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

项目1摘要/摘要 高危癌前病变(复杂性不典型增生，CAH)和1级非侵袭性病变 子宫内膜样癌(EEC)通常采用全子宫切除术和双侧输卵管切除术。 卵巢切除术；然而，保守治疗的必要性越来越大。保守疗法是 对于两组患者来说尤其重要，1)有高手术风险的病态肥胖女性，2) 希望保持生育能力的绝经前妇女。事实上，妇科癌症小组最近已经 将这些患者的保守治疗确定为关键的未得到满足的临床需求，应优先考虑 研究。此外，这两个群体在EEC患者中占很大比例。肥胖是一个很大的风险 EEC的因素，据估计，患有EEC的女性中有12%-17%是病态肥胖，这一比例 随着肥胖症流行的继续，这一数字可能会增加。此外，约20%的欧共体病例发生在 绝经前妇女，她们可能希望保留生育能力。 众所周知，孕激素可以抵消雌激素在子宫内膜中的作用，我们的研究已经 结果表明，孕激素洗脱宫内节育器(左旋诺孕酮宫内节育器)仅对50%的1级宫内节育器有效 癌症。复发EEC的临床前研究和临床试验表明，mTOR抑制(通过 联合阻断雌激素信号可能会进一步提高应答率。我们会 进行左旋诺孕酮宫内节育器单独或联合口服依维莫司的II期临床试验。我们预测 针对这一双途径途径将显著改善早期EEC的临床反应。我们会 然后利用先进的分子图谱技术，使用显微解剖的间质和上皮 子宫内膜组织样本成分以确定与左炔诺孕酮宫内节育器相关的异常 反应性CAH和1级疾病与左炔诺孕酮宫内节育器抵抗疾病(包括 埃维洛莫司应答者和非应答者)。我们的研究还将评估子宫内膜间质- 腺体串扰信号在治疗反应中的作用。这些高度翻译的研究将定义高- 需要与伊波利莫联合治疗的风险亚群，并可能识别额外的分子 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一种 以聚合物为基础的宫内给药系统可提高保守治疗的耐受性。我们建议 宫内给药可以长期持续地在宫内给药，而不需要 与全身给药有关的毒性。总体而言，该项目使用了临床和临床的综合专业知识 基础科学研究将迅速推进翻译研究，以改善保守治疗的临床方法 CAH和1级EEC的治疗。

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.