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)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Ibrahimpasic, Tihana; Xu, Bin; Landa, IƱigo 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
Orlacchio, Arturo; Ranieri, Michela; Brave, Martina et al. (2017) SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance. Cancer Res 77:6914-6926
Montero-Conde, Cristina; Leandro-Garcia, Luis J; Chen, Xu et al. (2017) Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene. Proc Natl Acad Sci U S A 114:E4951-E4960
Park, Spencer; Shevlin, Enda; Vedvyas, Yogindra et al. (2017) Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. Sci Rep 7:14366
Min, Irene M; Shevlin, Enda; Vedvyas, Yogindra et al. (2017) CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors. Clin Cancer Res 23:7569-7583
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:
Brito, Juan P; Ito, Yasuhiro; Miyauchi, Akira et al. (2016) A Clinical Framework to Facilitate Risk Stratification When Considering an Active Surveillance Alternative to Immediate Biopsy and Surgery in Papillary Microcarcinoma. Thyroid 26:144-9
Mandal, Rajarsi; Chan, Timothy A (2016) Personalized Oncology Meets Immunology: The Path toward Precision Immunotherapy. Cancer Discov 6:703-13

Showing the most recent 10 out of 29 publications