Therapeutic targets and novel anticancer agents for endocrine cancers

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%。间变性甲状腺癌是最致命的实体恶性肿瘤之一，目前尚无有效的系统治疗方法。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：我们已经完成了对4,292种新组装的化合物的高通量定量筛选，这些化合物包含临床批准的药物和人类细胞系中的生物活性化合物，包括甲状腺癌和肾上腺皮质癌。我们在筛选的一组甲状腺癌细胞中鉴定了100个泛活性化合物，到目前为止，利用我们分支机构发展的转移性甲状腺癌小鼠模型，我们已经鉴定了5个化合物，在我们的临床前研究中取得了有希望的结果。组蛋白脱乙酰酶和磷脂酰肌醇3-激酶的一流双重抑制剂CUDC-907就是其中之一。我们发现，来自低分化甲状腺癌和间变性甲状腺癌的6个甲状腺癌细胞的生长和转移受到显著抑制。在机制上，CUDC-907诱导caspase依赖的细胞凋亡和G2M停滞，这与p21表达增加有关，并降低N-钙粘蛋白和波形蛋白的表达水平。从我们使用包含4,292个化合物的药库对3个肾上腺皮质癌细胞株的高通量筛选中，我们鉴定了40个泛活性化合物。根据IC50、血清可达浓度和80%的药物疗效(与四辛基溴化铵相比)进行筛选，我们对氯硝柳胺的3种候选药物进行了跟踪研究，结果表明，在我们的临床前研究中，氯硝柳胺的效果最佳，并有效地针对肾上腺皮质癌常见的遗传驱动事件和信号改变。我们在研究中取得的另一个进展是一个合作的临床前项目，评估一种新的黄金纳米药物。在我们的甲状腺癌转移模型中，这种纳米药物显著减少了生长和转移，提高了总存活率，并诱导了细胞凋亡和肿瘤血管破裂。我们希望在未来将这些发现转化为I/II期试验。

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%. 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 have completed a quantitative high-throughput screening of 4,292 newly assembled compounds containing clinically approved drugs and bioactive compounds in human cell lines, including thyroid cancer and adrenocortical carcinoma. We identified 100 pan-active compounds in a panel of thyroid cancer cell lines screened and have thus far identified 5 compounds with promising results in our preclinical studies, using a mouse model of metastatic thyroid cancer developed in our branch. CUDC-907, a first-in-class dual inhibitor of histone deacetylase and phosphatidylinositol 3-kinase, is one of these compounds. We found significant inhibition of growth and metastases in 6 thyroid cancer cells originating from poorly differentiated thyroid cancer and anaplastic thyroid cancer. Mechanistically, CUDC-907 induced caspase-dependent apoptosis and G2M arrest that was associated with increased p21 expression, and reduced N-cadherin and vimentin expression levels. From our high-throughput screening in 3 adrenocortical carcinoma cell lines using a drug library of 4,292 compounds, we have identified 40 pan-active compounds. Filtering based on IC50, serum achievable concentration, and drug efficacy 80% (as compared to tetraoctylammonium bromide), we have performed follow up studies in 3 drug candidates with niclosamide showing the best results in our preclinical studies and also effectively targeting genetic driver events and signaling alterations common in adrenocortical carcinoma. Another progress we have made in our studies is a collaborative preclinical project evaluating a novel gold nanomedicine. This nanomedicine significantly reduced growth and metastasis, increased overall survival, and induced apoptosis and tumor vascular disruption in our metastatic model of thyroid cancer. We hope to translate these findings into Phase I/II trial in the future.