Patients with progressive metastatic papillary thyroid cancer (PTC) have a poor prognosis. Despite advances in developing new therapies complete responses have been elusive and non-durable responses are the best reported outcomes. The presence of gross local invasion and distant metastases are two predictors of death from PTC. We have focused on defining key regulators of these features in an effort to identify novel targets to improve treatment. We identified that the p21 activated kinase (PAK) signaling is activated in the invasive fronts of aggressive PTCs and determined that it regulated human thyroid cancer cell motility and proliferation in vitro. Because of the association between BRAF activation and tumor aggressiveness we analyzed the relationship between these two signaling molecules. We demonstrated that PAK activity was highly regulated by BRAF and that BRAF knock down inhibited PAK activity. Moreover, this effect was independent of MEK. We subsequently identified that PAK physically interacts with BRAF both overexpression and endogenous systems and that the complex occurs in mitosis consistent with a role in regulation cell division and growth. We have shown in vivo that acute activation of BRAF V600E in the thyroid is associated with increased levels of phosphorylated PAK. Finally, we have identified acquired mutations in upstream regulators of PAK in tumor samples from patients who developed resistance to BRAF inhibition. These data point to PAK being a critical downstream target of BRAF which plays an important functional role in PTC progression for tumors with RAS/RAF/ERK pathway activation. The hypotheses of this project is that PAK is a critical signaling node downstream of BRAF involved in thyroid cancer tumorigenesis and progression in vivo; that the mechanism of the interaction can be elucidated, and that it can be exploited to develop improved primary and secondary therapies for patients with progressive thyroid cancer and other patients with BRAF-mutated tumors.

Public Health Relevance

Metastatic progressive PTC is an incurable disease. We have identified a potentially important new pathway downstream of BRAF that may be involved PTC progression. Our goal is to determine the relevance of the pathway in vivo, clarify the mechanism by which the pathway is activated, and test several novel compounds that block pathway activation with a goal to determine if PAK is a viable therapeutic target for patients with BRAF-mutated PTC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA227847-01
Application #
9498415
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yassin, Rihab R
Project Start
2018-04-01
Project End
2023-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210