changes, including mutations in epigenetic modifiers. Disruption of the “epigenome” as a result of alterations in epigenetic regulators such as the ‘writers’, ‘readers’, or ‘editors’ of DNA methylation and/or chromatin states, is a fundamental mechanism in oncogenesis. In fact, changes in the epigenome can profoundly influence many hallmarks of cancer as well as clinical responses to anticancer therapies. Moreover, epigenetic mechanisms modulate a variety of transcriptional pathways resulting in a dynamic heterogeneous tumor cell population.
The U.S. Food and Drug Administration (FDA) has already approved epigenetic inhibitors as anticancer drugs (Jones et al., 2016). It is likely that many of these new epigenetic drugs offer synergistic benefits, and these new therapies may also synergize with conventional chemotherapies. This strategy of combination therapy may not only increase therapeutic efficacy but also reduce the likelihood of drug resistance.
Although the cancer epigenome is increasingly better understood, many current cancer drugs have not been associated with specific biomarkers that could guide therapies to maximize patient benefit. The observation that epigenetic inhibitors lead to dramatic effects in malignant cells, although their normal counterparts remain largely unaltered, highlights their potential as anti-cancer therapeutics. Moreover, recent studies have revealed that some epigenetic inhibitors alter only a few hundred genes, suggesting that these compounds can disrupt a selective set of genes (Dawson et al., 2011). Elucidating the networks of epigenetic regulators in different cancer types will provide a further mechanistic understanding of the interplay between genetic and epigenetic alterations, and this will allow for the development of novel epigenome-targeted therapeutic strategies.
Our goal is to investigate epigenetic regulators in cancer cells by performing a high-throughput (HTP) drug screen on cancer cell cultures with a collection of epigenetic inhibitors alone or synergized with first-line anticancer drugs. In order to preserve diversity and cell heterogeneity of the tumor, we will use patient-derived cell lines grown as 3D cultures. The obtained pharmacological profiles will then be linked to detailed epigenetic characterization to describe the molecular mechanisms of drug response as well as to allow for the identification of epigenetic and gene-expression-based predictors of drug sensitivity.
We work in collaboration with our project partner Prof. Dr. Mitchell Levesque (Mitchellpaul.firstname.lastname@example.org), who runs a translational Oncology lab and the URPP Live Cell Biobank at the University Hospital Zurich.
Research Group Levesque