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Last Updated: 10/10/18

SPORE in Thyroid Cancer

Sloan-Kettering Institute for Cancer Research

Principal Investigator:
James A. Fagin, M.D.

Principal Investigator Contact Information

James A. Fagin, M.D.
Memorial Sloan Kettering Cancer Center
1275 York Avenue
New York, NY 10065
Phone: 646-888-2136
Fax: 646-422-0890


The American Cancer Society estimated that approximately 56,000 new patients were diagnosed with thyroid cancer in the US in 2012. Although the mortality is comparatively low, It is now slowly rising, and the disease continues to be a major public health challenge. Thyroid cancer can present in many forms, from the indolent micropapillary carcinomas to the almost uniformly lethal anaplastic cancers, and in each of these manifestations there are major unresolved clinical dilemmas. This is despite important advances made in our understanding of the pathogenesis and the biology of the disease, which are only beginning to be projected into the clinic in a meaningful way. As will be described in the body of the application, the accomplishments of our proposed SPORE investigators in the past few years show that this is an attainable goal: i.e. that new, paradigm-shifting, thyroid cancer therapies can be developed based on genomic and biological observations made in patient samples, cell lines and mouse genetic models. The goals of this SPORE are to leverage new insights on disease pathogenesis to improve the outcomes of patients with thyroid cancer at all stages of presentation. Our specific translational research objectives are:

  1. To explore how to implement more rational care of patients with papillary microcarcinomas (PMC), which are highly prevalent and that mostly do not represent clinically significant disease. These PMC are over diagnosed and over treated in the community, leading to unacceptable morbidity and wasteful health care expenditures. We propose to identify genetic and biological predictors of progression in archival specimens and through a prospective observational study of patients with PMC left in situ, which will provide evidence-based guidelines for care.
  2. 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 down-regulating iodine transport and incorporation into cancer cells. We will build on recent experimental and clinical breakthroughs led by our research groups, which show that in a large fraction of patients RAI-refractoriness can be reversed pharmacologically.
  3. To identify new approaches to treat patients with life-threatening metastatic thyroid cancer, using targeted therapies designed against key drivers of the disease. This SPORE application links a multidisciplinary team of basic and translational investigators working on thyroid tumor genetics, biology and experimental therapies with experienced clinical investigators. Our groups will use a range of approaches, spanning from cancer cell signaling and biochemistry to studies in model organisms. Our measure of success, however, will be the extent to which our studies lead to improvements in patient outcomes. We structured our SPORE around four major research projects, three core facilities, and career development and developmental research programs. Each research project focuses on one of the broad translational goals listed above. The projects and cores are based at MSKCC, with the exception of one project led by Dr. Di Cristofano from the Albert Einstein College of Medicine (AECOM). The career development and developmental research programs will extend to a number of institutions in NYC.

Project 1: Genomic Predictors of Papillary Microcarcinoma Disease Progression

Project Leaders:
Michael Tuttle, MD
Michael Berger, PhD

Even though most patients with papillary microcarcinoma (PMC) do not require immediate surgery, very few are given the option of active surveillance. Our goal is to identify molecular predictors of disease progression that can be used to differentiate the PMC patients that may benefit from an early surgical intervention from the remaining majority that can be followed with observation.

The incidence of thyroid cancer has more than doubled in the last 30 years with nearly 50% of this increase attributable to papillary microcarcinomas (PMC). Despite compelling evidence that cautious observation is as afe and effective alternative to immediate surgical resection, very few PMC patients in the United States are given the option of an active surveillance approach. This is in part due to reports in the literature of a small percentage of patients with PMC that develop loco-regional or distant metastases. Unfortunately, neither clinical features, nor the mutational status of the known thyroid cancer oncogenes reliably identify the few PMC patients destined to develop clinically significant disease progression. Since only a small minority of PMC progress to clinically significant disease, it is imperative that we critically re-evaluate the current management paradigm that indiscriminately recommends immediate surgical Intervention without giving patients an option for active surveillance. We propose to use both paraffin embedded tissue samples from our pathology archives and fresh frozen PMC samples obtained after 2-5 years of observation in a prospective active surveillance trial to identify molecular events that are predictive of disease progression through a comprehensive evaluation of the PMC cancer genome using massively parallel next generation exon sequencing of 340 genes commonly mutated in cancer coupled to quantitative expression profiling using a custom-designed NanoString platform. Our goal is to identify genomic predictors of disease progression in PMC so that tumors likely to develop into clinically significant disease can be surgically removed, whereas the vast majority that are unlikely to grow or metastasize can be followed with periodic surveillance.

Aim 1: To perform in depth genomic profiling of PMCs without metastatic disease compared to PMCs with co-regional metastasis.

Aim 2: To identify genomic predictors of disease progression in a prospectively followed population of patients with PMC.

Project 2: Maximizing Effectiveness of Radioiodine Therapy by Inhibiting MAPK signaling

Project Co-Leaders:
James A. Fagin, MD
Steve Larson, MD

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 down-regulating 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 blocking ERK pathway activity.

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 mutation 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 HER3, 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 HERS or PI3Ksignaling 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 1311therapy of murine thyroid cancers pretreated with the combination therapy/s showing the best effects on 1241dosimetry.

