Molecular Landscape-based Innovative Therapies for Anaplastic Thyroid Carcinoma

基于分子景观的甲状腺未分化癌创新疗法

• 批准号: 8738872
• 负责人: Antonio Di Cristofano
• 金额: $ 53.12万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738872
• 关键词: Accounting; Anaplastic Carcinomas; Aneuploidy; Anthracyclines; BRAF gene; Bypass; Cell Line; Cells; Cessation of life; Chromosomal Instability; Clinical Trials; Combined Modality Therapy; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Development; Distant Metastasis; Drug resistance; Endocrine Gland Neoplasms; Epithelial; Esophageal; Family member; Foundations; Frequencies; Genes; Genetic; Genomic Instability; Growth; Human; Immunocompetent; In Vitro; Incidence; Innovative Therapy; Knowledge; Low Prevalence; Malignant Neoplasms; Malignant neoplasm of thyroid; Medical; Mesenchymal; Metastatic Neoplasm to the Lung; Microtubules; Mitosis; Mitotic; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Oncogenes; Oncogenic; Operative Surgical Procedures; Papillary thyroid carcinoma; Pathway interactions; Patients; Penetrance; Phosphotransferases; Pleomorphism; Radioactive Iodine; Radiosurgery; Relative (related person); Resistance; Route; S-Phase Fraction; Sampling; Series; Signal Pathway; Signal Transduction Pathway; TP53 gene; Testing; Therapeutic; Thyroid Gland; Thyroid carcinoma; Tumor Suppressor Proteins; Undifferentiated; Validation; Xenograft Model; base; chemotherapy; clinically relevant; design; in vivo Model; inhibitor/antagonist; innovation; member; mortality; mouse model; neoplastic cell; novel; outcome forecast; overexpression; thyroid neoplasm; tumor

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.

间变性甲状腺癌(ATC)是最具侵袭性的甲状腺癌。尽管相对较低 由于它对任何治疗方法的抵抗力，它在死亡人数中所占的比例很大 接近。绝大多数的ATC与BRAF的致癌突变或 是Pisk信号通路的成员，并且具有非常高的TP53突变频率。基于这些 基因数据，我们的团队和Fagin博士的团队已经开发出两种临床相关的ATC小鼠模型 通过结合甲状腺靶向的TP53缺失和纯合缺失的Pten或表达致癌的BRAF。 这些小鼠发育成具有非常高的外显率的ATC，显示出它们的人类同类的所有特征， 包括高有丝分裂指数、多形性、上皮-间充质转化、新生细胞、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成分，包括有丝分裂酶，在 小鼠ATC不依赖于它们的致癌基因改变，以及ii)尽管它们的遗传不稳定，这些 肿瘤仍然对其致癌驱动通路的抑制非常敏感。我们建议 扩展这些研究1)在一大组带有基因注释的人类间变性组织中验证我们的发现 甲状腺肿瘤，2)确定小鼠和人的ATCs是否对有丝分裂酶抑制敏感， 以及3)评估驱动致癌通路的药物抑制物增加 阻断导致ATC耐药的关键信号通路对细胞毒化疗的疗效 这些药物。这些研究将为将于#年进行的ATC新的临床试验奠定基础。 下一个项目期。