This project is directed toward developing effective therapies for the treatment of metastatic thyroid cancers with RAS mutation that have become refractory to radioiodide treatment. It is based on the following ideas: 1)The grovrth of RAS mutant tumors is dependent upon ERK signaling;2)in these tumors, activated ERK feedback inhibits RAF activity and receptor tyrosine kinase 3)lnhibition of ERK with standard MEK inhibitors relieves these feedbacks and activates RAF and RTK signaling. Activation of RAF attenuates inhibition of ERK signaling and, together with reactivation of receptor tyrosine kinase signaling attenuates the potential therapeutic effects of ERK pathway inhibition. We hypothesize that maximal pharmacologic inhibition of ERK will be obtained with drugs that prevent or are refractory to feedback reactivation of RAF and that they will have enhanced antitumor activity. We have developed two such drugs~an allosteric MEK inhibitor that causes MEK to bind tightly to RAF and inhibit its activity and an ERK inhibitor that causes ERK to be refractory to upstream activity of MEK. We now propose to:
Aim 1. Use these drugs, alone or in combination, to develop a regiment that optimally inhibits ERK activation by bypassing relief of RAF feedback and then test the antitumor activity of this regimen.
Aim 2. Maximal inhibition of RAF will powerfully reactivate receptor tyrosine kinase signaling and this will decrease its therapeutic effect. In this Aim, we will identify the receptor systems that are reactivated in RAS mutant thyroid cancers when ERK feedback is relieved.
Aim 3. We hypothesize that maximal inhibition of ERK signaling in combination with inhibition of reactivated receptor tyrosine kinase signaling will comprise effective therapy for these tumors. This assertion will be tested in this Aim in tissue culture and xenograte models of thyroid carcinoma with mutant RAS. The overall goal of this project is the development of novel effective therapy of thyroid cancer that is based on these principles.

Public Health Relevance

Metastatic carcinomas with mutant RAS are difficult to treat. This is the case for radioiodide-resistant RAS- mutant thyroid carcinomas as well. Efforts to directly inhibit RAS have been unsuccessful and targeted therapy has been only marginally successful. Our data suggests that the effects of targeted therapy are limited by reactivation of other pathways. We believe that by combining effective inhibition of ERK with inhibition of reactivated nathwavs we willl develop an effective treatment for RAS mutant tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-RPRB-0 (M1))
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Sloan-Kettering Institute for Cancer Research
New York
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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

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