Targeted Therapy for Endometrial Cancer

描述（由申请人提供）：虽然许多类型的癌症的治疗结果有了很大的改善，但子宫内膜癌的发病率和死亡率正在上升，如今的五年生存率比30年前还要低。对化疗不够敏感是治疗失败的主要原因。我们的中心假设是，基于对肿瘤表型的了解而选择的细胞周期检查点关键主调节因子的分子抑制剂与化疗协同作用并促进灾难性肿瘤细胞死亡。我们的假设是基于大量的初步数据，即对化疗的敏感性取决于在细胞周期的脆弱时期增加细胞数量的能力。紫杉烷类药物对M细胞有效，铂基化合物和蒽环类药物主要对s细胞有效。TP53、KRAS、PTEN、编码PI3Kinase的基因和生长因子受体（如FGFR2）的突变在子宫内膜癌中占主导地位，以独特和可预测的方式改变细胞周期检查点的主要调节因子。这项研究的基本原理是，为了解决子宫内膜癌生存率下降的惊人趋势，我们必须通过将标准化疗与适当的分子抑制剂相结合来克服这些驱动突变的影响，这些分子抑制剂可以增强细胞的敏感性，我们称之为分子增强化疗。我们提出三个具体目标来测试和实施这一战略：1。在已完成的临床试验GOG 177中，使用预处理保存的组织，确定突变对与化疗耐药相关的检查点激酶激活的影响。在gog210中验证与新鲜冷冻组织对化疗反应相关的细胞周期控制信号靶点。2. 通过在复制子宫内膜肿瘤亚型的细胞模型中使用分子抑制剂操纵细胞周期检查点来克服化疗耐药机制。3. 利用人鼠模型优化靶向药物与化疗的组合。因此，本建议的主要重点是合理开发新的子宫内膜癌治疗策略，这些策略具有早期转化为临床的重大潜力。这项综合研究计划的结果将迅速应用于未来的临床试验。

DESCRIPTION (provided by applicant): While outcomes have substantially improved for many types of cancer, endometrial cancer incidence and deaths are on the rise, with the five year survival rate worse today than three decades ago. Inadequate sensitivity to chemotherapy is a primary cause of therapeutic failure. Our central hypothesis is that molecular inhibitors of key master regulators of cell cycle checkpoints, chosen based upon the knowledge of the tumor phenotype, synergize with chemotherapy and promote catastrophic tumor cell death. Our hypothesis is based on substantial preliminary data that sensitivity to chemotherapy depends upon the ability to enhance the number of cells in vulnerable periods of the cell cycle: taxanes are effective for cells in M, and platinum-based compounds and anthracyclines work primarily in S. Mutations in TP53, KRAS, PTEN, genes encoding PI3Kinase, and growth factor receptors such as FGFR2 predominate in endometrial cancer, altering master regulators of cell cycle checkpoints in unique and predictable ways. The rationale for this study is that, in order to address the alarming trend towards declining survival in endometrial cancer, we must overcome the impact of these driving mutations by combining standard chemotherapy with appropriate molecular inhibitors which can enhance cell sensitivity, a concept we term molecularly enhanced chemotherapy. We propose three specific aims to test and implement this strategy: 1. Determine the effect of mutations on checkpoint kinase activation associated with chemoresistance in specimens from the completed clinical trial, GOG 177, using pretreatment preserved tissue. Validate signaling targets of cell cycle control which relate to response to chemotherapy from fresh frozen tissue in GOG 210. 2. Overcome mechanisms of resistance to chemotherapy by manipulating cell cycle checkpoints with molecular inhibitors in cell models replicating endometrial tumor subtypes. 3. Optimize combinations of targeted agents with chemotherapy using human-in-mouse models. Thus, the major emphasis of this proposal is on the rational development of novel therapeutic strategies for endometrial cancer that have a significant potential for early translation to the clinic. The findings from this comprehensive research plan will be rapidly deployed in future clinical trials.