Molecular Mechanisms of Aging and Cancer

For over a decade, our research has been directed at understanding the role of FOXO transcription factors in cancer and longevity and target their activity for therapeutic purposes. FOXO factors are involved in cellular homeostasis and play a key role in the defense system against cellular stress. Intriguingly, FOXO3 is the second most replicated gene associated with extreme human longevity. My lab generated cutting edge screening technologies to monitor the activity of the PI3K/AKT/FOXO signaling pathway. Based on these tools we identified and characterized several genetic and pharmacological means to manipulate the activity of FOXO proteins. A major breakthrough has been accomplished with the discovery of the FOXO repressor protein TRIB2 as a novel oncogene in melanoma. TRIB2 belongs to the Tribbles family of pseudokinases. Importantly, TRIB2 confers resistance to anticancer drugs via direct interaction with AKT. TRIB2 is overexpressed in melanoma and correlate with poor response to treatment. We are in a very privileged position to translate our knowledge on TRIB2 biology into useful tools to improve the clinical outcome of patients with melanoma and other solid cancers. We also explore the pharmacological modulation of FOXO proteins to treat cancer and other age-related diseases. Our research group is unique in the world in having access to a collection of over 200 small chemical compounds capable of activating FOXO factors. From these compounds several anti-cancer drug candidates have been developed. We have founded the biotech company Refoxy Pharma, Berlin/Boston (https://www.refoxy.com/) to explore the therapeutic potential of these small molecule FOXO modulating compounds. We also develop Nuclear Export Inhibitors as potential anti-cancer drugs. We have developed a multiplexed high content screening platform for systematic evaluation of small molecule inhibitors of the nuclear export.