Targeted therapies for thyroid tumors
Steven I Sherman
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA
Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness.
For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies
are needed to improve disease outcomes. Multiple novel therapies primarily targeting angiogenesis have entered
clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single-agent
studies, but prolonged disease stabilization is more commonly observed. The most successful agents target the
vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with
papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have
had promising preliminary results reported, and are being used selectively for patients who do not qualify for
clinical trials. At least one randomized, placebo-controlled phase III trial has been successfully completed,
showing improved progression-free survival in patients with advanced or metastatic medullary thyroid carcinoma
treated with vandetanib. Randomized trials for other agents are currently underway. Treatment for patients with
metastatic or advanced thyroid carcinoma now emphasizes clinical trial opportunities for novel agents with
considerable promise. Alternative options now exist for use of tyrosine kinase inhibitors that are well tolerated
and may prove worthy of regulatory approval for this disease.
Modern Pathology (2011) 24, S44–S52; doi:10.1038/modpathol.2010.165
Keywords: angiogenesis inhibitors; antineoplastic agents; protein kinase inihibitors; thyroid carcinoma
Thyroid carcinoma is a malignancy of rapidly
increasing importance in public health as well as
research into novel therapeutics. Across the world,
the incidence of the disease has been steadily
rising.1 In the United States, the age-adjusted
incidence of thyroid carcinoma increased by an
annual average 6.1% between 1998 and 2007, and
age-adjusted mortality increased by an annual
average of 0.9% during the same time period.2
Given that relative survival from thyroid cancer
markedly declines after age 65, and the doubling of
the population greater than 65 years old expected in
the next 20 years, mortality from thyroid cancer can
only be expected to rise further unless significant
improvements in treatment of metastatic disease can
be achieved.3,4
The treatment of most patients with differentiated
thyroid carcinoma (DTC; both papillary (PTC) and
follicular (FTC) histologies) is based on surgery,
radioactive iodine, and thyroid hormone therapy.5
When metastatic disease occurs, radioactive iodine
can be curative. In fact, the first reported instance
of cure of a patient with metastatic cancer was in a
man with metastatic FTC treated with four doses of
radioactive iodine.6 It was soon recognized, how-
ever, that radioiodine would only be curative in a
minority of patients with metastatic disease, often
due to ‘the spotty nature of iodine concentration’.7–9
TSH-suppressive thyroid hormone therapy can help
to slow the pace of the disease, as TSH can activate
its receptor on the cancer cell and promote tumor
growth and proliferation.10 However, for those
patients with metastatic DTC that progresses despite
radioiodine and TSH-suppressive thyroid hormone
therapy, no effective therapy exists.
Treatment of patients with medullary thyroid
carcinoma (MTC) is also based on surgery for
primary and regional metastatic disease. Because
the neuroendocrine-derived MTC is not responsive
to either radioiodine or TSH suppression, these
options are not available for treatment of progres-
sive, metastatic MTC. The outcomes of patients with
metastatic disease are no better than those with
radioiodine-unresponsive DTC.11
Cytotoxic systemic chemotherapies for advanced,
metastatic thyroid carcinomas have limited effec-
tiveness, with response rates typically 25% or less.12
With such poor outcomes, results from few clinical
trials of new therapies for thyroid carcinomas wereReceived and accepted 16 July 2010
Correspondence: Dr SI Sherman, MD, Department of Endocrine
Neoplasia and Hormonal Disorders, The University of Texas MD
Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1432,
Houston, TX 77030, USA.
E-mail: sisherma@mdanderson.org
Modern Pathology (2011) 24, S44–S52
S44 & 2011 USCAP, Inc. All rights reserved 0893-3952/11 $32.00
www.modernpathology.org

published during the latter half of the twentieth
century. Plaguing these early trials was the practice
of lumping patients with all histologies of thyroid
carcinoma, confounding interpretation of the re-
sults. The definitions of response used in these
earlier studies varied as well, and none is compar-
able to the currently used standard methodology.13,14
Thus, treatment with cytotoxic chemotherapy is
generally limited to patients with symptomatic or
rapidly progressive metastatic disease unresponsive
to or unsuitable for surgery, radioiodine (for tumors
derived from differentiated carcinomas), and exter-
nal beam radiotherapy.
