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Page 2 of 19 Davidson et al. J Cancer Metastasis Treat 2021;7:45 https://dx.doi.org/10.20517/2394-4722.2021.77

INTRODUCTION
Thyroid cancer (TC) is the most common endocrine malignancy and is a concern due to the rapidly
[1]
increasing incidence . There are specific subtypes of TC that differ in appearance, genetic drivers,
prognosis, and effective treatment options. Papillary thyroid cancer (PTC) is the most common subtype and
[2]
is often diagnosed in people under 55 years of age . PTC still resembles a normal thyrocyte and is well
differentiated. Resection is currently the most effective treatment option with radioactive iodine (RAI)
therapy serving as an ablation for remaining TC tissue . PTC is canonically driven by consistently active
[3]
BRAF via a V600E mutation . Follicular thyroid cancer (FTC) is usually more aggressive than PTC and is
[1]
often diagnosed in patients between 40 and 60 years old . It is most often treated with surgery and typically
[4]
carries a good prognosis. However, drug resistance and distant metastases can develop. FTC is unique
amongst the TC subtypes as BRAF mutations are rare . FTC is canonically driven by phosphoinositide 3-
[5]
kinase (PI3K) signaling, usually through activating mutations in PI3K and copy number gains in receptor
tyrosine kinases and Akt . Poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC) are highly
[1,6]
aggressive and metastatic. PDTC and ATC are driven by BRAF V600E , PI3K signaling, TERT promoter
mutations, and mutated or loss of p53 expression . The average lifespan for individuals diagnosed with
[7-9]
PDTC/ATC is six months, amongst the shortest timeframe of all solid tumors [4,10] . Current therapies only
extend survival to eleven months at best [3,10,11] ; therefore, there is a clear and significant need for new
treatment modalities in aggressive TCs for which current treatment regimens fail to significantly enhance
disease-free survival.

Metabolic inhibitors pose as attractive potential options to address this need, as they have garnered
significant treatment success in other tumor types, most notable antifolates in leukemias . Cancer cells
[12]
display a markedly different metabolic landscape, which parallels the altered signaling landscape these cells
typically exhibit . It is now known that many cancer cells demonstrate high glycolytic profiles with
[13]
[14]
dysregulated oxidative phosphorylation and mitochondrial dynamics . The increased rate of glycolysis not
only supplies rapid ATP for the cell but also provides metabolic intermediates for protecting against reactive
oxygen species and synthesizing nucleotides, lipids, and proteins for new daughter cells [13,14] . Although
multiple metabolic processes have been shown to be dysregulated in TC, there has not been great attention
on targeting these pathways for therapeutic intervention, particularly in cases of aggressive and often drug-
resistant ATC. This review serves to summarize results in metabolism across the spectrum of TC
differentiation while highlighting key areas that deserve further investigation that could potentially yield
promising therapeutic efficacy.

GLYCOLYSIS
Glucose transporters
Glucose transporters (GLUT) are the first rate-limiting step in glycolysis [Figure 1] and often regulate
cellular metabolism in general by limiting intracellular glucose flux . There are 14 distinct isoforms of
[15]
[15]
GLUTs which vary based on tissue localization and affinity for glucose . Normal thyroid cells express
GLUT 1, 3, 4, and 10 [16-19] . GLUT 4 and 10 have not been found to be overexpressed in TC, but GLUT 1 and
3 are overexpressed in multiple forms of TC [16,17,19] . GLUT1 expression is inversely correlated with TC
differentiation, as ATC has been shown to have the highest GLUT1 expression [16,17] . Furthermore, there
appears to be a strong correlation between BRAF V600E and GLUT1 expression, possibly suggesting that TC
cells driven by MAPK signaling require a high flux of glucose to fuel proliferation [19,20] . GLUT3 is expressed
even more than GLUT1 in some PTC tumors and was overexpressed in well differentiated TC cell lines .
[21]

There have been several GLUT inhibitors investigated for limiting glucose import in cancer cells. Although
not specific for GLUTs, the flavonol quercetin directly binds to GLUT1 and can limit GLUT4 localization to