DESCRIPTION (provided by applicant): Candidate. Dr Kate Lawrenson is a postdoctoral researcher at the University of Southern California who has developed a unique set of expertise in functional modeling of ovarian cancer development, and in the identification and characterization of long non-coding RNAs in ovarian cancer susceptibility. Through her graduate and postdoctoral studies Dr Lawrenson has established a productive track record in the ovarian cancer field, with 12 primary research papers published, five of which as first/joint-first author and one as last author. Her work has been published in high impact peer-reviewed journals including Nature Genetics, Nature Communications, Neoplasia and Laboratory Investigation. Dr Lawrenson's research has in part been funded by grants awarded to her by the Wright Foundation and the Ovarian Cancer Research Fund, and Dr Lawrenson has been awarded seven highly competitive travel awards, including three from the American Association for Cancer Research. Dr Lawrenson is an ideal candidate for a K99/R00 pathway to independence award. This award would enable her to achieve her goal of establishing an independent research group focusing on translational research into long non-coding RNAs (lncRNAs) lncRNAs as drivers of neoplasia and therapeutic targets for ovarian cancer. During the mentored phase Dr Lawrenson will work closely with her mentorship team to receive expert training in ovarian cancer modeling (from Dr S Gayther), lncRNA discovery and data analysis (from Dr TJ Triche), and clinical translation of the findings (from Dr D Tripathy). At the end of te K99 mentored phase Dr Lawrenson will apply for tenure-track research positions at USC or other institutions with exceptional ovarian cancer and/or genomics programs. Environment. USC is a nurturing, collaborative research environment in which talented early career scientists can genuinely thrive and develop independence. USC has a strong track history in analyses of the non protein- coding component of the genome: many of the group leaders at USC are part of large international consortia (such as TCGA, ROADMAP & ENCODE) and the environment at USC naturally promotes collaboration. The Faculty at USC place a strong emphasis on mentorship and career development, and within USC the Centre for Excellence in Research and the Clinical and Translational Science Institute have an established career development program, each semester hosting courses and workshops for formal training in grant writing, responsible conduct of research, management and ethics. Facilities and resources at USC are second to none. The Epigenome Core facility was the first dedicated epigenome centre in the US, and includes a world-class laboratory and extensive dedicated bioinformatics facilities. This core specializes in next-generation genomics approaches and will perform the RNA-sequencing aspects of this research. Additionally, the USC Norris Comprehensive Cancer Center (NCCC) is supported a NCI Canter Center Support Grant (P30CA014089). Within the NCCC is a wide range of core facilities, run by dedicated highly trained staff, that are available to all Cancer Centre members. Particularly relevant to this proposal are The Cell and Tissue Imaging Core, the Flow Cytometry core and the Small Animal Imaging core, all containing the newest state-of-the art equipment and analysis softwate. Research. Most cancer research to date has focused on the 2% of the genome that directly encodes proteins but recent advances in next-generation sequencing have enabled the detailed characterization of the non- protein coding genome. However, while projects such as the Encyclopedia of DNA Elements (ENCODE) have identified an abundance of DNA motifs and non-coding RNA species that regulate the human transcriptome and proteome, the relevance of these discoveries to cancer treatment and diagnosis remains largely unexplored. Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides in length that are often differentially expressed in cancer. LncRNAs drive many key pathways in cancer cells and can regulate aggressive tumor phenotypes including metastasis, proliferation, apoptosis and invasion and so represent a host of novel opportunities for therapeutic intervention that have not yet been explored. This research aims to characterize lncRNAs in ovarian cancer and test the hypothesis that lncRNAs can be novel therapeutic targets for this disease. I will take three complementary approaches. Firstly I will characterize the function of lncRNAs I have identified as being differentially expressed during ovarian cancer development. Secondly I will test for synthetic lethal interactions between lncRNAs and BRCA1, a gene that is commonly mutated/downregulated in ovarian cancer. Thirdly I will use The Cancer Genome Atlas data to identify lncRNAs that are prognostic for ovarian cancer, and I will use unique three-dimensional models of ovarian cancer that I have developed to test the whether prognostic lncRNAs are involved in chemoreponse. Women with ovarian cancer have been treated with the same broad-acting, toxic chemotherapies since the 1970's, and new and more effective therapies are urgently needed. Ultimately, the results of this research could help to improve prognoses for the 22,000 women diagnosed with this disease annually in the United States.

PUBLIC HEALTH RELEVANCE: Recent advances in massively parallel sequencing technologies have revolutionized genetic research by enabling detailed characterization of the human transcriptome. Ovarian cancers are highly lethal malignancies for which novel treatments are urgently needed; this research aims to identify and characterize the role of novel non-protein coding RNAs in the development of these tumors, and to evaluate their potential as clinical biomarkers and therapeutic targets for the disease.