Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer

描述（由申请人提供）：我们的长期目标是开发新的靶向治疗策略来治疗晚期卵巢癌。在我们之前对卵巢癌和乳腺癌的 E1A 基因治疗的研究中，我们发现 PEA15 负责 E1A 对癌细胞的抗增殖作用。我们随后对该现象的分子机制的探索使我们得出了该提议的中心假设：PEA15在卵巢癌的致瘤性和治疗反应中具有关键作用。支持这一假设的证据如下。首先，已知 PEA15 将 ERK 隔离在细胞质中，而 ERK 参与细胞周期并增强癌细胞的存活率。其次，PEA15 在丝氨酸 116 处未磷酸化的细胞通过肿瘤坏死因子 (TNF) 信号传导（一种主要的细胞凋亡途径）发生细胞凋亡。第三，PEA15的过度表达抑制卵巢癌细胞的活力。第四，PEA15 过度表达的卵巢癌患者比 PEA15 低表达肿瘤的患者存活时间更长。总的来说，这些发现表明 PEA15 通过其阻断 ERK 和增强 TNF 信号传导的能力而成为卵巢癌的关键分子，因此可以用作卵巢癌患者的双途径治疗基因。我们在该提案中的第一个主要目标是描述 PEA15 在卵巢癌细胞中的机制和功能意义。第二个主要目标是开发 PEA15 作为靶向分子。为了实现这两个目标，我们制定了一个综合计划，包括三个具体目标：（1）确定PEA15在卵巢癌致瘤性中的作用； (2)测定PEA15对卵巢癌细胞化疗敏感性的影响； (3) 确定 PEA15 如何调节卵巢癌细胞对厄洛替尼的敏感性。该提议具有创新性，因为 PEA15 被认为同时针对 ERK 和 TNF 信号通路，这些信号通路与癌症侵袭性、诱导细胞凋亡以及调节对化疗和 EGFR 酪氨酸激酶抑制剂的敏感性有关。拟议的研究与改善卵巢癌患者的预后高度相关，因为了解癌症的生物学将导致发现用于临床诊断和治疗的新靶点。该项目的最终目的是为设计基于基础研究的PEA15作为新靶点的临床试验奠定基础。拟议的研究与改善卵巢癌患者的预后高度相关，因为了解癌症的生物学将导致发现用于临床诊断和治疗的新靶点（PEA15或与PEA-15相关的分子）。

DESCRIPTION (provided by applicant): 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.