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.
Despite their relative rarity, ATCs account for a major fraction of the mortality from thyroid cancer. Medical therapy has been mostly ineffective. This application proposes to leverage novel knowledge gained from relevant in vivo models to design and test Innovative therapeutic approaches to this otherwise deadly cancer.
|Ganly, Ian; Makarov, Vladimir; Deraje, Shyamprasad et al. (2018) Integrated Genomic Analysis of Hürthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes. Cancer Cell 34:256-270.e5|
|De Martino, Daniela; Yilmaz, Emrullah; Orlacchio, Arturo et al. (2018) PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer. Cancer Lett 439:56-65|
|Marlow, Laura A; Rohl, Stephen D; Miller, James L et al. (2018) Methodology, Criteria, and Characterization of Patient-Matched Thyroid Cell Lines and Patient-Derived Tumor Xenografts. J Clin Endocrinol Metab 103:3169-3182|
|Krishnamoorthy, Gnana P; Davidson, Natalie R; Leach, Steven D et al. (2018) EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC. Cancer Discov :|
|Untch, Brian R; Dos Anjos, Vanessa; Garcia-Rendueles, Maria E R et al. (2018) Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers. Cancer Res 78:4642-4657|
|Knauf, Jeffrey A; Luckett, Kathleen A; Chen, Kuen-Yuan et al. (2018) Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. J Clin Invest 128:4086-4097|
|Xu, Bin; Tallini, Giovanni; Scognamiglio, Theresa et al. (2017) Outcome of Large Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features. Thyroid 27:512-517|
|Azouzi, Naïma; Cailloux, Jérémy; Cazarin, Juliana M et al. (2017) NADPH Oxidase NOX4 Is a Critical Mediator of BRAFV600E-Induced Downregulation of the Sodium/Iodide Symporter in Papillary Thyroid Carcinomas. Antioxid Redox Signal 26:864-877|
|Ibrahimpasic, Tihana; Xu, Bin; Landa, Iñigo et al. (2017) Genomic Alterations in Fatal Forms of Non-Anaplastic Thyroid Cancer: Identification of MED12 and RBM10 as Novel Thyroid Cancer Genes Associated with Tumor Virulence. Clin Cancer Res 23:5970-5980|
|Larson, Steven M; Osborne, Joseph R; Grewal, Ravinder K et al. (2017) Redifferentiating Thyroid Cancer: Selumetinib-enhanced Radioiodine Uptake in Thyroid Cancer. Mol Imaging Radionucl Ther 26:80-86|
Showing the most recent 10 out of 53 publications