Platinum compounds, such as cisplatin and carboplatin, are key drugs for the treatment of ovarian carcinoma. Both primary and acquired resistance to platinum compounds are serious clinical problems. The breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) play a critical role in repairing the DNA damage caused by platinum compounds. Consequently, BRCA 1/2-deficient cells are hypersensitive to platinum compounds. Recently, we found that platinum resistance of BRCA 1/2-mutated cancer can be mediated by secondary intragenic mutations in BRCA1/2 that restore the wild-type BRCA1/2 reading frame. Based on this finding, we hypothesize that restoration of BRCA1/2 is involved in acquired platinum resistance of BRCA1/2-deficient ovarian carcinomas. In this proposal, we focus on determining clinical relevance of restoration of BRCA1/2 function in BRCA 1/2-deficient hereditary and sporadic ovarian carcinomas. First, we will determine whether the occurrence of secondary mutations that restore DNA repair function of BRCA1/2 correlates with clinical outcomes of primary and recurrent hereditary ovarian carcinomas occurring in women with inherited BRCA1/2 mutations. Second, we will evaluate whether restoration of BRCA1 expression is involved in acquired resistance to platinum in sporadic ovarian carcinomas that initially have low BRCA1 expression before treatment. We will also determine whether ovarian cancer cells with reduced BRCA1 expression acquire restored BRCA1 function after in vitro selection in the presence of cisplatin and evaluate regulatory mechanisms that lead to restored BRCA1 expression. With these studies, we will assess the clinical significance of restoration of BRCA1/2 function during the treatment of BRCA 1/2-deficient ovarian carcinoma.

Public Health Relevance

Our study will provide critical information about the mechanisms of platinum-resistance of BRCA1/2-deficient tumors, which will enable us to predict platinum resistance of recurrent tumors, and may eventually lead to the establishment of a strategy to overcome platinum resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA083636-15
Application #
8523019
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$262,827
Indirect Cost
$78,450
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Wang, Yifan; Krais, John J; Bernhardy, Andrea J et al. (2016) RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance. J Clin Invest 126:3145-57
Norquist, Barbara M; Harrell, Maria I; Brady, Mark F et al. (2016) Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2:482-90
Yu-Rice, Yi; Edassery, Seby L; Urban, Nicole et al. (2016) Selenium Binding Protein 1 autoantibodies in ovarian disorders and ovarian cancer. Reproduction :
Yumul, Roma; Richter, Maximilian; Lu, Zhuo-Zhuang et al. (2016) Epithelial Junction Opener Improves Oncolytic Adenovirus Therapy in Mouse Tumor Models. Hum Gene Ther 27:325-37
Wang, Yifan; Bernhardy, Andrea J; Cruz, Cristina et al. (2016) The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. Cancer Res 76:2778-90
Andersen, M Robyn; Thorpe, Jason; Buist, Diana S M et al. (2016) Cancer Risk Awareness and Concern among Women with a Family History of Breast or Ovarian Cancer. Behav Med 42:18-28
Buas, Matthew F; Gu, Haiwei; Djukovic, Danijel et al. (2016) Identification of novel candidate plasma metabolite biomarkers for distinguishing serous ovarian carcinoma and benign serous ovarian tumors. Gynecol Oncol 140:138-44
Elias, Kevin M; Emori, Megan M; Westerling, Thomas et al. (2016) Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors. JCI Insight 1:
Gregory, Mark T; Bertout, Jessica A; Ericson, Nolan G et al. (2016) Targeted single molecule mutation detection with massively parallel sequencing. Nucleic Acids Res 44:e22
Bernards, Sarah S; Norquist, Barbara M; Harrell, Maria I et al. (2016) Genetic characterization of early onset ovarian carcinoma. Gynecol Oncol 140:221-5

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