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%。总结：我们在确定内分泌癌治疗的分子靶点和新型药物方面取得了进展。从我们对内分泌癌（甲状腺癌和肾上腺癌）的泛基因组学研究中，我们已经确定了改变的基因/途径，这些基因/途径是可药物治疗的靶点。通过将这些数据与超过3，000种化合物的定量高通量筛选相结合，这些化合物在甲状腺和肾上腺细胞系中显示出抗癌活性，我们已经确定了在研究的所有癌细胞系中均匀有效的化合物，并且具有不同的驱动突变。我们目前正在体内验证这些化合物的活性，并使用已建立的标准治疗药物对化合物进行基质药物筛选，以进行联合治疗评价。基于这项工作，我们目前还在开发两种用于甲状腺未分化癌和肾上腺癌的临床方案。

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 have made progress towards identifying molecular targets and novel agents for endocrine cancer therapy. From our pangenomic studies of endocrine cancers (thyroid and adrenal), we have identified altered genes/pathways which are druggable targets. By integrating this data with quantitative high throughput screening of over 3,000 compounds, which showed anticancer activity in thyroid and adrenal cell lines, we have identified compounds uniformly effective across all cancer cell lines studied and with different driver mutations. We are currently validating the activities of these compounds in vivo as well as performing matrix drug screening of compounds with established standard of care drugs for combination therapy evaluation. Based on this work we are also currently developing two clinical protocols for anaplastic thyroid cancer and adrenal cancer.