Chemopreventative Targets in BRCA1 Carrier Models with P53 Lesions

Project summary

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.

This grant was made possible in part by a generous donation from Gail Baird Foundation.