Our long-term goal is to develop novel targeted therapy strategies to treat advanced ovarian cancer. In our previous studies of E1A gene therapy for ovarian and breast cancer, we identified PEA15 as being responsible for the antiproliferative effects of E1A on cancer cells. Our subsequent explorations of the molecular mechanism of this phenomenon led us to the central hypothesis of this proposal: that PEA15 has a critical role in ovarian cancer tumorigenicity and treatment response. Supporting evidence for this hypothesis is as follows. First, PEA15 is known to sequester ERK in the cytoplasm, and ERK is known to be involved in cell cycling and enhanced survival of cancer cells. Second, cells in which PEA15 is not phosphorylated at serine 116 undergo apoptosis via tumor-necrosis factor (TNF) signaling, a major apoptosis pathway. Third, overexpression of PEA15 suppresses viability of ovarian cancer cells. Fourth, patients with ovarian cancers that overexpress PEA15 survive longer than those with low-PEA15-expressing tumors. Collectively, these findings implicate PEA15 as a key molecule in ovarian cancer via its ability to block ERK and enhance TNF signaling, and thus could be exploited as a dual-pathway therapeutic gene for patients with ovarian cancer. Our first major goal in this proposal is to delineate the mechanistic and functional significance of PEA15 in ovarian cancer cells. The second major goal is to develop PEA15 as a targeted molecule. To address these two goals, we have developed a comprehensive plan comprising three specific aims: (1) Determine the role of PEA15 in ovarian cancer tumorigenicity;(2) Determine the effects of PEA15 on the sensitivity of ovarian cancer cell to chemotherapy;and (3) Establish how PEA15 modulates erlotinib sensitivity in ovarian cancer cells. This proposal is innovative because PEA15 is thought to target both ERK and TNF signaling pathways, which have been implicated in cancer aggressiveness, induction of apoptosis, and regulation of sensitivity to chemotherapy and EGFR-tyrosine kinase inhibitors. The proposed research is highly relevant to improving outcomes for patients with ovarian cancer because understanding the biology of cancer will lead to the discovery of novel targets to be used in clinical diagnosis and treatment. The ultimate purpose of this project is to build a foundation upon which to design a clinical trial, based on basic research, of PEA15 as a novel target. The proposed research is highly relevant to improving outcomes for patients with ovarian cancer because understanding the biology of cancer will lead to the discovery of novel targets (PEA15 or molecules related to PEA-15) to be used in clinical diagnosis and treatment.
|Xie, Xinhua; Tang, Hailin; Pengliu et al. (2015) Development of PEA-15 using a potent non-viral vector for therapeutic application in breast cancer. Cancer Lett 356:374-381|
|Bartholomeusz, Chandra; Xie, Xuemei; Pitner, Mary Kathryn et al. (2015) MEK Inhibitor Selumetinib (AZD6244; ARRY-142886) Prevents Lung Metastasis in a Triple-Negative Breast Cancer Xenograft Model. Mol Cancer Ther 14:2773-81|
|Xie, Xuemei; Bartholomeusz, Chandra; Ahmed, Ahmed A et al. (2013) Bisphosphorylated PEA-15 sensitizes ovarian cancer cells to paclitaxel by impairing the microtubule-destabilizing effect of SCLIP. Mol Cancer Ther 12:1099-111|
|Bartholomeusz, Chandra; Oishi, Tetsuro; Saso, Hitomi et al. (2012) MEK1/2 inhibitor selumetinib (AZD6244) inhibits growth of ovarian clear cell carcinoma in a PEA-15-dependent manner in a mouse xenograft model. Mol Cancer Ther 11:360-9|
|Itamochi, Hiroaki; Yoshida, Tomokazu; Walker, Cheryl Lyn et al. (2011) Novel mechanism of reduced proliferation in ovarian clear cell carcinoma cells: cytoplasmic sequestration of CDK2 by p27. Gynecol Oncol 122:641-7|
|Bartholomeusz, Chandra; Gonzalez-Angulo, Ana M; Kazansky, Anna et al. (2010) PEA-15 inhibits tumorigenesis in an MDA-MB-468 triple-negative breast cancer xenograft model through increased cytoplasmic localization of activated extracellular signal-regulated kinase. Clin Cancer Res 16:1802-11|
|Bartholomeusz, Chandra; Rosen, Daniel; Wei, Caimiao et al. (2008) PEA-15 induces autophagy in human ovarian cancer cells and is associated with prolonged overall survival. Cancer Res 68:9302-10|