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Davidson et al. J Cancer Metastasis Treat 2021;7:45 https://dx.doi.org/10.20517/2394-4722.2021.77 Page 9 of 19

[96]
use in AML . IDH inhibitors may be useful in treating TC tumors harboring IDH mutations or elevated 2-
HG levels.

FATTY ACID METABOLISM
Fatty acids have long been accepted to play an oncogenic role in cancer. They represent a rich carbon source
that can be synthesized de novo or taken up from the bloodstream to contribute to hormone synthesis,
membrane expansion, energy storage, and cell signaling [97-99] . In ATC, fatty acid synthesis is crucial for
maintaining endoplasmic reticulum homeostasis and the unfolded protein response [100,101] . Fatty acids are
first synthesized from citrate produced in the TCA cycle. Citrate is exported to the cytoplasm via CIC where
it is split into acetyl-CoA and OAA via malate dehydrogenase 1. The liberated malate is converted to
pyruvate via malic enzyme [15,35] . Excess acetyl-CoA in the cytoplasm is converted to malonyl CoA via the
rate-limiting enzyme, acetyl-CoA carboxylase (ACC), which is overexpressed in PTC, FTC, and ATC .
[102]
[103]
Although not tested in TC, ND-646 can specifically inhibit ACC . The ACC inhibitor TOFA [5-
(tetradecyloxy)-2-furoic acid], inhibited PTC, FTC, and ATC growth in vitro, which was reversible with the
[102]
addition of palmitic acid . Several rounds of fatty acid synthase will form long chain fatty acids in the
cytoplasm. When the cell reaches a low energy state, fatty acids are catabolized to acyl CoA via acyl-CoA
synthetase. Acyl-CoA is converted to acyl-carnitine via carnitine palmitoyltransferase 1 (CPT1) for entry
into the mitochondria via carnitine acylcarnitine translocase (CACT) [15,35] . CPT1 is overexpressed in several
cancers, including PTC . Although the classic CPT1 inhibitor etomoxir does not appear to have been
[104]
tested in TC models, siRNA against CPT1 decreased PTC growth . CACT can be overexpressed in FTC
[104]
tumors harboring a PPAR-PAX8 fusion, but the specific CACT inhibitor, SLC25A20-IN-21, has not been
investigated in cancer models [105,106] . Acyl-carnitine requires conversion back to acyl-CoA via CPT2 and
several rounds of beta oxidation using multiple enzymes to liberate acetyl-CoA for use in the TCA
cycle [15,35] . Fatty acid metabolism represents an exciting if underrepresented area in TC metabolism.

NUCLEOTIDE SYNTHESIS
Highly proliferative cancer cells require an abundance of nucleotides for replicating the genome. Although
some of this high nucleotide requirement is met by diet and bloodstream uptake, the vast majority is
synthesized de novo [73,107-111] . Nucleotide synthesis makes use of several metabolites from central metabolic
pathways [Figure 4]. The PPP is required for the ribose base and NADPH as a reducing agent; glutamine
and aspartate donate nitrogen, and glycine and serine donate specific carbon atoms for the nucleoside
base [15,35] . Although specific purine metabolism enzymes do not appear to be overexpressed in TC,
pyrimidine enzymes are shown to be aberrantly expressed in multiple models of TC.

Pyrimidine synthesis
Pyrimidine synthesis begins with R5P following conversion to phosphoribosylpyrophosphate (PRPP). Five
additional steps requiring glutamine transform PRPP to UMP [15,35] . UMP is phosphorylated to UDP via
uridine-cytidine kinase 2 (UCK2), which is overexpressed in PTC (TCGA) . Flavokawain B from the kava
[112]
plant has activity against UCK2 and was effective against FTC in vivo . UDP can be phosphorylated to
[113]
UTP and converted to CTP using glutamine and CTP synthetase (CTPS), which is overexpressed in PTC
(TCGA) . CTPS can be inhibited using the nucleoside analog gemcitabine which is incorporated into
[112]
[114]
replicating DNA strands . Gemcitabine is currently in a phase II clinical trial for differentiated and
metastatic PTC and FTC , while in vitro efficacy has been demonstrated in ATC . Inhibiting CTPS is an
[116]
[115]
attractive target because in addition to preventing CTP synthesis, UTP is necessary for glycogen synthesis,
and excess UTP has potential for incorporation into DNA, forming mismatches with GTP [35,117-119] . UDP can
also be reduced and phosphorylated in sequence to form dUMP, which is converted to dTMP by
thymidylate synthase (TYMS) [15,35] . TYMS is overexpressed in a variety of cancers including PTC and