Oncogenic activation of MAPK in thyroid cells leads to loss of expression of genes required for thyroid hormone biosynthesis, including the sodium iodide transporter (NIS) and thyroid peroxidase (TPO). Tumors with BRAF nnutation have lower expression of NIS, which likely explains why BRAF mutant PTCs are often resistant to RAI therapy. We developed mouse models of thyroid cancer driven by BRAF-V600E, and these tumors also lose the ability to concentrate radioiodine, which is restored by treatment with RAF or MEK inhibitors. Moreover, the MEK inhibitor AZD6244 reactivated iodide uptake at metastatic sites in patients with RAI-refractory thyroid cancer, allowing many of them to be treated with 131-iodine, with remarkable clinical responses. These beneficial results were seen although MEK inhibitors do not fully block MAPK signaling in thyroid cancer cells, because they relieve a feedback leading to upregulation of receptor tyrosine kinases, in particular HERS, which confers resistance to therapy. In addition, activation of TGFp signaling, which is a common feature of advanced forms of thyroid cancer, may be further induced in response to MAPK inhibitors, leading to further downregulation of NIS. The goals of this project are to determine how to optimize inhibition of MAPK signaling to further enhance radioactive iodine uptake and response to RAI therapy in thyroid cancer. This will be done through the following specific aims: 1) Determine the effect of MEK inhibitors on the kinetics of iodine-124 incorporation in patients with metastatic RAI refractory thyroid cancer, and test the hypothesis that this is due to increased expression of genes required for incorporation of inorganic iodide into proteins. 2) Determine if a combination of inhibitors that target MAPK and HER3 signaling is more effective in restoring RAI incorporation than the single agents in mouse models of BRAF- induced thyroid cancers. 3) Determine if pharmacological inhibitors of TGFp signaling enhance iodide uptake alone or in combination with inhibitors of the RAF-MEK-ERK pathway.4) Evaluate the response to 1311 therapy of murine thyroid cancers pretreated with the combination therapy/s showing the best effects on 1241 dosimetry.
We aim to improve the effectiveness of radioiodine (RAI) therapy in patients with RAI-refractory metastatic thyroid cancer, based on new insights on the role of MAPK signaling in downregulating iodine incorporation into cancer cells. We will build on recent experimental and clinical breakthroughs by our research group that show that in a large fraction of patients RAI-refractoriness can be reversed.by blocking ERK pathway activity.
|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|
|Sherman, Eric J; Dunn, Lara A; Ho, Alan L et al. (2017) Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer. Cancer 123:4114-4121|
|Di Cristofano, Antonio (2017) SGK1: The Dark Side of PI3K Signaling. Curr Top Dev Biol 123:49-71|
|Anelli, Viviana; Villefranc, Jacques A; Chhangawala, Sagar et al. (2017) Oncogenic BRAF disrupts thyroid morphogenesis and function via twist expression. Elife 6:|
|Tuttle, R Michael; Fagin, James A; Minkowitz, Gerald et al. (2017) Natural History and Tumor Volume Kinetics of Papillary Thyroid Cancers During Active Surveillance. JAMA Otolaryngol Head Neck Surg 143:1015-1020|
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