Thyroid cancer is the most common endocrine malignancy, with a rapidly rising incidence in recent years. Development of more effective management strategies for this cancer is needed and requires better understanding of its molecular mechanisms. The PI3K/Akt pathway has recently emerged as a major source of molecular derangements in thyroid cancer. In particular, genetic and epigenetic alterations within or linked to this pathway and their relationships, which have been largely unexplored, are conceivably critical molecular events in the pathogenesis of thyroid cancer. Consequently, we propose to pursue four Specific Aims to test our central hypothesis that coupling of altered methylation of important genes (e.g., tumor suppressor genes, thyroid iodide-handling genes, and oncogenes) to the PI3K/Akt pathway driven by its genetic alterations is a fundamental mechanism in thyroid cancer pathogenesis.
In Specific Aim 1, we will extend our recent findings of several key genetic alterations that are most effective in activating the PI3K/Akt pathway in anaplastic thyroid cancer to explore them in a large set of follicular and papillary thyroid cancers to establish the genetic basis for a general role of the PI3K/Akt pathway in thyroid cancer. Analogous to our previous findings of aberrant gene methylation linked to the MAP kinase pathway and with our recent findings on the link of methylation of some genes to the PI3K/Akt pathway in thyroid cancer, we will investigate, in Specific Aim 2, the relationship of major genetic alterations in the PI3K/Akt pathway with methylation of known tumor suppressor and thyroid iodide-handling genes as well as potentially novel hypermethylated tumor suppressor genes and hypomethylated oncogenes coupled to the PI3K/Akt pathway that are revealed by CpG methylation microarray analysis. We further hypothesize that if the genetic and epigenetic alterations in, or linked to, the PI3K/Akt pathway are important in thyroid cancer pathogenesis, they are likely to be associated with poorer clinicopathological outcomes of thyroid cancer. This will be tested in Specific Aim 3 by examining the correlation of these genetic and epigenetic alterations with clinicopathological outcomes of thyroid cancer, a strategy that can reveal diagnostic and prognostic molecular markers. We finally hypothesize that altered methylation and, hence, expression of genes, as a consequence of aberrant PI3K/Akt pathway signaling, may be reversible by suppressing this pathway, a strategy that may have important therapeutic potential. This is to be tested in Specific Aim 4 by functionally manipulating the PI3K/Akt signaling and subsequently examining the change in methylation and expression of selected functionally important genes in thyroid cancer cell lines. This is a novel proposal that for the first time investigates both genetic and epigenetic molecular events in the PI3K/Akt pathway and their relationship as a fundamental molecular mechanism in thyroid cancer pathogenesis. With the proposed strategy to focus on selected genetic and epigenetic alterations and with the experienced laboratory of the PI that is equipped with state-of-the-art expertise and equipments for this project, successful completion of the proposed studies is expected, which should produce key insights into the molecular mechanisms of thyroid cancer pathogenesis and uncover novel diagnostic and prognostic molecular markers and therapeutic targets to improve the current management of patients with thyroid cancer.

Public Health Relevance

Thyroid cancer is the most common malignancy of the endocrine system, with a rapidly rising incidence in the United States. Several major clinical obstacles are encountered in the management of thyroid cancer, demanding more effective strategies to overcome that can be best based on the understanding of the molecular mechanisms in the pathogenesis of this cancer. This novel project is proposed to explore particularly genetic and epigenetic alterations in the PI3K/Akt pathway and is expected to produce important insights into the molecular mechanisms of thyroid cancer pathogenesis and uncover novel molecular markers and therapeutic targets to improve the management of patients with thyroid cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134225-05
Application #
8474705
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Sorg, Brian S
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$310,286
Indirect Cost
$121,087
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Murugan, Avaniyapuram Kannan; Alzahrani, Ali; Xing, Mingzhao (2013) Mutations in critical domains confer the human mTOR gene strong tumorigenicity. J Biol Chem 288:6511-21
Xing, Mingzhao; Alzahrani, Ali S; Carson, Kathryn A et al. (2013) Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309:1493-501
Liu, Xiaoli; Bishop, Justin; Shan, Yuan et al. (2013) Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer 20:603-10

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