2018 Mentored Investigator Grant Recipient — Justyna Kanska, PhD
Justyna Kanska, PhD
Cedars-Sinai Medical Center
Identifying Synthetic Lethal Targets to Mutant p53 in Development of HGSOC
Project Summary
Despite great improvements in our understanding of ovarian cancer biology, this disease still ranks among the top five deadliest cancers in women. Mostly, it is due to (1) genetics of ovarian cancer varying enormously from patient to patient, which makes the treatment very challenging; and (2) the lack of shared among patients genomic mutations that are currently targetable. However, one genetic event, the mutation of p53 gene, is present in over 96% of ovarian cancer cases. Furthermore, mutation in p53 is frequently observed in ovarian cancer precursor lesions, suggesting that it is one of the first genomic alterations, which likely determine the fate of pre-cancerous cell. P53 is probably the most important anti-cancer gene (so called tumour suppressor) as it instructs cell to die or stop multiplying, when harmful DNA damage is detected. This cellular defence mechanism ensures survival of only healthy cells. Currently, there are no drugs specifically targeting mutant p53 and finding new inhibitors that can kill p53-mutant, but not p53-normal cells, would be critical for combating ovarian cancer without harming non-cancerous cells, which is often observed after chemotherapy. Also, this therapeutic strategy could be used to eliminate p53-mutated cells during early stages of disease development. There is a dire need to develop such a chemopreventive approach because symptoms of ovarian cancers often manifest themselves in the late stages, where survival prognosis is very low and the chance of recurrence is the highest. Since ovarian cancer lacks other genomic changes as frequent as p53 mutation, we propose to prioritize our research on identifying targetable vulnerabilities of p53-mutant ovarian cancer precursor cells and cancer cell lines to find new ways of fighting this deadly disease.
For this purpose, I have designed a screen utilizing genome editing technology to delete all human genes (almost 20,000) in normal fallopian tube epithelial cells, while making sure that only one gene is deleted per cell (AIM 1). Using DNA sequencing I will identify genes, which deletion cause cell death, since DNA of those cells will be reduced compared to DNA of cells that survive. Because this experiment will be performed in p53-normal versus mutant cells, I will be able to identify specifically what genes are necessary for survival of p53-mutant cells. Later, I will determine the mechanism, by which the deletion of these genes eliminate p53-mutant cells (AIM2). Also, I will treat precursor cells with commercially available pharmacological inhibitors specific for selected targets to evaluate their therapeutic potential. Cancer cell lines will be additionally treated with a combination of inhibitor and chemotherapeutic agent to identify putative synergistic effect in killing cancer cells. I will be mentored by the renowned specialists in ovarian cancer genetics, Dr. Simon Gayther, and functional genomics, Dr. Simon Knott, to ensure a success of this project.
Bio
Justyna Kanska is a Postdoctoral Scientist in the Center for Bioinformatics and Functional Genomics at Cedars-Sinai Medical Center in Los Angeles. She earned her M.Sc. in Molecular Biotechnology at Wroclaw University of Science and Technology in Poland, and received her Ph.D. in Developmental Biology at National University of Ireland, Galway.
During her doctoral studies in Dr. Uri Frank’s laboratory, she worked with the cnidarian model organism Hydractinia to identify the role of Nanos and Myc genes in stem cell lineage commitment and differentiation. In particular, Dr. Kanska found that Nanos plays a crucial role in neural cell fate determination, which was unknown prior to these studies. These results are highly relevant in the field of developmental biology, since the evolution of nervous system and mechanisms of maturation of neural progenitors remains poorly understood. For her studies on the Nanos gene, Dr. Kanska was awarded the Thomas Crawford Hayes Research Fund, as well as First Prize for best oral presentation in the “Regenerative Medicine” session at the Irish Young Life Scientists Symposium.
During her postdoctoral training in the laboratory of Dr. Wolf R. Wiedemeyer at Cedars-Sinai Women's Cancer Program, Dr. Kanska studied the biology and vulnerabilities of the mesenchymal subtype of High Grade Serous Ovarian Cancer (HGSOC). Her research was focused on the role of ETV5, NNMT, and nutritional stress in the evolution, metastasis and drug resistance of HGSOC. Dr. Kanska’s work on the NNMT gene was recognized by the Marsha Rivkin Center for Ovarian Cancer Research and the American Association for Cancer Research on the 11th Biennial Ovarian Cancer Research Symposium, where Dr. Kanska was awarded the competitive Scholar-in Training Award. Currently, her work in Dr. Gayther’s laboratory is focused on modeling early genetic events contributing to oncogenic transformation of ovarian cancer precursor cells, as well as identifying targetable synthetic lethal genes for these genetic events. p53 mutation was found to be ubiquitously shared among all HGSOC patients, and thus, one of Dr. Kanska’s research projects focuses on identifying synthetic lethality for p53-mutant fallopian tube epithelial cells. Dr. Kanska believes that studying these ovarian cancer precursor models will allow her to find prophylactic targets in order to eliminate pre-cancerous p53-mutant cells before cancer arises. In her research, she is employing high-throughput CRISPR/Cas9 screens to functionally address these biological questions. Clinically, her studies provide a strong potential for development of novel and much needed therapeutic targets for HGSOC.