IGF::OT::IGF PREVENTION OF ENDOMETRIAL HYPERPLASIA AND ITS TRANSITION TO ENDOMETRIAL CANCER WITH SHETA2 POP 6/1/2017 - 5/31/2019

子宫内膜增生（EH）是一种子宫内膜过度增生的癌前状态，通常在慢性雌激素暴露而不与黄体酮对抗的情况下出现。它代表了一个连续的组织学上不同的过程，从没有非典型性的简单EH开始，发展到没有非典型性的复杂EH，然后是有非典型性的复杂EH。子宫内膜活检中出现最严重的EH（伴异型性的复杂EH）表明并发和未来子宫内膜癌（EC）的风险很高（29%-52%）。目前EH的治疗方法有限，主要包括子宫切除术或激素治疗。越来越多的证据表明，与健康的人子宫内膜组织相比，在复杂增生的人子宫内膜腺和子宫内膜样腺癌中，cyclin D1的表达渐进式增加。SHetA2是一种无毒的口服药物，可导致转化细胞中细胞周期蛋白D1降解和G1细胞周期阻滞。与对照组小鼠相比，SHetA2还诱导口服或阴道栓剂治疗小鼠子宫组织中周期蛋白D1的降低。此外，SHetA2通过抑制伴侣蛋白GRP75及其客户蛋白（如ER）向线粒体的迁移，选择性地触发肿瘤细胞的凋亡。本任务令的目的是评估口腔和阴道形式的SHetA2对啮齿动物模型中EH和EC发展的影响。

Endometrial hyperplasia (EH), a pre-cancerous condition of excessive proliferation of the endometrium, generally arises in the context of chronic estrogen exposure unopposed by progesterone. It represents a continuum of histologically distinct processes, starting from simple EH without atypia that progresses to complex EH without atypia, followed by complex EH with atypia. The presence of the most severe form of EH (complex EH with atypia) in an endometrial biopsy denotes a high (29%-52%) risk of concurrent and future endometrial cancer (EC). Current treatment approaches for EH are limited, involving primarily hysterectomy or hormone therapy. Growing evidence has shown progressive increases in cyclin D1 expression in human endometrial glands with complex hyperplasia and in endometrioid adenocarcinoma, compared with healthy human endometrium tissue. SHetA2 is a nontoxic, orally bioavailable drug that causes cyclin D1 degradation and G1 cell cycle arrest in transformed cells. SHetA2 also induces decreases in cyclin D1 in uterine tissues from mice treated with oral or vaginal suppository administration, compared with control mice. Furthermore, SHetA2 selectively triggers apoptosis in tumor cells by inhibiting migration of the chaperone GRP75 and its client proteins (such as the ER) to the mitochondria. The purpose of this Task Order is to evaluate the effects of oral and vaginal forms of SHetA2 on the development of EH and EC in a rodent model.