Targeted Therapy for Endometrial Cancer

对于晚期子宫内膜癌患者，目前的反应是部分的，持续时间短;今年将有7,000多名妇女死于子宫内膜癌。因此，迫切需要测试新药并开发更有效的治疗方案。靶向治疗，如使用小分子抑制导致肿瘤的分子途径， 为优化子宫内膜癌的治疗提供了新的机会。然而，这种疗法需要仔细考虑哪些途径促进治疗下的肿瘤增殖，以及哪些补偿途径可以响应于治疗而被激活。在第一个阶段，我们 确定了子宫内膜增殖的三个主要相关途径：这些途径相互连接并形成由EGFR/cErbB 2、mTOR/Akt和VEGF/VEGFR及其下游靶点组成的网络。我们假设， 有数据支持用靶向分子阻断一种受体，如EGFR的吉非替尼，导致选择激活网络中其他代偿途径的肿瘤细胞，如通过mTOR/Akt。在此授权期间，我们建议使用体外细胞和体内动物模型在实验室中单独和共同阻断三种途径时诱导的抗性途径，并将这些发现与正在进行的临床试验联系起来。具体而言，在目标1中，我们将评估与敏感性和抗性相关的分子事件，以响应对三个关键子宫内膜生长途径EGFR/ErbB 2、VEGF和mTOR/Akt的阻断。对于这些研究，我们将在I型和II型子宫内膜癌的成熟细胞模型中使用抑制剂拉帕替尼、贝伐单抗、雷帕霉素及其衍生物坦西罗莫司。在目标2中，我们将三种关键子宫内膜生长途径EGFR/ErbB 2、VEGF和mTOR/Akt的敏感性和耐药性标志物（由目标1确定）与小分子抑制剂在异种移植有来自（a）目标1中研究的细胞系和（B）患者来源的子宫内膜癌的肿瘤的无胸腺小鼠中的治疗效果相关联 这些标本构成了我们的活肿瘤组织库。在目标3中，我们将确定在接受拉帕替尼、贝伐珠单抗和替西罗莫司单药治疗的患者中，目标1和2中确定的敏感性和耐药性标志物是否与应答分离。这些研究将为多智能体的合理设计提供依据 未来的治疗方案有可能显著增强晚期子宫内膜癌妇女的治疗选择。

For patients with advanced endometrial cancer, the current responses are partial and of short duration; over 7,000 women will die of endometrial cancer this year. Hence, there is a critical need to test new drugs and develop more effective regimens. Targeted therapy, such as the use of small molecules that inhibit the molecular pathways leading to endometrial proliferation, provides a new opportunity to optimize treatment for endometrial cancer. However, such therapies require careful consideration as to which pathways are promoting proliferation in the tumor under therapy and what compensatory pathways may be activated in response to treatment. In the first grant period, we identified three major linked pathways to proliferation in the endometrium: These pathways interconnect and form a network composed of EGFR/cErbB2, mTOR/Akt, and VEGF/VEGFR and their downstream targets. We hypothesize and have data to support that blocking one receptor with a targeted molecule, such as gefitinib for EGFR, results in the selection of tumor cells that activate the other compensatory pathways in the network, such as through mTOR/Akt. In this grant period, we propose to map the pathways of resistance that are induced when each of the three pathways are blocked independently and together in the laboratory using in vitro cell and in vivo animal models and link these findings with ongoing clinical trials through the GOG. Specifically, in Aim 1 we will evaluate the molecular events relating to sensitivity and resistance in response to the blockade of the three critical endometrial growth pathways, EGFR/ErbB2, VEGF, and mTOR/Akt. For these studies, we will use the inhibitors lapatinib, bevacizumab, rapamycin and its derivative temsirolimus in well established cell models for type I and II endometrial cancers. In Aim 2, we will correlate the markers of sensitivity and resistance (determined from Aim 1) for the three critical endometrial growth pathways, EGFR/ErbB2, VEGF, and mTOR/Akt, with the therapeutic effectiveness of the small molecule inhibitors in athymic mice xenografted with tumors from (a) the cell lines studied in Aim 1 and (b) patient-derived endometrial cancer specimens that comprise our Viable Tumor Tissue Bank. In Aim 3, we will determine whether identified markers for sensitivity and resistance from Aims 1 and 2 segregate with response in patients treated with lapatinib, bevacizumab, and temsirolimus as single agents. These studies will form the basis for the rational design of multi-agent targeted regimens in the future which have the potential to significantly enhance therapeutic options for women with advanced endometrial cancer.