SEMINAR:Small molecule RNA therapeutics to target prostate cancer

Guest: Duygu Kuzuoglu Öztürk, Sabancı University

Abstract: Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate cancer, castration-resistant prostate cancer (CRPC), we use a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eIF4A. Zotatifin represses tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis reveals two important translational targets: Androgen Receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential cancer modulator in hypoxia. We solve the structure of the 5’UTRs of these oncogenic mRNAs and strikingly observe complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to radiotherapy, usually blunted by HIF1A. Therefore, ‘translatome therapy’ opens new avenues to treat the deadliest cancers.

Bio: Duygu received her undergraduate degree in Molecular Biology and Genetics from Istanbul Technical University and her master’s degree in Biological Sciences and Bioengineering from Sabanci University, Turkey. Her master’s thesis focused on the identification and functional analysis of an autophagy-related gene in wild wheat under different stress conditions. After completing her master’s studies, she moved to Germany to pursue her doctorate. She worked in the lab of the late Dr. Elisa Izaurralde at the Max Planck Institute for Developmental Biology in Tuebingen, where she studied the role of the main deadenylase complex, CCR4-NOT, in miRNA-mediated gene silencing. Upon finishing her PhD with the highest honor (summa cum laude), she joined Dr. Davide Ruggero’s lab at the University of California, San Francisco (UCSF) as a postdoctoral fellow. For her postdoctoral research, Duygu received several competitive awards, including the long-term European Molecular Biology Organization (EMBO) fellowship, the International Human Frontier Science Program (HFSP) postdoctoral fellowship, and a research award from the UCSF Prostate Cancer Program as well as Department of Defense. During her postdoctoral studies, she had the opportunity to work with various cancer models, focusing on understanding the regulation of gene expression at the translational level, particularly by the major cap-binding protein, eukaryotic initiation factor eIF4E. She conducted a genome-wide screen to identify eIF4E-interacting partners that represent novel cancer-specific vulnerabilities with therapeutic potential. Duygu joined Sabanci University as a faculty member very recently and is looking forward to pursue her scientific career in her hometown.