Gail Baird Foundation Research Grant Recipient
Ovarian cancer (OC) ranks among the top five deadliest cancers in women and its low survival rate has not improved significantly in the last 40 years. Relatively no new drug therapies for prevention and treatment are available because of a lack of understanding in the early mutations leading to the development of this devastating disease. Heritable forms of OC are most associated with BRCA1 gene mutations which increase a women’s risk of developing OC by 16-42%. Not all women with BRCA1 mutations develop OC, hence BRCA1 dysfunction is not the only genetic event required to drive tumor formation. All high grade serous OC tumors also require another genetic hit in the gene, P53. The P53 mutation is the only genetic event in all high grade serous OC tumors and frequently observed in pre-cancerous lesions for this tumor type formed from cells in the fallopian tube. p53 acts as one of the most important “brakes” in cancer formation, because of its critical role in inhibiting cellular division and causing cell death, while BRCA1 is essential for DNA damage repair. DNA undergoes duplication during every cell division and it is here where cells are at risk of accruing cancer-promoting mutations and they rely on key players like P53 and BRCA1 to maintain their proper, healthy cycle. Mutations in P53 are known to hang around in tissue of patients who have not developed cancer and this mutant P53 appears to be a key early stage driver for several cancers. This study seeks to address the hypothesis that genes critical in P53 stability in BRCA1 carriers as key drivers in early stage development of high grade serous OC and represent targets for developing novel chemopreventive agents. Using advanced technological tools, I will evaluate each and every human gene for the potential to promote or reduce growth of fallopian tube cells engineered to carry both p53 and BRCA1 mutations most commonly found in OC risk. Our primary goal is to identify genes, which reestablish normal p53 signaling pathway in pre-cancerous cells and target the reversal of these mutations in a drug screen for therapeutic targets. From a pilot screen, the target genes that I have already identified: KEAP1, a regulator of BRCA1 have known roles in HGSOC. In fact, KEAP1 has four known putative drug targets which can be screened for reversal of mutant P53. Identifying drugs which specifically targeting these mutations will prevent transformation of normal cells to tumor cells. This study provides opportunities to treat precancerous cells before they become too advanced in cancer development to treat and protect women from developing OC to begin with.
Dr. Jasmine Plummer, PhD is an Associate Member of St. Jude Faculty and Director, Center for Spatial OMIC. She was formerly an Assistant Professor in the Department of Biomedical Sciences and Associate Director of the Applied Genomics, Computational and Translational Core at Cedars Sinai. She graduated with honors, BSc from University of Toronto. Her MSc was completed in the laboratory of Roger Croll, PhD at Dalbousie University (Halifax, Canada) in the Department of Neuroscience and the Department of Physiology Under the mentorship of Dr. Joe Culotti, she received her PhD at the University of Toronto, Mount Sinai Hospital (Toronto, Canada). In her doctoral work, Dr Plummer used genome wide screens to identifying novel genes that regulate the nervous system development. In her post-doctoral work in the laboratory of Dr. Pat Levitt at Children’s Hospital Los Angeles and University of Southern California, Dr. Plummer utilized system biology approaches to understanding the genetic risk of neuropsychiatric disorders, including autism, schizophrenia, attention-deficit/hyperactivity disorder, bipolar disorder and major depressive disorder. As an Autism Speaks postdoctoral fellow, her research focused on the discovery and function of gene regulatory networks involving autism risk genes. Dr. Plummer is currently a principal investigator on several institutional and foundational grants in which her research is focused on understanding the mechanisms by which cancers, specifically ovarian, breast and prostate, share common genetic risk and how this translates to susceptibility and oncogenesis. Dr. Plummer’s lab uses a mult-iomic approach through genomic, epigenomic and transcriptomic data to functionally interrogate ovarian cancer genetic risk. From this current work, Dr. Plummer tries to understand how early genetic events trigger cancer pathogenicity to find early biomarkers of ovarian cancer.