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.
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.
|Seo, Hyeonglim; Choi, Ikjang; Whiting, Nicholas et al. (2018) Hyperpolarized Porous Silicon Nanoparticles: Potential Theragnostic Material for 29 Si Magnetic Resonance Imaging. Chemphyschem 19:2143-2147|
|Mitamura, T; Pradeep, S; McGuire, M et al. (2018) Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP). Oncogene 37:722-731|
|Yuan, Jiao; Hu, Zhongyi; Mahal, Brandon A et al. (2018) Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers. Cancer Cell 34:549-560.e9|
|Liu, Xiaojun; Jiang, Yingjun; Nowak, Billie et al. (2018) Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations. Cancer Chemother Pharmacol 81:255-267|
|Haemmerle, Monika; Stone, Rebecca L; Menter, David G et al. (2018) The Platelet Lifeline to Cancer: Challenges and Opportunities. Cancer Cell 33:965-983|
|Allen, Julie K; Armaiz-Pena, Guillermo N; Nagaraja, Archana S et al. (2018) Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction. Cancer Res 78:3233-3242|
|Umamaheswaran, Sujanitha; Dasari, Santosh K; Yang, Peiying et al. (2018) Stress, inflammation, and eicosanoids: an emerging perspective. Cancer Metastasis Rev 37:203-211|
|Wang, Jue; Zhao, Wei; Guo, Huifang et al. (2018) AKT isoform-specific expression and activation across cancer lineages. BMC Cancer 18:742|
|Huang, Yan; Hu, Wei; Huang, Jie et al. (2018) Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer. Mol Cancer Ther 17:464-473|
|Yang, Hailing; Mao, Weiqun; Rodriguez-Aguayo, Cristian et al. (2018) Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability. Clin Cancer Res 24:5072-5084|
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