Advanced stage low-grade ovarian serous cancer (OSC) represents approximately 10% of all advanced stage ovarian serous carcinomas. While the 5-year survival rates of patients with the disease is significantly higher than those with high-grade OSC, most patients with low-grade OSC eventually succumb to their disease. Recent genetic and genomic studies have shown that low-grade OSC and high-grade OSC have different pathogenetic pathways. Furthermore, recent clinical evidence has indicated that low-grade OSC is a unique disease and is less sensitive to standard chemotherapy. In spite of differences in histology and clinical outcomes, patients with low-grade or high-grade OSC are currently treated with the treatments, which are not that effective in low-grade OSC. Thus, new therapeutic strategies and novel molecular targets are desperately needed to improve the outcome of this patient cohort. Recent studies have demonstrated that the MAP kinase pathway is activated predominately in low-grade OSC because of activating KRAS/BRAF mutations or other unknown mechanisms suggesting that molecules targeting the MAP kinase pathway are promising therapeutics. In collaboration with the Gynecologic Oncology Group, we recently initiated a phase II clinical trial (GOG 0239) targeting the activated MAP kinase pathway in recurrent low-grade OSC using the MEK inhibitor, AZD6244, as a single agent. Preliminary analysis showed promising results with a number of responders in an initial data analysis. In addition, using microarray analysis on microdissected tumor samples, we identified activation of the IGF1-AKT pathway predominately in low-grade OSC. Furthermore, we recently showed that FOXOSa is a common target of PI3K/AKT, MEK/ERK, IKK signaling, and its localization and expression may be a predictor for AZD6244 sensitivity in low-grade ovarian cancer cells. Based on the results from these studies, we hypothesize that multiple signaling pathways are activated in low-grade OSC, and molecular markers identified through comprehensive genomic and proteomic analyses of responders and non-responders to pathway-targeted inhibitors can be used to predict drug responses and stratify patients for future clinical trials of pathway-targeted regimens. To test these hypotheses, we propose (1) to identify genomic and proteomic predictors of anti-tumor efficacy of the MEK inhibitor AZD6244 using GOG 0239 specimens;(2) to investigate the functional role of FOXOSa in conferring resistance to inhibitors of PISK/AKT and MEK/ERK kinases in low-grade ovarian cancer cells;(3) to investigate the IGF1-P1SK pathway as a potential therapeutic target for low-grade OSC;and (4) to develop clinical trials involving novel combined targeted agent approaches. We believe that our studies will help us to develop individualized treatment regimens that will have lower toxicity and higher efficacy, for women with low-grade OSC.

Public Health Relevance

This project is targeting low-grade serous ovarian cancer patients using basic research findings from the laboratory to clinical settings and will impact on the prognosis and treatment of this patient group.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA083639-13
Application #
8380483
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$208,290
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
AACR Project GENIE Consortium (2017) AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov 7:818-831
Sans, Marta; Gharpure, Kshipra; Tibshirani, Robert et al. (2017) Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging. Cancer Res 77:2903-2913
Robertson, A Gordon; Shih, Juliann; Yau, Christina et al. (2017) Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell 32:204-220.e15
Yeung, Tsz-Lun; Leung, Cecilia S; Wong, Kwong-Kwok et al. (2017) ELF3 is a negative regulator of epithelial-mesenchymal transition in ovarian cancer cells. Oncotarget 8:16951-16963
Gangwar, Ruchika; Meena, Avtar S; Shukla, Pradeep K et al. (2017) Calcium-mediated oxidative stress: a common mechanism in tight junction disruption by different types of cellular stress. Biochem J 474:731-749
Cho, Min Soon; Noh, Kyunghee; Haemmerle, Monika et al. (2017) Role of ADP receptors on platelets in the growth of ovarian cancer. Blood 130:1235-1242
Harjes, U; Bridges, E; Gharpure, K M et al. (2017) Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4. Oncogene 36:912-921
Sekihara, Kazumasa; Saitoh, Kaori; Han, Lina et al. (2017) Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1. Oncotarget 8:34552-34564
Yang, Wei-Lei; Gentry-Maharaj, Aleksandra; Simmons, Archana et al. (2017) Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer. Clin Cancer Res 23:5912-5922
Nagaraja, Archana S; Dood, Robert L; Armaiz-Pena, Guillermo et al. (2017) Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. JCI Insight 2:

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