Mechanism of SHeA2 Action in Ovarian Cancer

描述（由申请人提供）：SHetA 2是一种新型抗癌化合物，其调节生长和分化的作用类似于类维生素A，但不直接激活RAR或RXR。SHetA 2抑制卵巢癌异种移植物的生长，而没有毒性的证据。其他动物模型已证明SHetA 2不会诱导致畸性或皮肤刺激。因此，与能够激活类维生素A受体的类维生素A相比，SHetA 2表现出改善的治疗比率。由于SHetA 2目前正通过美国国家癌症研究所（NCI）的快速干预和发展（RAID）计划进行临床前开发，因此需要额外的基础科学研究（RAID不支持）来了解这种化合物的作用机制。假设SHetA 2直接与线粒体相互作用，导致产生活性氧、线粒体膜去极化、抑制NF-κ B活性和胸苷磷酸化酶表达以及血小板反应蛋白-4基因表达。在内皮细胞中，该途径抑制毛细血管的发育。卵巢癌细胞的过度活跃的代谢状态增加了其线粒体对SHetA 2扰动的敏感性，最终结果是诱导细胞凋亡的内在途径。正常细胞更稳定的线粒体状态使它们对SHetA 2诱导的细胞凋亡更具抵抗力。SHetA 2通过激活肝核因子-4诱导腺体分化，肝核因子-4调节参与糖蛋白代谢、半乳糖胺（N-乙酰基）-6-硫酸酯硫酸酯酶和UDP-半乳糖-4-差向异构酶以及TSP-4糖蛋白的基因。具体目的是破译SHetA 2分子途径：1）癌性卵巢细胞与正常卵巢细胞的差异性凋亡，2）腺体分化和3）内皮细胞毛细血管形成的抑制。这些研究的结果将提供适当设计临床试验和改进化合物所需的SHetA 2机制信息，以及细胞凋亡和分化的科学信息。阐明SHEtA 2通路中的蛋白质将为卵巢癌的诊断、预防和治疗策略提供潜在的生物标志物。

DESCRIPTION (provided by applicant): SHetA2 is a novel anti-cancer compound that regulates growth and differentiation similar to retinoids, but does not directly activate RARs or RXRs. SHetA2 inhibited the growth of ovarian cancer xenografts without evidence of toxicity. Additional animal models have demonstrated that SHetA2 does not induce teratogenicity or skin irritation. Thus, SHetA2 exhibits an improved therapeutic ratio over retinoids capable of activating the retinoid receptors. Because SHetA2 is currently in pre-clinical development through the Rapid Access to Intervention and Development (RAID) program of the National Cancer Institute (NCI), additional basic science research, which is not supported by RAID, is needed to understand the mechanism of action of this compound before it is tested in humans. The hypothesis is that SHetA2 directly interacts with the mitochondria resulting in generation of reactive oxygen species, mitochondrial membrane depolarization, and inhibition of NF-kappaB activity and expression of thymidine phosphorylase and thrombospondin-4 gene expression. In endothelial cells this pathway inhibits the development of capillaries. The hyperactive metabolic state of ovarian cancer cells, increases the sensitivity of their mitochondria to the SHetA2 perturbations with the ultimate outcome being the induction of the intrinsic pathway to apoptosis. The more stable mitochondrial state of normal cells makes them more resistant to SHetA2-induced apoptosis. SHetA2 induces glandular differentiation through activation of hepatic nuclear factor-4, which regulates genes involved in glycoprotein metabolism, Galactosamine (N-acetyl)-6-sulfate sulfatase and UDP-galactose-4-epimerase and the TSP-4 glycoprotein. The specific aims are to decipher the SHetA2 molecular pathways of: 1) differential apoptosis in cancerous versus normal ovarian cells, 2) glandular differentiation and 3) inhibition of endothelial cell capillary formation. The results of these studies will provide mechanistic information on SHetA2 required for appropriate design of clinical trials and improved compounds, and scientific information on apoptosis and differentiation. The elucidation of the proteins involved in the SHetA2 pathwayswill provide potential biomarkers for ovarian cancer diagnosis, prevention and treatment strategies.