权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Therapeutic targets and novel anticancer agents for endocrine cancers

内分泌癌的治疗靶点和新型抗癌药物

基本信息

批准号：
8349445
负责人：
Electron Kebebew
金额：
$ 79.62万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8349445
关键词：
Ablation Adrenocortical carcinoma Antineoplastic Agents Cancer Patient Candidate Disease Gene Cell Line Cell Proliferation Cells Chemicals Chemistry Clinical Trials Collaborations Combined Modality Therapy Disease Excision External Beam Radiation Therapy Family Follicular thyroid carcinoma Genes Genomics Goals Human In Vitro Incidence Investigational Drugs Malignant Epithelial Cell Malignant neoplasm of thyroid MicroRNAs Molecular Molecular Profiling Neoplasm Metastasis Patients Quality of life Refractory Disease Role Sampling Strategic Planning Survivors Testing Thyroid Hormones Translating Tumor Angiogenesis United States National Institutes of Health anticancer activity cancer care chemotherapy compound 30 conventional therapy functional genomics high throughput screening improved in vivo Model mRNA Expression malignant endocrine gland neoplasm malignant phenotype migration new therapeutic target novel outcome forecast research study tumor

项目摘要

Background: Thyroid cancer: The incidence of thyroid cancer has doubled over the last two decades. Although most patients with thyroid cancer of follicular cell origin have an excellent prognosis, 10% - 15% will have refractory disease to conventional therapy (resection combined with radioiodine ablation and thyroid hormone for TSH suppression). Chemotherapy and external beam radiation are ineffective in patients with metastatic disease. The overall 10 year survival of patients with metastatic thyroid cancer of follicular cell origin is approximately 40-50%. Adrenocortical carcinoma: Approximately two-thirds of patients who present with adrenocortical carcinoma have locoregional disease and metastasis. Unfortunately, despite combined multimodality therapy, the overall prognosis of patients with adrenocortical carcinoma remains dismal, with a 5-year survival of less than 35%. Summary We are using functional genomics approach to determine the role of candidate genes, differentially expression by mRNA and microRNA expression profiling in thyroid cancer and adrenocortical carcinoma human tumor samples, in in vitro and in vivo models. The role of the candidate genes in regulating the hallmarks of malignant phenotype such as cellular proliferation, invasion and migration, and tumor angiogenesis is being tested using gene knockdown and knockin experiments to identify critical regulators and thus targets for therapy. We have completed a quantitative high throughput screening strategy for the identification of novel agents for thyroid cancer and adrenocortical carcinoma. In collaboration with the Chemistry group at the NIH Chemical Genomic Center, we screened 2,816 compounds to determine their antiproliferative effect in thyroid cancer and adrenocortical carcinoma cell lines. All of the compounds have either FDA approval for other indications or have investigational new drug designation by the FDA. We have identified over 30 compounds with high confidence activity against thyroid cancer and adrenocortical carcinoma cell lines. We are currently validating the anticancer activity of the most potent compounds and plan to translate these findings into clinical trials for patients with advance thyroid cancer and adrenocortical carcinoma.

背景：甲状腺癌：在过去的二十年里，甲状腺癌的发病率翻了一番。尽管大多数滤泡细胞型甲状腺癌患者预后良好，但仍有10%-15%的患者存在常规治疗(切除联合放射性碘消融和甲状腺激素抑制TSH)的顽固性疾病。化疗和外照射对转移性疾病患者无效。滤泡细胞来源的转移性甲状腺癌患者的总体10年生存率约为40-50%。肾上腺皮质癌：大约三分之二的肾上腺皮质癌患者有局部疾病和转移。不幸的是，尽管联合多种治疗，肾上腺皮质癌患者的总体预后仍然很差，5年生存率不到35%。摘要我们正在使用功能基因组学的方法来确定候选基因在体外和体内模型中的作用，通过mRNA和microRNA表达谱在甲状腺癌和肾上腺皮质癌人类肿瘤样本中进行差异表达。候选基因在调节细胞增殖、侵袭和迁移以及肿瘤血管生成等恶性表型特征方面的作用正在通过基因敲除和敲打实验进行测试，以确定关键的调控因子，从而确定治疗的靶点。我们已经完成了一种用于鉴定甲状腺癌和肾上腺皮质癌新药的定量高通量筛选策略。与NIH化学基因组中心的化学小组合作，我们筛选了2816种化合物，以确定它们在甲状腺癌和肾上腺癌细胞系中的抗增殖作用。所有这些化合物要么获得了FDA对其他适应症的批准，要么获得了FDA的试验性新药指定。我们已经确定了30多个具有高可信活性的化合物，它们对甲状腺癌和肾上腺癌细胞株具有抑制作用。我们目前正在验证最有效的化合物的抗癌活性，并计划将这些发现转化为晚期甲状腺癌和肾上腺皮质癌患者的临床试验。