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Ovarian Cancer Chemoprevention

卵巢癌化学预防

基本信息

批准号：
9093746
负责人：
DORIS Mangiaracina BENBROOK
金额：
$ 50.4万
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/9093746
关键词：
Adult Animal Model Apoptosis Apoptotic Appearance Autophagocytosis Binding Blood Breast CCNE1 gene CDK2 gene Cancer cell line Cancerous Cell Culture Techniques Cell Cycle Arrest Cell Cycle Proteins Cells Chemoprevention Client Clinical Clinical Trials Coculture Techniques Complex Congresses Cyclin D1 Cyclins 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 Ovarian Ovary PTEN gene Parents Patient Schedules Peritoneal Pharmaceutical Preparations Pharmacologic Substance Phase Phosphorylation Plasma Prevention Protein Array Proteins Proteome Rattus Research Support Resistance Role SHetA2 Schedule Serous Specimen Staging Stromal Cells Tissue Microarray Tissues Toxic effect Ubiquitination United States Food and Drug Administration Woman Xenograft procedure cancer cell cancer chemoprevention capsule dietary supplements drug sensitivity healthy volunteer in vitro activity in vivo in vivo Model meetings mortalin mutant ovarian cancer prevention overexpression patient population preclinical study prevent theories treatment duration tumor tumor microenvironment 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.