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Leveraging copper chelators as targeted therapy for BRAFV600E mutant thyroid cancer

dc.contributor.advisor Counter, Christopher M Xu, MengMeng 2019-06-07T19:47:56Z 2018
dc.description Dissertation
dc.description.abstract <p>The incidence of thyroid cancer, and in particular papillary thyroid cancer (PTC), is rising faster than that of any other malignancy in the United States. Thyroid cancer is now the most common endocrine cancer and the fifth most common cancer in women. While most thyroid cancers are treated effectively with surgical resection and radioiodine therapy, survival drops precipitously in metastatic or radioiodine-resistant disease. 60% of papillary thyroid cancers (PTC) have an oncogenic V600E mutation in the kinase BRAF, which leads to a constitutively active and oncogenic kinase. This mutation has been associated with as well as a 2.14-fold increase in recurrent/persistent disease. Excitingly, inhibitors against this mutant kinase or its substrates, the MEK1/2 kinases, can prolong progression free survival or stabilize disease in radioiodine-refractory thyroid cancer patients. However, the indolent nature of PTC may be a challenge to the clinical adaption of these inhibitors, as the financial and physical toxicities of these treatments may be amplified over the prolonged time-course typical of PTC. MEK1/2 require copper (Cu) for kinase activity and can be inhibited with the well-tolerated and economical Cu chelator tetrathiomolybdate (TM). Cu chelators have been in use for decades in patients with Wilson’s Disease, a disease of Cu accumulation. Unlike current BRAF and MEK inhibitors, Cu chelators can be well tolerated for decades with few side effects, and thus may find use in long-term inhibition of BRAFV600E signaling in PTC. </p><p>Here I test the ability of Cu chelator TM to inhibit tumor growth in BRAFV600E-mutant PTC. TM inhibited MEK1/2 kinase activity and transformed growth of human BRAFV600E-mutant PTC cells as well as or more potently than standard-of-care drugs. Consistent with TM deriving its antineoplastic activity by inhibiting MEK1/2, expression of activated ERK2, a substrate of MEK1/2, overcame the ability of TM to suppress growth of BRAFV600E-mutant PTC cells. TM was also effective in a genetically engineered mouse model of BrafV600E-mutant PTC; oral TM reduced tumor burden as well as a clinical BRAF inhibitor. This in vivo effect was attributed to a reduction of phospho-Erk1/2 signaling in the tumors. Additionally, long-term maintenance therapy using TM after cessation of a clinical BRAF inhibitor reduced tumor volume in the same mouse model. Genetic reduction of the Cu transporter CTR1 in developing tumors also trended towards a survival advantage in mice with BrafV600E-mutant PTC. Finally, TM also enhanced the antineoplastic activity of standard of care clinical BBRAF inhibitor drugs. These results support the clinical evaluation of Cu chelation as targeted therapy for BrafV600E-mutant PTC and suggests three possible avenues for clinical exploration: i) as a less toxic monotherapy for BrafV600E-mutant PTC, ii) as long-term maintenance therapy after initial treatment, and iii) as a combination-therapy amplifying the antineoplastic effects of other treatment modalities.</p>
dc.subject Medicine
dc.subject Molecular biology
dc.subject Pharmacology
dc.subject BRAF mutant
dc.subject Copper chelation
dc.subject MAPK inhibition
dc.subject Mouse model
dc.subject Papillary thyroid cancer
dc.subject Thyroid Cancer
dc.title Leveraging copper chelators as targeted therapy for BRAFV600E mutant thyroid cancer
dc.type Dissertation
dc.department Pharmacology
duke.embargo.months 5
duke.embargo.release 2019-11-21T00:00:00Z

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