Therapeutic targets and novel anticancer agents for endocrine cancers

背景：甲状腺癌：在过去的二十年中，甲状腺癌的发病率翻了一番。虽然大多数滤泡细胞源性甲状腺癌患者预后良好，但10% - 15%的常规治疗（切除联合放射性碘消融和甲状腺激素抑制TSH）将难治性疾病。化疗和外束放疗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病变和转移。不幸的是，尽管联合多模式治疗，肾上腺皮质癌患者的总体预后仍然令人沮丧，5年生存率低于35%。我们正在利用功能基因组学方法确定候选基因的作用，通过mRNA和microRNA表达谱分析在甲状腺癌和肾上腺皮质癌人类肿瘤样本中体外和体内模型中的差异表达。候选基因在调节恶性表型特征（如细胞增殖、侵袭和迁移以及肿瘤血管生成）中的作用正在通过基因敲低和敲入实验进行测试，以确定关键的调节因子和治疗靶点。我们已经完成了一项定量高通量筛选策略，用于鉴定甲状腺癌和肾上腺皮质癌的新型药物。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，以确定它们对甲状腺癌和肾上腺皮质癌细胞系的抗增殖作用。所有的化合物都获得了FDA的其他适应症批准，或者被FDA指定为研究性新药。我们已经鉴定出30多种具有高可信度的抗甲状腺癌和肾上腺皮质癌细胞活性的化合物。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。

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.