P1: Novel Targeted Strategies for Prevention and Conservative Management of Complex Atypical Hyperplasia and Grade 1 Endometrioid Endometrial Cancer

项目1概要/摘要 高危癌前病变（复杂不典型增生，CAH）和1级非侵袭性 子宫内膜样癌（EEC）通常通过全子宫切除术和双侧输卵管切除术治疗。 卵巢切除术;然而，对保守治疗的需求日益增加。保守治疗 对于两组患者特别重要，1）具有高手术风险的病态肥胖女性，以及2） 希望保持生育能力的绝经前妇女。事实上，妇科癌症国际小组最近 将这些患者的保守治疗确定为应优先考虑的关键未满足的临床需求， research.此外，这两个群体构成了EEC患者的重要部分。肥胖是一个很大的风险 EEC的因素，据估计，12-17%的女性与EEC是病态肥胖，这一百分比 随着肥胖症流行的持续，可能会增加。此外，大约20%的EEC病例发生在 绝经前妇女，可能需要保留生育能力。 众所周知，孕酮可以抵消子宫内膜中雌激素的作用，我们的研究表明， 孕激素洗脱宫内节育器（左炔诺孕酮宫内节育器）仅对50%的1级 癌的复发性EEC的临床前研究和临床试验表明，mTOR抑制（通过 依维莫司）联合阻断雌激素信号传导可进一步提高反应率。我们将 开展左炔诺孕酮宫内节育器单独使用或与口服依维莫司联合使用的II期临床试验。我们预测 靶向这种双途径方法将显著改善早期EEC的临床反应。我们将 然后利用先进的分子分析技术， 子宫内膜组织样本的成分，以确定与左炔诺孕酮IUD相关的畸变- 反应性CAH和1级疾病与左炔诺孕酮IUD耐药疾病（包括 依维莫司应答者和依维莫司非应答者）。我们的研究还将评估子宫内膜间质- 治疗反应中的腺体串扰信号传导。这些高度转化的研究将定义高- 需要与依维莫司联合治疗的风险亚组， 未来研究的目标集中在癌症预防和治疗上。我们的总体目标是确保 保守治疗是一种有效的临床选择。为此，我们正在开发和优化 基于聚合物的宫内给药系统，以提高保守治疗的耐受性。我们提出 子宫内药物递送可以使依维莫司的长期持续子宫内给药成为可能， 与全身给药相关的毒性。总的来说，该项目利用临床和 基础科学研究，以迅速推进转化研究，以改善临床方法，以保守 治疗CAH和1级EEC。

Project 1 SUMMARY/ABSTRACT High-risk precancerous lesions (complex atypical hyperplasia, CAH) and grade 1 non-invasive endometrioid endometrial cancer (EEC) are typically treated by total hysterectomy and bilateral salpingo- oophorectomy; however, there is an increasing need for conservative treatment. Conservative therapy is particularly important for two groups of patients, 1) morbidly obese women with high surgical risks, and 2) premenopausal women who wish to maintain fertility. In fact, the Gynecologic Cancer InterGroup has recently identified conservative therapy for these patients as a key unmet clinical need that should be prioritized for research. Moreover, these two groups make up a significant portion of EEC patients. Obesity is a strong risk factor for EEC, and it is estimated that 12-17% of women with EEC are morbidly obese, with this percentage likely to increase as the obesity epidemic continues. In addition, approximately 20% of EEC cases occur in premenopausal women, for whom fertility-preservation may be desired. Progesterone is known to counteract the effects of estrogen in the endometrium, and our studies have shown that a progestin-eluting intrauterine device (levonorgestrel IUD) is effective against only 50% of grade 1 cancers. Preclinical studies and clinical trials in recurrent EEC have shown that mTOR inhibition (via everolimus) in combination with blocking estrogen signaling may further improve response rates. We will conduct a phase II clinical trial of levonorgestrel IUD alone or in combination with oral everolimus. We predict that targeting this dual pathway approach will significantly improve clinical responses in early EEC. We will then leverage advanced molecular profiling technologies using microdissected stromal and epithelial components of endometrial tissue samples to identify aberrations that are associated with levonorgestrel IUD- responsive CAH and grade 1 disease versus levonorgestrel IUD-resistant disease (including subgroups of everolimus responders and everolimus non-responders). Our studies will also evaluate endometrial stroma- gland crosstalk signaling in treatment response. These highly translational studies will define profiles for high- risk subgroups that warrant combination treatment with everolimus and potentially identify additional molecular targets for future studies focused on cancer prevention and therapeutics. Our overall goal is to ensure that conservative management is an effective clinical option. For this reason, we are developing and optimizing a polymer-based intrauterine drug delivery system to improve tolerability of conservative therapy. We propose that intrauterine drug delivery can enable long-term sustained intrauterine administration of everolimus without toxicities related to systemic administration. Overall, this project uses the combined expertise of clinical and basic science research to rapidly advance translational studies to improve clinical approaches to conservative therapy in CAH and grade 1 EEC.