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%。间变性甲状腺癌是最致命的实体恶性肿瘤之一，目前尚无有效的全身治疗方法。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%。摘要：我们在确定甲状腺和肾上腺皮质癌治疗的分子靶点和新药方面取得了进展。从我们对内分泌癌（甲状腺癌和肾上腺癌）的全基因组学研究中，我们已经确定了可药物靶点的改变基因/途径，如肿瘤抑制基因甲基化失调和组蛋白去乙酰化酶表达，以及低分化和间变性甲状腺癌中survivin表达升高。通过将这些数据与我们的3,000多种化合物的定量高通量药物文库筛选相结合，证明了针对甲状腺癌细胞中失调基因/途径的化合物具有丰富的活性。我们目前正在对这些药物进行临床前研究，希望将其转化为临床试验。同时，我们正在使用高通量平台在间变性甲状腺癌细胞中进行基质药物筛选（活性化合物的联合筛选），以确定具有协同效应的药物组合，我们可以在转移性间变性甲状腺癌的临床前模型中进行评估。对于肾上腺皮质癌，我们已经建立了一个转移模型临床前模型来测试从我们的高通量筛选中发现的活性化合物。

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%. Anaplastic thyroid cancer is one of the most lethal solid malignancies with no currently available effective systemic therapy. 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 making progress towards identifying molecular targets and novel agents for thyroid and adrenocortical carcinoma therapy. From our pangenomic studies of endocrine cancers (thyroid and adrenal), we have identified altered genes/pathways which are druggable targets such as dysregulated methylation of tumor suppressor genes and histone deacetylase expression, and elevated survivin expression in poorly differentiated and anaplastic thyroid cancer. By integrating this data with our quantitative high throughput drug library screening of over 3,000 compounds, which demonstrated enriched activity of compounds targeting dysregulated genes/pathways in thyroid cancer cells. We are currently performing preclinical studies of these agents in the hopes of translating them into clinical trials. In parallel, we are performing matrix drug screening (combination screening of active compounds) in anaplastic thyroid cancer cells using a high throughput platform to identify drug combinations with a synergistic effect that we can evaluate in our preclinical model of metastatic anaplastic thyroid cancer. For adrenocortical carcinoma, we have established a metastatic model preclinical model to test compounds found to be active from our high throughput screening.