Targeted Therapy for Endometrial Cancer

虽然许多类型的癌症的预后有了实质性的改善，但子宫内膜癌的发病率和 死亡人数正在上升，如今的五年存活率比30年前还差。不足之处 对化疗的敏感性是治疗失败的主要原因。为了改善患者的预后，我们必须 确定适当的分子靶向药物与化疗相结合，这是一个我们称之为 分子强化化疗。这样的组合必须建立在对 肿瘤细胞的脆弱性可以被利用来创造协同效应和合成杀伤力。我们的目标是 这一新的应用是为了利用高危子宫内膜癌中最常见的突变P53，以 设计新的、更有效的组合方案，以提高预先设置的反应。P53 突变以可预测但不同的方式改变细胞周期检查点的主调节器，这可能是 利用靶向药物阻断代偿作用克服化疗耐药性 生存之路。因此，我们的中心假设是关键的主要调节因子的分子抑制物， 根据对P53突变状态的了解选择，与化疗协同促进 灾难性的肿瘤细胞死亡。我们将这一概念称为分子增强化疗。在具体目标1中， 我们将确定p53、其他细胞周期检查点控制器和血管生成标记物作为预测因子的作用 抗血管生成分子抑制剂与化疗联合应用时的敏感性。这一目标 纳入了来自完成的试验GOG/NRG 86P的临床样本，这是第一项将 分子抑制剂联合化疗治疗晚期/复发子宫内膜癌。在具体目标2中，我们将 根据NRG/GOG 86P的结果评估耐药机制，并确定 另一种分子增强的组合。在具体目标3中，我们将询问P53的功能 突变是未知意义的变异(VUS)，以定义这些肿瘤的最佳治疗方法。这个 此目标的主要目标是将VU从NRG/GOG 86P绑定到功能类别并了解其影响 复发性VUS对细胞转录和细胞周期调控的影响。在完成这些研究后，我们的 预期我们将设计并测试针对特定药物量身定做的协同药物组合 子宫内膜癌亚型。这些研究将对该领域产生重大的积极影响， 未来子宫内膜癌临床试验的设计和治疗选择。

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. To improve patient outcomes, we must identify the appropriate molecularly targeted agents to combine with chemotherapy, a concept we term molecularly enhanced chemotherapy. Such combinations must be based upon a mechanistic understanding of tumor cell vulnerabilities which can be exploited to create synergism and synthetic lethality. Our objective in this renewal application is to capitalize on the most common mutation in high-risk endometrial cancers, p53, to design new and more active combinatorial regimens that can improve response in the upfront setting. p53 mutations alter the master regulators of cell cycle checkpoints in predictable yet distinct ways which can be capitalized upon to overcome resistance to chemotherapy using targeted agents that block compensatory survival pathways. Therefore, our central hypothesis is that molecular inhibitors of key master regulators, chosen based upon the knowledge of the p53 mutational status, synergize with chemotherapy and promote catastrophic tumor cell death. We term this concept molecularly enhanced chemotherapy. In Specific Aim #1, we will determine the role of p53, other cell cycle checkpoint controllers and angiogenic markers as predictors of sensitivity when anti-angiogenic molecular inhibitors are combined with chemotherapy. This aim incorporates clinical specimens from a completed trial, GOG/NRG 86P, the first national study to combine molecular inhibitors with chemotherapy for advanced/recurrent endometrial cancer. In Specific Aim #2, we will assess the mechanisms of resistance to therapy as defined by outcomes from NRG/GOG 86P and identify alternative molecularly enhanced combinations. In Specific Aim #3, we will interrogate the function of p53 mutations that are variants of unknown significance (VUS) to define the best therapy for these tumors. The major goal of this aim is to bin VUS from NRG/GOG 86P into functional categories and understand the impact of recurrent VUS on cell transcription and cell cycle regulation. At the completion of these studies, it is our expectation that we will have designed and tested synergistic drug combinations tailored for specific endometrial cancer subtypes. These studies will make a significant positive impact on the field by enhancing the design and choice of therapy for future endometrial cancer clinical trials.