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，持续时间很短；今年将有超过7000名妇女死于子宫内膜癌。因此，迫切需要测试新药和开发更有效的方案。靶向治疗，例如使用小分子来抑制分子通路 对子宫内膜的增殖，为优化治疗子宫内膜癌提供了新的契机。然而，这样的治疗需要仔细考虑哪些途径促进了正在治疗的肿瘤的增殖，以及哪些代偿途径可能会在治疗后被激活。在第一个授权期内，我们 在子宫内膜中发现了三条与增殖相关的主要途径：这些途径相互连接，形成一个由EGFR/cErbB2、mTOR/Akt和VEGF/VEGFR及其下游靶点组成的网络。我们假设和 有数据支持用靶向分子(如EGFR的吉非替尼)阻断一个受体，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。在这一资助期间，我们建议使用体外细胞和体内动物模型在实验室中绘制当三条途径中的每一条单独和一起被阻断时诱导耐药的途径，并通过GOG将这些发现与正在进行的临床试验联系起来。具体地说，在目标1中，我们将评估与三条关键的子宫内膜生长途径EGFR/ErbB2、VEGF和mTOR/Akt阻断有关的敏感性和耐药性的分子事件。在这些研究中，我们将在I型和II型子宫内膜癌的成熟细胞模型中使用拉帕替尼、贝伐单抗、雷帕霉素及其衍生物替西罗莫斯。在目标2中，我们将把EGFR/erbB2、VEGF和mTOR/Akt这三个关键的子宫内膜生长途径的敏感性和耐药性标记物与小分子抑制剂在裸鼠移植瘤中的治疗效果相关联，这些肿瘤来自于目标1中研究的细胞系和(B)患者来源的子宫内膜癌。 组成我们的活肿瘤组织库的标本。在目标3中，我们将确定在接受拉帕替尼、贝伐单抗和替西罗莫司作为单一药物治疗的患者中，来自目标1和2的已识别的敏感性和耐药性标记物是否与反应分离。这些研究将为多智能体靶向的合理设计奠定基础 未来的治疗方案有可能显著增加晚期子宫内膜癌的治疗选择。

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.