Ovarian cancer is the fifth leading cause of cancer mortality in women in the U.S., killing 70% of afflicted patients and accounting for over 15,000 deaths annually. While most women initially respond to platin-containing regimens, cisplatin resistance commonly develops. Our previous studies have demonstrated that fiavopiridol, a small molecule inhibitor of cyclin-dependent kinases, interacts with DNA and selectively disrupts transcription mediated by STAT3, a transcription factor implicated in ovarian cancer pathogenesis. In addition, we have demonstrated that fiavopiridol enhances intracellular cisplatin accumulation, Pt-DNA adducts and cisplatin cytotoxicity in ovarian cancer cell lines. These data led to an ongoing phase II trial of fiavopiridol + cisplatin in platinum-resistant ovarian cancer demonstrating a 33% response rate (11% CRs, 22% PRs) and enhanced overall survival (16 mos vs. 6 mos for analogous patients treated with historical Phase II regimens). To extend these promising results, we now propose the following Specific Aims for SPORE Project #4:
Aim 1 : Define the mechanisms of fiavopiridol + cisplatin synergy and resistance in ovarian cancer. We will examine drug-induced alterations in cisplatin transporter activity, STAT3 signaling or polypeptide expression (e.g., Mcl-1, BRCA1/2, and HtrAI) in order to gain mechanistic insight that will allow a) selection of the patients most likely to benefit from ^flavopirldol + cisplatin therapy and b) formulation of strategies to overcome resistance to this regimen.
Aim 2 : Identification of biomarkers of response to fiavopiridol + cisplatin. We will examine the predictive value of pretreatment levels of polypeptides known to be affected by fiavopiridol (e.g., Mcl-1, phospho-STAT3, p65 NFDB) and identify additional candidate predictive biomarkers through analysis of samples obtained from patients enrolled in our ongoing fiavopiridol + cisplatin phase 11 trial.
Aim 3 : Utilize preclinical models to evaluate various strategies for maximizing the impact of the flavopiridol/cisplatin combination on ovarian cancer treatment. Using mouse models, we will examine the effects of f/7ree-agent combinations (e.g., fiavopiridol + cisplatin combined with paclltaxel, capecitabine, or gemcitabine) to identify a strategy that we can take forward into the

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA136393-05
Application #
8547767
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$219,848
Indirect Cost
$81,579
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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-κB. 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

Showing the most recent 10 out of 225 publications