Project 3: Elucidating and Targeting the Molecular Foundations of Hurthle Cell Cancer

Project Co-Leaders:
Timothy Chan, MD, PhD
Eric Sherman, MD

Metastatic HCCs account for a disproportionate share of mortality from thyroid cancer, as they are almost universally refractory to RAI therapy and do not respond to currently available treatments. Here, we will apply a conceptually and technically innovative, systematic, and highly collaborative approach to elucidate the mutational landscape underlying HCC oncogenesis, uncover the function of primary oncogenic drivers, and set the foundation for new experimental treatment paradigms for HCC.

Hurthle cell carcinoma (HCC) is a malignancy that arises from the thyroid gland. HCCs demonstrate a wide range of aggressiveness, with some metastasizing early and others behaving in a more indolent fashion. Metastatic HCC is almost invariably refractory to radioactive iodine (RAI) and is associated with clinical outcomes inferior to those of papillary and follicular thyroid carcinoma. HCC is an understudied malignancy with a poorly understood molecular foundation. Our long-term goal is to understand the genomic changes that lead to HCC and to use this information to develop better therapeutic and diagnostic modalities for HCC patients. Recently, our group has shown that HCCs comprise a unique class of thyroid malignancy with distinct genomic and transcriptomic features. Importanfiy, we revealed that HCCs are driven primarily by 2pathways, non-canonical PI3K signaling and Ephrin A signaling, which are known to promote cell growth and angiogenesis respectively. This is buttressed by our discovery of somatic mutations by whole exome sequencing in a pilot set of HCCs, that fall into two classes - Group 1: non-canonical PI3K/MT0R signaling, and Group 2: Ephrin A mediated angiogenesis. Perhaps not coincidentally our recent phase 2 trial of the combination of everolimus. an mTOR inhibitor, and sorafenib, an anti-angiogenic kinase inhibitor, demonstrated an excellent response rate in HCC patients. The objective of this proposal is to understand the genetic alterations underlying HCC pathobiology and determine the efficacy of targeting top recurrent drivers. We plan to accomplish our objective by pursuing the following 3 specific aims. Aim 1 is to elucidate the mutational landscapes of Hurthle cell carcinomas with varying aggressiveness. Aim 2 is to dissect the function of PIK3C2G/MTOR effector mutants in Hurthle cell cancers. Aim 3 is to evaluate the molecular underpinnings of clinical response to targeting the driver pathways in a prospective trial of Hurthle cell cancer patients. Altogether, the work in this proposal will provide the first global characterization of the HCC mutational landscape, uncover the function of the most frequently mutated candidate oncogenes in HCC, and establish a rational foundation for new therapeutic approaches.

Project 4: Molecular Landscape-based Innovative Therapies for Anaplastic Thyroid Carcinoma

Project Co-Leaders:
Antonio Di Cristofano, PhD
Alan Ho, MD, PhD

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.

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, affecting mostly elderly patients. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer related deaths, due to its resistance to any therapeutic approach. Cytotoxic chemotherapy with antimicrotubule agents or anthracyclines in combination with radiation therapy extends survival to a modest extent in patients with tumors confined to the neck, but has minimal activity in patients with metastatic ATC.ATCs are associated with oncogenic mutations of effectors in the P13K signaling pathway, as well as of BRAF, and have a very high frequency of TP5S mutations. They have a very high mitotic index, areaneuploid and genetically unstable. We have developed the first mouse models of ATC by combining Tp53loss with homozygous deletion of Pten or expression of oncogenic Braf. The ATCs developed by these mice display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion, and distant metastases. The analysis of these novel models has revealed that: i) several mitotic kinases are markedly overexpressed in mouse ATCs, and ii) these tumors are still remarkably sensitive to the inhibition of their oncogenic driver pathway. We propose to validate these findings in human tumors and exploit them to design and test novel therapeutic approaches to ATC, by implementing the following two Specific Aims: 1- To identify and validate clinically relevant oncogenic pathways and molecular signatures in anaplastic thyroid carcinoma; 2- To test the hypothesis that selective inhibition of driver oncogenic pathways will increase the efficacy of cytotoxic chemotherapy. Successful completion of these Aims will provide us with innovative therapeutic modalities that are rationally designed, according to the tumor's molecular landscape, and validated in relevant preclinical models.

Core A: Biospecimen Repository Core

Project Co-Leaders:
Ronald Chossein, MD
Marc Ladanyi, MD

The Thyroid Cancer SPORE, supported by the Biospecimen Repository Core, aims to increase our understanding of the clinical, biologic, and genetic basis of thyroid cancer in an effort to improve patient outcomes, to facilitate a range of scientific activities that could lead to new genomic- and proteomic-based interventions for cancer, including target identification, validation, and development of new biomarkers and diagnostic analyses.

Core B: Biostatistics Core

Core Leaders:
Venkatraman Seshan, PhD
Irina Ostrovnaya, PhD

The Thyroid Cancer SPORE, supported by the Bioinformatics and Biostatistics Core, aims to increase our understanding of the clinical, biological, and genetic basis of thyroid cancer in an effort to improve patient outcomes, to facilitate a range of scientific activities that could lead to new genomic- and proteomic-based interventions for cancer, including target identification, validation, and development of new diagnostic biomarkers and therapeutic approaches.

Core C: Administrative Core

Core Leaders:
James Fagin, MD
Steve Larson, MD

The Administrative Core serves the essential purpose of centralizing and optimizing collaboration between SPORE investigators. In addition, it will provide the institutional environment for proper monitoring of scientific progress, administrative compliance and financial management.