Therapeutic targets and novel anticancer agents for endocrine cancers

内分泌癌的治疗靶点和新型抗癌药物

• 批准号: 10014590
• 负责人: Naris Nilubol
• 金额: $ 96.48万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10014590
• 关键词: 1-Phosphatidylinositol 3-Kinase; Ablation; Adrenocortical carcinoma; Apoptosis; Blood Vessels; Bromides; Cancer Patient; Cancer cell line; Caspase; Cell Line; Cells; Clinical; Combined Modality Therapy; Disease; Event; Excision; External Beam Radiation Therapy; Family; Follicular thyroid carcinoma; Follow-Up Studies; Future; Genetic; Goals; Gold; Growth; Histone Deacetylase Inhibitor; Human Cell Line; Incidence; Libraries; Malignant Neoplasms; Malignant neoplasm of thyroid; Modeling; N-Cadherin; Neoplasm Metastasis; Patients; Pharmaceutical Preparations; Phase I/II Trial; Quality of life; Radioactive Iodine; Refractory Disease; Serum; Signal Transduction; Solid; Strategic Planning; Survivors; Systemic Therapy; Thyroid Hormones; Translating; Vimentin; anaplastic thyroid cancer; base; cancer care; cancer cell; chemotherapy; conventional therapy; drug candidate; drug efficacy; high throughput screening; improved; malignant endocrine gland neoplasm; molecular targeted therapies; mouse model; nanomedicine; novel; novel anticancer drug; outcome forecast; pre-clinical; preclinical study; safety testing; therapeutic target; tumor

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. 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%. 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. CUDC-907 was utilized in a Phase I/II trial to test for safety and efficacy. The medication was found to be well-tolerated, but was not efficacious. 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 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 for niclosamide and gold nanomedicine into Phase I/II trial in the future.

过去二十年来，甲状腺癌的发病率翻了一番。尽管大多数滤泡细胞来源的甲状腺癌患者预后良好，但仍有 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。化疗和外照射对于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%。甲状腺未分化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。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，尽管采用联合多学科治疗，肾上腺皮质癌患者的总体预后仍然不佳，5年生存率低于35%。我们已经完成了对 4,292 种新组装的化合物的定量高通量筛选，这些化合物含有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。我们在一组筛选的甲状腺癌细胞系中鉴定出了 100 种全活性化合物，迄今为止，我们使用我们分支机构开发的转移性甲状腺癌小鼠模型，在临床前研究中鉴定了 5 种具有良好结果的化合物。 CUDC-907 是此类化合物之一，是一种首创的组蛋白脱乙酰酶和磷脂酰肌醇 3-激酶双重抑制剂。我们发现来自低分化甲状腺癌和未分化甲状腺癌的 6 种甲状腺癌细胞的生长和转移受到显着抑制。从机制上讲，CUDC-907 诱导 caspase 依赖性细胞凋亡和 G2M 停滞，这与 p21 表达增加以及 N-钙粘蛋白和波形蛋白表达水平降低相关。 CUDC-907 用于 I/II 期试验以测试安全性和有效性。研究发现该药物耐受性良好，但效果不佳。通过使用 4,292 种化合物的药物库对 3 种肾上腺皮质癌细胞系进行高通量筛选，我们鉴定出了 40 种全活性化合物。根据IC50、血清可达到浓度和药效80%（与四辛基溴化铵相比）进行筛选，我们对氯硝柳胺的3种候选药物进行了后续研究，显示出我们临床前研究中的最佳结果，并有效针对肾上腺皮质癌中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评估一种新型金纳米药物的临床前合作项目。在我们的甲状腺癌转移模型中，这种纳米药物显着减少生长和转移，提高总体生存率，并诱导细胞凋亡和肿瘤血管破坏。我们希望未来将氯硝柳胺和金纳米药物的这些发现转化为 I/II 期试验。