Ovarian cancer has the highest case fatality rate of any gynecological malignancy, killing 70% of patients and accounting for almost 16,000 deaths in the U.S. annually. While most women initially respond to platin-based chemotherapy, the high relapse rate and poor response to subsequent therapy highlight the need for more effective therapy for platin-resistant disease. Our previous studies examining the action of topotecan (TPT), a topoisomerase I (topo l)-directed agent that is approved for the second-line treatment of ovarian cancer, have demonstrated that TPT induces replication fork stalling followed by activation of a kinase cascade involving ATR and checkpoint kinase 1. Building on reports that poly(ADP-ribose) polymerase-1 (PARP1) is involved in restarting stalled replication forks as well as reversing trapped topo I- DNA complexes, we have more recently demonstrated that the PARP inhibitor ABT-888 enhances TPT cytotoxicity in ovarian cancer cell lines. Even though this sensitization is more prominent in BRCA1/2- deficient cells, it also occurs in ovarian cancer cells with wildtype BRCAI and BRCA2. Moreover, this sensitization occurs at ABT-888 concentrations that are 20-fold lower than those required to kill BRCAI/2- deficient cells directly. Additional results indicate that ABT-888 is sensitizing cells through a base excision repair pathway that involves XRCC1 and suggest that PARP1 must be present for this sensitization. To further study this interaction between TPT and ABT-888, as well as extend the potential benefits of PARP inhibitor therapy to as large a subset of ovarian cancer patients as possible, we now propose to:
Aim 1 : Identify the mechanism by which PARP1 inhibition enhances the antiproliferative effects of TPT In ovarian cancer cells by further elucidating the DNA repair pathway that is critical for ABT- 888 mediated sensitization and determining how inhibited PARP1 actively sensitizes cells to TPT.
Aim 2 : Determine the mechanism of ABT-888 Induced antiproliferative effects in BRCA1/2-deflcient cells by identifying the endogenous DNA lesions that contribute to the cytotoxicity of ABT-888 as well as examining how PARP inhibition contributes to this demise.
Aim 3 : Evaluate the ability of a series of markers to predict response to the TPT/ABT-888 combinat? ion in a CTEP-sponsored phase II trial In patients with relapsed ovarian cancer. Samples from patients enrolled on this trial will provide a unique opportunity to search for potential predictive markers of response to this regimen. These studies, which make extensive use of the Biospecimens/Patient Registry and Biostatistics Cores of the Mayo Ovarian SPORE, are designed to increase understanding of the action of the PARP inhibitor ABT- 888, both alone and in combination with TPT, in ovarian cancer, thereby advancing clinical development of the PARP inhibitor as a potentially promising ovarian cancer therapeutic.
Ovarian cancer is a lethal malignancy that claims 16,000 lives annually in the United States. ABT-888 is an investigational drug that enhances the ability of topotecan, an FDA-approved treatment for ovarian cancer, to kill ovarian cancer cells in the laboratory. The present studies are designed to not only increase understanding of the mechanism by which ABT-888 exerts its effects, but also identify ovarian cancer patients who are most likely to respond to the topotecan/ABT-888 combination in the clinic.
|Karami, Sara; Han, Younghun; Pande, Mala et al. (2016) Telomere structure and maintenance gene variants and risk of five cancer types. Int J Cancer 139:2655-2670|
|Clyde, Merlise A; Palmieri Weber, Rachel; Iversen, Edwin S et al. (2016) Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci. Am J Epidemiol 184:579-589|
|Radecki Breitkopf, Carmen; Ridgeway, Jennifer L; Asiedu, Gladys B et al. (2016) Ovarian cancer patients' and their family members' perspectives on novel vaccine and virotherapy trials. Clin Trials 13:660-664|
|Ezewuiro, Obiageli; Grushko, Tatyana A; Kocherginsky, Masha et al. (2016) Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy. PLoS One 11:e0147145|
|Li, Zheng; Block, Matthew S; Vierkant, Robert A et al. (2016) The inflammatory microenvironment in epithelial ovarian cancer: a role for TLR4 and MyD88 and related proteins. Tumour Biol 37:13279-13286|
|Pharoah, Paul D P; Song, Honglin; Dicks, Ed et al. (2016) PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations. J Natl Cancer Inst 108:|
|(2016) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nat Commun 7:12675|
|Karyampudi, Lavakumar; Lamichhane, Purushottam; Krempski, James et al. (2016) PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-ÎºB. Cancer Res 76:239-50|
|French, Juliet D; Johnatty, Sharon E; Lu, Yi et al. (2016) Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer. Oncotarget 7:6353-68|
|Harris, Faye R; Kovtun, Irina V; Smadbeck, James et al. (2016) Quantification of Somatic Chromosomal Rearrangements in Circulating Cell-Free DNA from Ovarian Cancers. Sci Rep 6:29831|
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