Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Clin Endocrinol Metab. 2021 Sep 27;106(10):2962-2978. doi: 10.1210/clinem/dgab424.
Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development.
Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft (PDX) models were used to validate the selected agents.
Seventeen compounds were effective, and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the US Food and Drug Administration for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53.
HTS identified classes of systemic agents that demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early-phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.
尽管采用了积极的多模式治疗，但大多数间变性甲状腺癌（ATC）患者在诊断后一年内死亡。虽然 BRAF 和 MEK 抑制剂的联合治疗最近已被批准用于 BRAF 突变型 ATC，但它们在可能发生耐药性的少数患者中仍然有效。对于 ATC，仍然存在迫切的临床需求，需要具有合理毒性特征的有效全身药物，以允许快速转化发展。
使用具有全面基因组特征的 12 个人甲状腺癌细胞系，对 257 种化合物进行高通量筛选（HTS），以选择具有最大生长抑制作用的药物。细胞增殖、集落形成、原位甲状腺模型和患者来源的异种移植（PDX）模型用于验证所选药物。
有 17 种化合物有效，多西他赛、LBH-589 和普拉曲沙被选中进行进一步的体外和体内分析，因为它们之前已被美国食品和药物管理局批准用于治疗其他癌症。在接受 LBH-589 治疗的所有测试模型中均检测到明显的肿瘤生长抑制（TGI）；普拉曲沙在原位甲状腺乳头状癌模型和 2 个 PDX 模型中显示出明显的 TGI；多西他赛仅在突变 TP53 的情况下显示出明显的 TGI。
HTS 确定了一系列系统药物，它们对侵袭性甲状腺癌具有优先的有效性，特别是那些具有突变 TP53 的癌症。在原位和 PDX 模型中的临床前验证，这些模型在体内准确模拟肿瘤微环境，可能支持在非 BRAF 突变或对 BRAF/MEK 抑制耐药的 ATC 中启动早期临床试验。
