Yonathan Lissanu, MD, PhD

My long-term career goal is to understand the molecular basis of lung cancers with genomic alterations in chromatin and epigenetic regulators and make an impact through identification of therapeutically relevant vulnerabilities in such tumors. I have extensive training and experience in cancer functional genomics under multiple institutions and proven track record of productivity. Hence, I have the expertise and deep motivation to successfully carry out the proposed research project. Currently, the research in my laboratory is focused on two major projects:

Identification of therapeutically relevant vulnerabilities in SWI/SNF chromatin remodeling complex mutant lung cancer including clinically applicable combinations for faster translation. Genomic studies have identified frequent mutations in the SWI/SNF complex (~20% of all human tumors). However, our understanding of how these mutations cause cancer is rudimentary. Furthermore, there are no therapies approved for targeting cancer with mutations in this complex. By developing a novel GEM model to study this complex in vivo and coupling it to analysis of human tumors, I have identified metabolic rewiring and dependence on oxidative phosphorylation of SWI/SNF mutant lung cancer. Importantly, I have demonstrated that SWI/SNF mutants are exquisitely sensitive to a newly discovered OXPHOS inhibitor. These observations are recently published in Nature Medicine.

Lissanu Deribe Y, Sun Y, Khan F, Peng Q, Marszalek J, Futreal AP. Mutations in the SWI/SNF complex induce metabolic rewiring and dependence on oxidative phosphorylation. Nat Med 24(7):1047-1057, 7/2018. PMID: 29892061. PMCID: PMC6650267

Leveraging my biochemical training and experience in the field of ubiquitination, I am also leading an effort to design, synthesize and characterize bifunctional small molecules, also known as proteolysis targeting chimeras (PROTACs) that induce ubiquitination and degradation of target proteins against a variety of cancer relevant targets. This project is in close collaboration with medicinal chemists at the Pharmaceutical Chemistry Core Facility (PCF) of MD Anderson. Proving my capacity to lead such a project, we have already successfully developed potent PROTACs that induce the degradation of the glucocorticoid receptor (GR). GR is emerging as a major mechanism of drug resistance in multiple cancer types. The Technology Commercialization office of MD Anderson has recently filed patent application for our GR PROTACs ( # PCT/US19/27163) where I am an inventor.