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

子宫内膜增生症（EH）是子宫内膜过度增生的癌前状态，通常在长期雌激素暴露而不受孕酮抵抗的情况下发生。它代表了一系列组织学上不同的过程，从单纯型EH无动脉硬化开始，发展为复杂型EH无动脉硬化，然后是复杂型EH伴动脉硬化。在子宫内膜活检中存在最严重形式的EH（复杂EH伴子宫内膜癌）表明并发和未来子宫内膜癌（EC）的风险较高（29%-52%）。目前EH的治疗方法有限，主要涉及子宫切除术或激素治疗。越来越多的证据表明，与健康人子宫内膜组织相比，在人子宫内膜腺体复杂增生和子宫内膜样腺癌中，细胞周期蛋白D1的表达逐渐增加。SHetA 2是一种无毒的口服生物可利用药物，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。与对照小鼠相比，SHetA 2还诱导口服或阴道栓剂给药小鼠子宫组织中细胞周期蛋白D1的减少。此外，SHetA 2通过抑制伴侣GRP 75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。本任务指令的目的是在啮齿动物模型中评价口服和阴道形式的SHetA 2对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.