During the past decade, biologic discoveries have
sparked trials testing novel, biologically targeted
therapies for advanced thyroid carcinomas. Of prime
importance has been recognition of key oncogenic
mutations in PTC and MTC. BRAF and RAS genes
code for kinases that activate signaling through the
mitogen-activated protein kinase (MAPK) pathway,
regulating growth and function in many cells both
normal and neoplastic. Evidence from various
tumor models supports the contention that most
PTCs arise as a result of single activating somatic
mutations in one of three genes: BRAF, RAS,
and translocations producing RET/PTC oncogenes.15
The resultant RET/PTC proteins signal upstream
from RAS, thus activating the same MAPK pathway.
The presence of BRAF mutations is associated with
decreased expression of mRNAs for proteins that
yield differentiated functions of follicular cells, such
as the sodium iodide symporter and the TSH
receptor.16 Clinically, BRAF mutations are associated
with radioiodine unresponsiveness and increased
rates of disease recurrence and mortality.17,18 For
MTC, almost all familial forms of the disease arise
because of inheritable germ-line activating mutations
in RET, and identical somatic mutations occurring in
C cells commonly cause sporadic disease. Activated
RET mutant proteins also enhance MAPK signaling.
Consistent with the ‘oncogene addiction’ hypothesis,
inhibition of these etiologic activating mutations
leads to either tumor stabilization or regression.
Therefore, interest arose in the therapeutic potential
of kinase inhibitors for these diseases.
A second development was recognition of pro-
cesses facilitating tumor growth, reflecting either
normal (such as hypoxia-inducible angiogenesis)
or abnormal (such as epigenetic modifications
of chromosomal DNA and histones) adaptations.
Angiogenesis is critical in supporting tumor cell
growth and metastasis, supplying nutrients and
oxygen, removing waste products, and facilitating
distant metastasis.19 Of the identified proangiogenic
factors, vascular endothelial growth factor (VEGF)
is key, binding to two receptor tyrosine kinases,
VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), that also
trigger MAPK signaling.20 In PTC, the intensity of
VEGF expression correlates with a higher risk of
metastasis and recurrence, a shorter disease-free
survival, and BRAF mutation status.21–23
This review will focus on findings from key
studies that reflect this new paradigm for research-
driven treatment using targeted therapies for meta-
static thyroid carcinoma.24 (Online databases that
can be searched to identify clinical trials currently
recruiting patients can be found at www.thyroid.org
andwww.clinicaltrials.gov).
Targeting oncogenic kinases
Given the oncogenic roles of activated BRAF, RET,
and RET/PTC kinases, it is theorized that specific
targeting of these kinases could block tumor growth
and induce senescence.25 To date, only selective
inhibitors of BRAF have entered clinical trials as
a test of this hypothesis, as the agents available
to target RET and RET/PTC generally also inhibit
VEGFR and other kinases.26 In contrast with the
experience of treating gastrointestinal stromal
tumors containing activating c-KIT mutations with
the KIT-inhibitor imatinib, use of selective BRAF
inhibitors has not yet yielded impressive results in
BRAF-mutant PTC.27 The emerging evidence of a
high frequency of squamous cell neoplasms as an
adverse event seen with all BRAF inhibitors may
reveal a novel mechanism of oncogenesis.
PLX 4032
PLX 4032 is an orally available small molecule that
specifically inhibits only the V600E mutant BRAF
kinase, without significant impairment of wild-type
BRAF or other RAF kinases.28 In melanoma and
colon carcinoma cell lines bearing the V600E BRAF
mutation, the IC50 values for inhibiting phosphoryla-
tion of ERK were 10–30nM and for inhibiting
cellular proliferation were 47–126nM.28,29 The RET/
PTC mutant thyroid cancer cell line TPC1, however,
was poorly inhibited, with an IC50 for cellular
proliferation of 10mM. In contrast, BRAF mutant cell
lines are effectively inhibited at concentrations
o100nM, inducing a cell-cycle blockade but not
leading to cell death.30 Preliminary data from a phase
I study of escalating doses of PLX 4032 described the
outcomes of three patients with BRAF-mutant PTC.29
One PTC patient experienced a partial response with
shrinkage of lung metastases, whereas the other two
patients had prolonged stable disease. Among the
overall cohort of 55 patients with solid tumors (49 of
whom had melanoma), the most common adverse
events were skin rash, fatigue, pruritus, photosensi-
tivity, and nausea. Although severe side effects
were uncommon, 11% of the patients developed
cutaneous squamous cell carcinomas.
XL281
XL281, an oral small molecule that inhibits
both wild-type and mutant BRAF kinases at low
Thyroid carcinoma targeted therapies
SI Sherman S45
Modern Pathology (2011) 24, S44–S52