Ovarian Cancer Chemoprevention

卵巢癌化学预防

基本信息

批准号：
9316591
负责人：
DORIS Mangiaracina BENBROOK
金额：
$ 50.02万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9316591
关键词：
Adult Animal Model Apoptosis Apoptotic Appearance Autophagocytosis Binding Blood Breast CCNE1 gene CDK2 gene Cancer cell line Cancerous Canis familiaris Cell Culture Techniques Cell Cycle Arrest Cell Cycle Proteins Cells Chemoprevention Client Clinical Clinical Trials Coculture Techniques Complex Congresses Cultured Cells Cyclin A Cyclin D1 Data Development Disease Drug Targeting Epithelial Epithelial Cells Epithelial ovarian cancer Epithelium Etiology Event Fallopian Tube Neoplasms Fibroblasts G1 Arrest Genetically Engineered Mouse Glutathione Growth Health Histology Human Hysterectomy Image Analysis In Vitro Incidence Individual Induction of Apoptosis Investigational Drugs Knock-out Liver Liver Microsomes Maintenance Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Measures Membrane Potentials Metabolic Mitochondria Mitochondrial Proteins Mitochondrial Swelling Modeling Molecular Chaperones Mus Neoplasm Metastasis Normal Cell Oral Oral Administration Organ Ovarian Ovary PTEN gene Parents Patient Schedules Peritoneal Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phosphorylation Plasma Prevention Protein Array Proteins Proteome Rattus Research Support Resistance Role SHetA2 Schedule Serous Specimen Stromal Cells Teratogens Tissue Microarray Tissues Toxic effect Ubiquitination United States Food and Drug Administration Woman adduct cancer cell cancer chemoprevention capsule dietary supplements drug sensitivity healthy volunteer in vitro activity in vivo in vivo Model mortalin mutant ovarian cancer prevention overexpression patient population preclinical study prevent public health relevance theories treatment duration tumor tumor microenvironment tumor xenograft volunteer

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer is the most deadly of gynecologic cancers because it is most often detected at late stage and little is known of its etiology. A current theory is that high grade serous, the most common ovarian cancer, originates in the fallopian tube. We propose to study pharmaceutical and chemoprevention activity of our non-toxic oral chemoprevention agent, NSC 721689 (SHetA2) in fallopian tube tissue and cells. Our drug interferes with the function of a molecular chaperone called mortalin leading to mitochondrial swelling and mitophagy that transitions to apoptosis in cancer cells, while normal cells are resistant to these effects. A clue to understanding the reason for this differential effet is an altered form of mortalin that appears in NSC-721689-treated normal epithelial cell cultures and is gradually lost as the cultures undergo stasis, immortalization and transformation. We observed mortalin overexpression in the ovarian cancer tumor microenvironment. NSC 721689 also causes G1 cell cycle arrest through phosphorylation, ubiquitination and degradation of cyclin D1; events that occur in both cancer and non- cancer cells in vitro, and in a murine chemoprevention model in vivo. Extensive preclinical studies of our drug conducted by the NCI demonstrated chemoprevention activity in vitro and in vivo, lack of mutagenic metabolites, mutagenicity or teratogenicity, no toxicity and a pharmacologic profile suitable for an oral chemoprevention agent. Our objectives are to study NSC 721689 in ovarian cancer chemoprevention producing data needed to: 1) bring this promising drug to clinical trials for ovarian cancer chemoprevention and 2) develop additional chemoprevention strategies that may be applicable to all cancers. Aim 1 will conduct a Phase 0 clinical trial to determine the number of oral NSC 721689 capsules needed to achieve micromolar drug levels in the blood of healthy volunteers and in fallopian tube tissues of patients scheduled for hysterectomy. Aim 2 will generate Dicer-Pten Double Knock Out [Dicerflox/flox Ptenflox/flox Amhr2cre/+] mice, which have been shown to develop fallopian tube tumors that spread to the ovary, and study the effects of oral NSC 721689 on fallopian tube tumor histology and multiplicity. Aim 3 will measure NSC 721689 effects on cell cycle regulatory proteins and mortalin in specimens from the clinical trial and animal model. Significant results will be validated in cultures of human fallopian tube secretory epithelial cells (hFTSECs) established from the clinical specimens. Aim 3 will also determine the identity of the NSC 721689-induced alteration in mortalin and will study how sensitivity to NSC 721689-induced autophagy and apoptosis is gained, while NSC 721689-induced mortalin alteration is lost, as hFTSECs are passaged, immortalized and transformed. Tissue microarrays (TMAs) and image analysis to separately evaluate cancer and stromal cells, reverse phase protein arrays (RPPAs) and hFTSEC/fibroblast co-cultures will be used to study the roles of mortalin and other NSC 721689 altered proteins in drug sensitivity.

描述（由适用提供）：卵巢癌是妇科癌症中最致命的癌症，因为它经常在后期被发现，并且对其病因却一无所知。当前的理论是，高级浆液是最常见的卵巢癌，起源于输卵管。我们建议在输卵管组织和细胞中研究我们的无毒口服化学预防剂NSC 721689（Sheta2）的药物和化学预防活性。我们的药物干扰了一种称为玛alin蛋白的分子链酮的功能，导致线粒体肿胀和线粒能过渡到癌细胞中凋亡，而正常细胞对这些作用具有抗性。理解这种差异作用原因的线索是一种改变了凡尔林的形式，它出现在NSC-721689处理过的正常上皮细胞培养物中，并且随着培养物的静止，永生化和转化而逐渐消失。我们观察到卵巢癌肿瘤微环境中的Mortalin过表达。 NSC 721689还通过磷酸化，泛素化和降解细胞周期蛋白D1引起G1细胞周期停滞；体外发生在癌症和非癌细胞中发生的事件，以及体内的鼠化学预防模型。 NCI对我们进行的药物进行的广泛临床前研究表明，体外和体内的化学预防活性，缺乏诱变代谢产物，诱变或致死性，无毒性和适用于口服化学预防剂的药物。我们的目标是研究NSC 721689在卵巢癌的化学预防生产数据中所需的：1）将此承诺的药物带入卵巢癌化学预防的临床试验和2）制定可能适用于所有癌症的其他化学预防策略。 AIM 1将进行0期临床试验，以确定在健康志愿者血液中达到微摩尔药物水平所需的口服NSC 721689的数量，以及计划进行子宫切除术的患者的输卵管组织中。 AIM 2将产生DICER-PTEN双重敲除[DICERFLOX/FLOX PTENFLOX/FLOX AMHR2CRE/+]小鼠，这些小鼠已证明会发展出扩散到卵巢的输卵管肿瘤，并研究口服NSC 721689对子宫肿瘤肿瘤的作用。 AIM 3将测量NSC 721689对临床试验和动物模型的标本中细胞周期调节蛋白的影响。在临床标本中建立的人类输卵管分泌上皮细胞（HFTSEC）的培养物中，将验证重大结果。 AIM 3还将确定NSC 721689诱导的Mortalin改变的身份，并将研究如何获得对NSC 721689诱导的自噬和凋亡的敏感性，而NSC 721689诱导的Mortalin的改变却丢失了，因为HFTSECS被丢失，Immentalliped and Immbieltal和变形。组织微阵列（TMA）和图像分析分别评估癌症和基质细胞，反相蛋白阵列（RPPA）和HFTSEC/成纤维细胞共培养将用于研究Mortalin和其他NSC 721689改变药物敏感性中蛋白质的作用。