Targeting Ovarian Cancer via Cooperative Oncogene Interactions

通过协同癌基因相互作用靶向卵巢癌

基本信息

批准号：
9104260
负责人：
Diana Clare Hargreaves
金额：
$ 24.9万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
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：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104260
关键词：
1-Phosphatidylinositol 3-Kinase Automobile Driving Binding Binding Sites Biochemical Bioinformatics Biological Markers Cancer cell line Cataloging Catalogs Catalytic Domain Cell Cycle Arrest Cell Death Cell Line Cell Survival Cell division Cells Chromatin Remodeling Factor Clear Cell Collection Complex DNA DNA Structure DNA topoisomerase II alpha Data Diagnosis Disease Down-Regulation Endometrial Carcinoma Event Exhibits Gene Expression Gene Targeting Genes Genome Genomic Instability Genotype Growth Health Human Human Cell Line Link Macromolecular Complexes Malignant Neoplasms Malignant neoplasm of ovary Molecular Mus Mutation Nature Normal tissue morphology Nucleosomes Oncogenes Outcome Ovarian Clear Cell Tumor Ovarian Endometrioid Adenocarcinoma PIK3CA gene PTEN gene Pathway interactions Patients Phase Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Primary Neoplasm Proteins Resistance Role Signal Pathway Signal Transduction TOP2A gene Testing Tumor Suppressor Proteins Up-Regulation Woman Yeasts base cancer cell cytotoxic effective therapy exome sequencing genome-wide high throughput screening individualized medicine inhibitor/antagonist insight killings kinase inhibitor loss of function mutation mTOR Inhibitor mutant novel novel therapeutics ovarian neoplasm phosphatidylinositol 3,4,5-triphosphate protein expression research study response senescence small molecule transcriptome sequencing tumor tumor growth tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer is the most lethal of the gynecological malignancies. Certain ovarian tumors can be particularly difficult to treat as they are often not responsive or become resistant to the chemotherapeutics that are currently in use for the treatment of ovarian cancer. Recently, it was found that clear cell and endometrioid ovarian cancer have mutations in the ARID1A gene and lack ARID1A protein expression. These mutations were found in tumors, but not in normal tissue from the same patient, suggesting a causal link between loss of ARID1A protein and tumor initiation or growth. This breakthrough, along with other sequencing efforts to profile and categorize ovarian cancer by genotype, could provide the first step in tailoring treatment for more effective survival outcomes. Paradoxically, loss of ARID1A causes growth arrest and cell death, not the uncontrolled cell division that occurs in cancer. Thus, there must be mutations in other proteins that cooperate with mutations in ARID1A to drive tumor formation. Recent data suggests that mutations in ARID1A are most often paired with activating mutations in PIK3CA, the catalytic subunit of Phosphatidylinositol 3-Kinase (PI3K), which uses ATP to convert phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). Small molecule inhibitors of PI3K and downstream components of the PI3K pathway have been developed and are currently in use as chemotherapeutics. I aim to understand how mutations in these two proteins cause cells to become transformed and whether ARID1A mutant cells from human clear cell and endometrioid ovarian cancers are more sensitive to PI3K inhibitors by virtue of this pairing. As PIK3CA mutation may be only one of the mechanisms by which cells overcome ARID1A mutation to become transformed, I plan to perform high- throughput screens for small molecules that are specifically cytotoxic to human ARID1A mutant ovarian cancer cell lines. I then hope to determine how such inhibitors debilitate ARID1A mutant cells with the aim of providing better, more personalized chemotherapeutic treatment. In summary, such studies will validate the use of ARID1A loss as a biomarker in the diagnosis of ovarian cancer and provide mechanistic insight and potentially new therapeutics for the treatment of clear cell and endometrioid ovarian cancer.

描述（由申请人提供）：卵巢癌是妇科恶性肿瘤中最致命的。某些卵巢肿瘤可能很难治疗，因为它们通常不反应或对目前用于治疗卵巢癌的化学治疗剂具有抗性。最近，发现清晰的细胞和子宫内膜样卵巢癌在ARID1A基因中具有突变，并且缺乏ARID1A蛋白表达。这些突变是在肿瘤中发现的，但在同一患者的正常组织中没有发现，这表明ARID1A蛋白与肿瘤起始或生长之间存在因果关系。这一突破以及其他测序努力概率和按基因型分类的卵巢癌可以为定制治疗的第一步，以实现更有效的生存结果。矛盾的是，ARID1A的丧失会导致生长停滞和细胞死亡，而不是癌症中发生的不受控制的细胞分裂。因此，其他蛋白质中必须有突变与ARID1A中突变合作以驱动肿瘤形成。最近的数据表明，ARID1A中的突变通常与PIK3CA中的激活突变配对，PIK3CA是磷脂酰肌醇3-激酶（PI3K）的催化亚基，它使用ATP转化了磷脂酰辛醇4,5-磷酸磷酸盐（PIP2），以磷脂型（PIP2），以磷脂型磷脂型3,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,5---phosphosphate（poopsphate）。 PI3K的小分子抑制剂和PI3K途径的下游成分已经开发出来，目前正在用作化学治疗药。我的目标是了解这两种蛋白质中的突变如何导致细胞转化，以及来自人类透明细胞和子宫内膜类卵巢癌的ARID1A突变细胞是否对PI3K抑制剂更敏感。由于PIK3CA突变可能只是细胞克服ARID1A突变转化的机制之一，因此我计划对特异性细胞毒性对人ARID1A突变体卵巢癌细胞系进行高吞吐量筛选。然后，我希望确定这种抑制剂如何使ARID1A突变细胞虚弱，以提供更好，更个性化的化学治疗治疗。总而言之，此类研究将验证ARID1A损失作为诊断卵巢癌的生物标志物，并提供机械洞察力，并提供新的新疗法，用于治疗透明细胞和子宫内膜类药物卵巢癌。