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%。摘要：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(甲状腺和肾上腺)的泛基因组研究中，我们已经确定了改变的基因/途径是可用药的靶点。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，这些化合物显示出在甲状腺和肾上腺细胞系中的抗癌活性，我们已经确定了在所有研究的癌细胞系和具有不同驱动因素突变的化合物中统一有效的化合物。我们目前正在验证这些化合物的体内活性，并对具有用于联合治疗评估的既定护理药物标准的化合物进行基质药物筛选。在这项工作的基础上，我们目前还在开发两种治疗间变性甲状腺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.