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

描述(由申请者提供)：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与E1a对癌细胞的抗增殖作用有关。我们随后对这一现象的分子机制的探索使我们得出了这一提议的中心假设：PEA15在卵巢癌的致瘤性和治疗反应中起着关键作用。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，ERK已知参与细胞周期和提高癌细胞的存活率。其次，PEA15在丝氨酸116处未被磷酸化的细胞通过肿瘤坏死因子(TNF)信号途径进行凋亡，这是一种主要的凋亡途径。第三，PEA15的过表达抑制了卵巢癌细胞的活力。第四，过度表达PEA15的卵巢癌患者比低表达PEA15的肿瘤患者存活时间更长。总之，这些发现表明PEA15是卵巢癌中的关键分子，它通过阻断ERK和增强肿瘤坏死因子信号转导而成为卵巢癌的关键分子，因此可以作为卵巢癌患者的双途径治疗基因。我们在这项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。第二个主要目标是将PEA15开发为靶向分子。为了解决这两个目标，我们制定了一个包括三个具体目标的综合计划：(1)确定PEA15在卵巢癌致瘤性中的作用；(2)确定PEA15对卵巢癌细胞对化疗的敏感性的影响；以及(3)确定PEA15如何调节卵巢癌细胞对厄洛替尼的敏感性。这一建议是创新的，因为PEA15被认为针对ERK和TNF信号通路，这两个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。这项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新的靶点，用于临床诊断和治疗。这个项目的最终目的是建立一个基础，在此基础上设计一项以基础研究为基础的PEA15临床试验作为一个新的目标。这项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新的靶点(PEA15或与PEA-15相关的分子)，用于临床诊断和治疗。

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.