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%。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%。综述：我们在寻找内分泌癌的分子靶点和新的药物方面取得了进展。在我们的活体研究中，我们开发了两种新的方法来评估治疗反应。在转基因小鼠甲状腺癌模型中，我们已经能够用高分辨率超声对肿瘤进行定量测量，并显示出大体解剖肿瘤测量与甲状腺超声测量之间的良好相关性。在另一个稳定转染荧光素酶报告基因的癌细胞系肺转移模型中，我们能够通过定量测量与肿瘤负荷相关的荧光素酶活性(肿瘤体积)来成像转移部位。这种评估肿瘤反应的方法有几个优点，包括1)实时评估肿瘤对治疗的反应，以及2)确定治疗的自然历史，因为不是为了评估反应而牺牲小鼠，所以取消了导致肿瘤退化的药物。从我们的全基因组表达分析中，我们已经确定了在大多数癌症中可药物靶点和改变的基因(例如，100%被分析的肾上腺皮质癌样本中TOP2A的过度表达)。此外，我们还将我们从细胞系中显示出抗癌活性的化合物的定量高通量筛选的数据与来自人类肿瘤样本的基因组数据进行了整合。这导致在某些类型的肿瘤(如肾上腺皮质癌的拓扑异构酶抑制剂)中发现了几类具有优先高抗癌活性的药物(80%的类药物)。我们目前正在体内验证这些化合物的抗癌活性，并希望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 making progress towards identifying molecular targets and novel agents for endocrine cancers. We have developed two novel approaches of evaluating response to therapy in our in vivo studies. In transgenic mouse model of thyroid cancer, we have been able to quantitatively measure tumors by high-resolution ultrasound and demonstrated excellent correlation between gross post-mortem tumor measurements and thyroid ultrasound measurements. In another model of lung metastasis of cancer cell lines stably transfect with a luciferase reporter, we are able to image sites of metastasis with a quantifiable measurement of luciferase activity (tumor volume) with correlates with tumor burden. Such approaches for assessing tumor response have several advantages including 1) real time assessment of tumor response to therapy, and 2) determining the natural history of therapy withdrawal of agents inducing tumor regression as mice are not sacrificed to evaluate response.From our genome-wide expression analysis, we have identified genes which are druggable targets and altered in most cancers (e.g. overexpression of TOP2A in 100% of adrenocortical carcinoma samples analyzed). Furthermore, we have integrated our data from our quantitative high throughput screening of compounds which showed anticancer activity in cell lines with the genomic data from human tumor samples. This has resulted in identifying several classes of drugs with preferentially high anticancer activity (80% of drugs in class) in certain types of tumors (e.g. topoisomerase inhibitors in adrenocortical carcinoma). We are currently validating the anticancer activity of these compounds in vivo and hope to translate these findings into clinical trials for patients with advance thyroid cancer and adrenocortical carcinoma.