The focus of my lab is to identify novel molecular targets relevant to papillary and anaplastic thyroid cancer (PTC and ATC) with the ultimate goal of advancing these studies to clinical trials for thyroid cancer patients who do not respond to standard treatments. Much attention has been devoted to the mitogen activated protein kinase (MAPK) pathway as a therapeutic target due to the large percentage of activating mutations in this pathway (BRAF, RAS, RET/PTC), yet the efficacy of MAP kinase pathway inhibitors in thyroid cancer has thus far been limited. The Focal Adhesion Kinase (FAK)-Src pathway has emerged as a major player in cancer progression, especially relating to metastasis, yet how FAK and Src promote disease progression and the metastatic process is not well understood. Our lab recently discovered that FAK is overexpressed and phosphorylated in thyroid tumor samples, which provided the necessary justification to pursue this pathway as an alternative, clinically relevant target in thyroid cancer (Schweppe et al 2009). We have further shown that the majority of cell lines derived from advanced thyroid cancer patients exhibit high levels of phospho-FAK and that inhibition of the FAK-Src pathway blocks growth and invasion in cells with high phospho-FAK. Importantly, we found that FAK/Src signals independently of the MAP kinase pathway, suggesting that the FAK-Src pathway may represent a second independent risk factor for thyroid cancer patients, especially in relation to tumor aggressiveness and metastatic spread.
Current projects in the lab:
1. The goals of the first project, which are the focus of my R01, are to further understand the role of FAK in thyroid cancer. FAK functions as a signaling kinase or scaffolding protein, yet how these dual functions contribute to specific pro-tumorigenic processes is currently unclear. Our preliminary data using pharmacologic and genetic approaches to block the kinase and/or scaffolding functions of FAK, suggest that these dual functions may regulate different cellular processes in thyroid cancer. To further understand the regulation and function of FAK, we are using genetic shRNA FAK knockdown in parallel with pharmacologic approaches with recently developed FAK inhibitors to define the kinase and scaffolding functions of FAK in the growth, invasion, and survival of thyroid cancer cells in vitro, as well as in vivo using a novel orthotopic thyroid cancer model and an experimental metastasis model. Ultimately, this combined genetic and pharmacologic approach will help identify specific signaling mechanisms, which can be exploited for the development of novel and more selective inhibitors of the pathway.
2. The goals of the second project, which are the focus of my ACS grant, are to understand the regulation and function of the Src signaling pathway in thyroid cancer to determine the most effective therapeutic strategy. Given that advanced tumors often harbor multiple genetic lesions that result in the activation of several oncogenic signaling pathways which drive tumor progression, it is likely that molecular-targeted therapies, such as Src inhibitors, will need to be combined for maximal therapeutic efficacy. Thus, the goals of this project are to define pathways that promote sensitivity versus resistance to Src inhibition. For these studies, we are using a genome-wide short inhibitory RNA (shRNA) library screen to identify genes and pathways that promote survival in the presence of Src inhibitors. Our goal is to identify rational therapeutic strategies that when targeted in combination with Src, will eliminate thyroid cancer cells. To further address the specific role of Src in thyroid cancer growth, invasion, and metastasis, we are using an orthotopic thyroid cancer model and a novel metastasis model. We have already shown that inhibition of Src inhibits tumor growth in an orthotopic model, and metastatic growth in an experimental metastasis model, consistent with our in vitro findings (Chan CM et al 2012). We are further validating the clinical relevance of FAK/Src signaling using a comprehensive thyroid tumor microarray.
Ultimately the results from both projects will 1) allow for identification of biomarkers to better predict which tumors will respond to inhibitors of the FAK-Src pathway; 2) develop more specific targeted therapies to block distinct components of this pathway that are deregulated; and 3) develop new approaches for limiting the metastatic spread of disease.
Schweppe, RE, Klopper, JP, Korch, C, Pugazhenthi, U, Benezra, M, Knauf, JA, Fagin, JA, Marlow, L, Copland, JA, Smallridge, RC, and BR Haugen. DNA Profiling Analysis of 40 Human Thyroid Cancer Cell Lines Reveals Cross-Contamination Resulting in Cell Line Redundancy and Misidentification. 2008. J. Clin. Endocrinol. Metab., 93: 4331-4441. [PMID: 18713817].
Schweppe, RE, Kerege, A, Sharma, V, Poczobutt, JM, Gutierrez-Hartmann, A, Grzywa, RL, and BR Haugen. Distinct Genetic Alterations in the MAPK Pathway Dictate Sensitivity of Thyroid Cancer Cells to MKK1/2 Inhibition. 2009. Thyroid., 19: 825-835 [PMID: 19500021].
Schweppe, RE, French, JD, Kerege, AA, Sharma, V, Grzywa, RL, and BR Haugen. Inhibition of Src with AZD0530 Reveals the Src-Focal Adhesion Kinase as a Therapeutic Target in Papillary and Anaplastic Thyroid Carcinoma. 2009. J. Clin. Endocrinol. Metab., 94: 2199-2203 [PMID: 19293266].
Schweppe, RE. Thyroid Cancer Cell Lines: Critical Models to Study Thyroid Cancer Biology and New Therapeutic Targets. 2012. Frontiers in Cancer Endocrinology, 3:81. [PMID: 22723793].
Chan, CM, Jing, X, Pike, LA, Zhou,Q, Lim, D-J, Sams, SB, Lund,GA, Sharma, V, Haugen, BR, and RE Schweppe. Targeted Inhibition of Src Kinase with Dasatinib Blocks Thyroid Cancer Growth and Metastasis. 2012. Clin Cancer Res., 18:3580-3591 [PMID: 22586301].