Therapeutic targets and novel anticancer agents for endocrine cancers

背景：甲状腺癌：甲状腺癌的发病率在过去二十年中翻了一番。虽然大多数滤泡细胞来源的甲状腺癌患者预后良好，但10% - 15%的患者对常规治疗（切除联合放射性碘消融和甲状腺激素抑制TSH）难以治疗。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患有局部疾病和转移。不幸的是，尽管采用了综合治疗，肾上腺皮质癌患者的总体预后仍然很差，5年生存率低于35%。我们正在使用功能基因组学的方法，以确定候选基因的作用，差异表达的mRNA和microRNA表达谱在甲状腺癌和肾上腺皮质癌人类肿瘤样本，在体外和体内模型。候选基因在调节恶性表型的标志如细胞增殖、侵袭和迁移以及肿瘤血管生成中的作用正在使用基因敲低和敲入实验进行测试，以鉴定关键调节因子，从而鉴定治疗靶点。我们还在进行研究，以确定甲状腺癌和肾上腺皮质癌的新药。这些研究涉及使用国家化学基因组中心药物收集的2，816种化合物来确定它们在甲状腺癌和肾上腺皮质癌细胞系中的抗增殖作用。所有这些化合物都已获得FDA批准用于其他适应症，或已被FDA指定为研究性新药。因此，在甲状腺癌和肾上腺皮质癌动物模型中验证其抗增殖作用后，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将相对有效。

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 are also performing studies to identify novel agents for thyroid cancer and adrenocortical carcinoma. These studies involve using the National Chemical Genomic Center pharmaceutical collection of 2,816 compounds to determine their antiproliferative effect in thyroid cancer and adrenocortical carcinoma cell lines. All of these compounds have either FDA approval for other indications or have investigational new drug designation by the FDA. Thus, translating these findings, after validation of their antiproliferative effect in animal models of thyroid cancer and adrenocortical carcinoma, into clinical trials for patients with advance thyroid cancer and adrenocortical carcinoma would be relatively efficient.