Molecular Landscape-based Innovative Therapies for Anaplastic Thyroid Carcinoma

甲状腺癌是甲状腺癌中最常见的恶性肿瘤。尽管相对较低， 流行，它占了不成比例的死亡人数，由于其抵抗任何治疗 approach.绝大多数ATC与BRAF的致癌突变或 它是PISK信号通路的成员，并且具有非常高的TP 53突变频率。基于这些 根据遗传数据，我们的小组和Fagin博士的小组已经开发了两种临床相关的ATC小鼠模型。 通过结合甲状腺靶向Tp 53缺失与Pten纯合缺失或致癌Braf表达。 这些小鼠具有非常高的抗肿瘤细胞，显示出人类对应物的所有特征， 包括高有丝分裂指数、多形性、上皮-间充质转化、异倍性、局部侵袭 和远处转移。对这些新模型的分析揭示了i）几组基因 主要信号通路的编码组分，包括有丝分裂激酶，在细胞中显著过表达。 小鼠ATC独立于它们的驱动致癌改变，和ii）尽管它们的遗传不稳定性，这些 肿瘤仍然对抑制其致癌驱动途径非常敏感。我们建议 扩展这些研究1）以验证我们在大量基因注释的人类间变性中的发现， 甲状腺肿瘤，2）确定小鼠和人ATC是否对有丝分裂激酶抑制敏感， 和3）评估驱动致癌通路的药理学抑制剂增加肿瘤细胞增殖的能力。 通过阻断导致ATC耐药的关键信号通路实现细胞毒化疗的疗效 这些药物。这些研究将为ATC的新临床试验奠定基础， 下一个项目周期。

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Despite a relatively low prevalence, it accounts for a disproportionate number of deaths, due to its resistance to any therapeutic approach. The vast majority of ATCs is associated with oncogenic mutations of BRAF or alterations of members of the PISK signaling pathway, and has a very high frequency of TP53 mutations. Based on these genetic data, our group and Dr. Fagin's group have developed two clinically relevant mouse models of ATC by combining thyroid-targeted Tp53 loss with homozygous deletion of Pten or expression of oncogenic Braf. These mice develop with very high penetrance ATCs that display all the features of their human counterpart, including high mitotic index, pleomorphism, epithelial-mesenchymal transition, aneupioidy, local invasion, and distant metastases. The analysis of these novel models has revealed that i) several groups of genes encoding components of major signaling pathways, including mitotic kinases, are markedly overexpressed in mouse ATCs independent of their driver oncogenic alteration, and ii) despite their genetic instability, these tumors are still remarkably sensitive to the inhibition of their oncogenic driver pathway. We propose to extend these studies 1) to validate our findings in a large set of genetically annotated human anaplastic thyroid tumors, 2) to establish whether mouse and human ATCs are sensitive to mitotic kinases inhibition, and 3) to assess the ability of pharmacologic inhibitors ofthe driver oncogenic pathways to increase the efficacy of cytotoxic chemotherapy by blocking critical signaling pathways that contribute to ATC resistance to these drugs. These studies will lay the foundation for new clinical trials for ATC to be carried out during the next project period.