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Identifying Biomarkers of Cisplatin Resistance Mechanisms in Ovarian Cancer

鉴定卵巢癌顺铂耐药机制的生物标志物

基本信息

批准号：
9277423
负责人：
Sharon B Cantor
金额：
$ 34.76万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277423
关键词：
Apoptosis BRCA1 gene BRCA2 gene Biological Assay Biological Markers Biological Models Biological Process Bypass Cancer Etiology Cancer Patient Cancer cell line Candidate Disease Gene Cells Cessation of life Cisplatin Clinic Clinical Computer Simulation DNA Damage DNA Repair Data Data Set Defect Development Disease Ectopic Expression Female Genital Neoplasms Gene Expression Gene Targeting Genes Genetic Determinism Genome Goals Hand Hereditary Breast Carcinoma Histone Deacetylase Histone Deacetylase Inhibitor Human In Vitro Knowledge Learning Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Molecular Mus Mutagens Mutate Mutation Oncogenes Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Platinum Platinum Compounds Primary Neoplasm RNA interference screen Reagent Regulation Regulatory Pathway Research Resistance Resistance development Role Sampling Series Surveys Testing Therapeutic Studies Treatment Efficacy Tumor Suppressor Genes United States Woman Work Xenograft Model base cancer biomarkers cancer cell cancer therapy chemotherapy chromatin modification chromatin remodeling clinically relevant epigenetic drug experimental study gene function genome-wide genome-wide analysis in vivo in vivo Model innovation insight knock-down mutant new therapeutic target novel novel therapeutic intervention novel therapeutics ovarian neoplasm overexpression predicting response predictive marker predictive signature prevent programs public health relevance resistance mechanism response screening small hairpin RNA success therapy resistant tool treatment response tumor tumor growth tumorigenesis validation studies

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer is the most common cause of cancer death from gynecologic tumors in the United States. While some ovarian tumors initially respond to first line chemotherapy, the majority of advanced-stage ovarian cancers develop chemoresistance and patients succumb to their disease. Without a full molecular understanding of how resistance is mediated, even promising new therapies could ultimately fail. Thus, we propose to define these mechanisms and develop tools to anticipate when resistance to chemotherapy will occur. This knowledge will be critical to guide therapy choice and will provide insight into new therapies targeting the mechanisms of resistance. Our innovative idea was to identify mechanisms of chemoresistance in ovarian cancer by an unbiased screen. Indeed, our survival based genome-wide shRNA screen enabled us to identify genes, whose loss is essential for the cancer cells to resist cisplatin therapy. Significantly, several of these genes ae mutated or lost in ovarian cancer and associated with patient response to therapy indicating that our screening strategy was a success. Now, with these genes in hand, our proposed research plan in Aim 1 is to further validate genes in vitro and in vivo. In Aim 2, we will define how depletion of these genes confers resistance. Not only will we learn how loss of these genes unleashes resistance in ovarian cancer, but also these studies will help identify what resistance pathways should be inhibited to enhance the efficacy of therapy. In particular, we will test the hypothesis that genes whose loss confers cisplatin resistance also confer a drug tolerant state (DTS), in which chromatin modifications and DNA damage responses are reduced. Thus, we will determine if knocking down validated gene candidates induces a DTS, or, conversely, ectopic expression of validated gene candidates reverses a DTS. Because epigenetic drugs that preserve chromatin modifications and restore a robust DNA damage response sensitize cells in a DTS, we will test whether epigenetic drugs will re-sensitize cisplatin resistant ovarian cancer cells. Finally, in Aim 3, we will test the hypothesis that genes identified in our screen will be useful as biomarkers. Given that resistance uniquely requires that these genes be depleted, low expression of these genes in ovarian tumors could predict poor response to cisplatin. Thus, it will be critical not only to determine whether these genes are tumor suppressors disrupted in ovarian cancer, but also whether these genes provide a signature predicting cisplatin response in patients, ideas we will test with outstanding reagents and expertise provided by our clinical collaborators. Altogether, the research plan proposed here will provide opportunities to define, detect (biomarkers), and ultimately disable compensatory mechanisms in ovarian cancer.

描述（由申请人提供）：卵巢癌是美国妇科肿瘤导致癌症死亡的最常见原因。虽然一些卵巢肿瘤最初对一线化疗有反应，但大多数晚期卵巢癌会产生耐药性，患者会死于疾病。如果没有对耐药性是如何介导的完整分子理解，即使是有希望的新疗法最终也可能失败。因此，我们建议定义这些机制，并开发工具来预测何时会发生化疗耐药。这些知识对于指导治疗选择至关重要，并将提供针对耐药机制的新疗法的见解。我们的创新想法是通过无偏筛选来确定卵巢癌化疗耐药的机制。事实上，我们基于生存的全基因组shRNA筛选使我们能够识别基因，这些基因的缺失对于癌细胞抵抗顺铂治疗至关重要。值得注意的是，这些基因中有几个在卵巢癌中突变或丢失，并与患者对治疗的反应有关，表明我们的筛选策略是成功的。现在，有了这些基因，我们在目标1中提出的研究计划是进一步在体外和体内验证基因。在目标2中，我们将定义这些基因的缺失如何赋予抗性。我们不仅将了解这些基因的丢失如何释放卵巢癌的耐药性，而且这些研究将有助于确定应该抑制哪些耐药途径以提高治疗效果。特别是，我们将测试的假设，其损失赋予顺铂耐药的基因也赋予耐药状态（MDR），其中染色质修饰和DNA损伤反应减少。因此，我们将确定是否敲低验证的候选基因诱导了一个突变，或者相反，验证的候选基因的异位表达逆转了一个突变。由于表观遗传药物可以保留染色质修饰并恢复强大的DNA损伤反应，因此我们将测试表观遗传药物是否会重新敏化顺铂耐药的卵巢癌细胞。最后，在目标3中，我们将测试在我们的筛选中鉴定的基因将用作生物标志物的假设。考虑到耐药独特地需要这些基因被耗尽，这些基因在卵巢肿瘤中的低表达可以预测顺铂的不良反应。因此，不仅要确定这些基因是否是卵巢癌中被破坏的肿瘤抑制因子，而且还要确定这些基因是否提供了预测患者顺铂反应的特征，我们将用我们的临床合作者提供的优秀试剂和专业知识来测试这些想法。总之，这里提出的研究计划将提供机会来定义，检测（生物标志物），并最终禁用卵巢癌的代偿机制。