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of experimental evidence supporting a stem cell origin, and mTOR inhibitors have been studied in MTC, and
more lineage tracking studies are needed to identify the have shown preliminary efficacy in small trials. [149,150] One
cellular origin of MCC. ongoing trial (NCT01625520) is examining the efficacy
of SOM230/pasireotide alone and in combination with
Notch signaling has been an area of active investigation everolimus in progressive metastatic or postoperative
in MCC as a result of the genome-wide studies that have persistent MTC. More recently, new drugs that targets
highlighted the Notch pathway as one of key interest, with both PI3K and mTOR have been developed, with
somatic single nucleotide variants identified in Notch1, BEZ235 showing efficacy in preclinical studies of thyroid
and Notch2 that were independent MCPyV status. [114] The cancer. [151] Antibody therapy is also in development for
inactivating mutations detected in Notch genes were located MTC. Carcinoembryonic antigen or CEA is an antigen
in the EGF-like and ankyrin repeat regions, consistent with expressed by MTC cells and an anti-CEA monoclonal
loss-of-function events characterizing a tumor suppressive antibody combined with autologous hematopoietic stem
role for Notch in MCC. [115] Further, the data on Notch and cell rescue has shown promise in a phase 1 study in rapidly
other genes dysregulated in MCC are common with SCLC, progressing metastatic MTC. [152]
suggesting that these pathways are also cornerstones
of neuroendocrine differentiation in epithelial cells. [114] Tyrosine kinase inhibitors are also in development and
Another study examined the Notch signaling pathway as AMG706/motesanib was studied in locally advanced or
a target of microRNA-375, which is highly overexpressed metastatic, progressive or symptomatic MTC in a single-
in well-differentiated MCC cell lines yet strikingly arm phase 2 study. [153] Despite the 81% of patients in this
downregulated in highly aggressive, undifferentiated trial that achieved stable disease, there was no placebo or
MCC cell lines. [141] miR-375 overexpression caused post- standard of care arm, making the interpretation of drug
transcriptional repression of Notch2 and RBPJ resulting efficacy and toxicity a challenge. Axitinib was also studied
in decreased cell proliferation, migration and invasion in a small trial of locally advanced MTC (n = 6), and resulted
in vitro. This led to the conclusion that miR-375 is a in 5/6 or 83% of patients with stable disease > 16 weeks. [154]
putative regulator of cancer cell aggressiveness through However, as with the motesanib trial, the single-arm study
inhibition of Notch signaling. [141] In contrast, Panelos et design, as well as the small number of MTC patients
al. [142] performed immunohistochemical studies of Notch1 included makes the trial results difficult to interpret. The
expression in MCC and found 30/31 cases had Notch1 ZETA and EXAM trials studied two additional compounds,
cytoplasmic and membrane expression in greater than vandetanib and cabozantinib, in advanced, unresectable,
50% of cells. These data contradict the data in other NETs, locally advanced or metastatic MTC. The first randomized,
including other data on MCC, which suggest Notch1 is a double-blind, placebo controlled study (ZETA trial; NCT
tumor suppressor in MCCs. 00410761) tested vandetanib and detected an increase in
PFS (30.5 vs. 19.3 months for placebo) in the 331 patients
NETs - THYROID recruited to the study. Stratification of the patients by RET
mutation suggested that there was an improved response
Medullary thyroid carcinoma (MTC) is a NET that in patients with RET M918T mutation and also in MTC
originates from the thyroid C-cells and express high cases with no RET mutation identified. [155] These data
levels of calcitonin, chromogranin A, synaptophysin led to FDA and EMA approval for vandetanib for the
and achaete-scute complex-like 1 (ASCL1). MTCs are treatment of symptomatic or progressive, unresectable,
relatively slow growing tumors that comprise 1-2% of locally advanced or metastatic MTC. The EXAM trial
all thyroid cancers and have a 10 year median survival (NCT00704730) was a randomized, double-blind,
of 65%. [143,144] The majority of these tumors are sporadic, placebo controlled study of cabozantinib in advanced
but they can be hereditary and arise with other NETs and progressive MTC. This study recruited 330 patients
as a part of MEN2A/2B or as familial MTC. Gain-of- and reported a median PFS of 11.2 months for treatment
function mutations in the RET tyrosine kinase gene (most versus 4.0 months in controls. [156] The responses in this
commonly M918T) are the known driver mutation in the trial were similar regardless of RET mutational status, and
majority of these tumors. [145,146] Those tumors that are the results from this trial led to FDA and EMA approval
RET mutation negative frequently have RAS mutations of cabozantinib for progressive, metastatic MTC. Another
– and the presence of these mutations appears mutually tyrosine kinase inhibitor, regorafenib which has been
exclusive. [147,148] As with other NETs discussed above, approved for treatment of metastatic colorectal cancer,
there are no curative therapies for MTC. Surgery is the is now being studied as a second or third line therapy in
first line of treatment for localized disease, but there are no MTC (NCT02657551). For recent, more comprehensive
therapeutic options for patients who present with regional reviews of new molecular therapies and thyroid cancer
or widespread metastases, highlighting the critical need clinical trials including those for MTC, see. [143,157]
for additional therapeutics.
Although the genetic gain-of-function RET mutations are
Several promising new directed therapies for MTC are in well established as the basis for MTC, additional genetic
development or clinical trials. As with other NETs, SSAs studies have been performed to understand the etiology of
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