I found this interesting article, "Role of vandetanib in the management of medullary thyroid cancer by, MaryseBrassard and Geneviève Rondea", in regards to treating
medullary thyroid cancer (MTC).
“Medullary thyroid cancer (MTC) is a neuroendocrine tumor originating
from parafollicular cells of the thyroid and which accounts for fewer than 10%
of all diagnosed thyroid cancers” (Maryse Brassard and Geneviève
Rondeau). When treating
metastatic MTC, traditional treatments are chemotherapy and external-beam
radiation therapy, which limit the options for treatments. Recently, tyrosine
kinase inhibitors (TKI), have been introduced in the field of thyroid cancer,
which have shown effective results in curing other cancerous tumors. This
article focuses on “vandetanib (ZD6474, Zactima™; AstraZeneca, Mississauga, ON)
and it’s effect on curing metastatic medullary thyroid cancer.
Background
Information
MTC is linked with the RET
proto-oncogene, and when mutated the RET gene causes multiple endocrine neoplasias. “RET was one of the first
receptor tyrosine kinases (RTKs) to be implicated in tumorigenesis” (Maryse
Brassard and Geneviève Rondeau). The vascular endothelial growth factor receptor (VEGFR)
pathway is key in the pathogenesis of MTC. VEGFR-2 is thought to be implicit in
tumor growth and metastasis especially. That is tumor cells secrete VEGF, that
act as ligands for the VEGF receptors, which starts signaling to different
pathways. In MTC, overexpression of VEGF associates with metastasis. Vandetanib
is a 4-anilinoquinazoline, a Tyrosine kinase inhibitor (TKI) that affects signaling
pathways. It targets the VEGF receptors 2 and 3, RET, and at higher
concentrations, epidermal growth factor receptor (EGFR). It works is by
docking to the ATP-binding site of the RET kinase, which creates an inhibition. Below is an image on the VEGFR signaling pathway withing a tumor cell.
Figure 2
VEGFR pathways within the tumor cell.
Abbreviations:
AKT, serine/threonine protein kinase; FAK, focal adhesion kinase-1;
MAPK, mitogen-activated protein kinase; NOS, nitric oxide synthase;
PI3K, phosphoinositide 3-kinase; PLC, phospholipase; PKC, protein
kinase; Shc, proteins containing Src homology-2 domains; RAS, rat
sarcoma; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
In thyroid cancer, it is effective by inhibiting the “RET/PTC1 and RET/PTC3
mutations in some Papillary thyroid cancers and M918T
RET mutations in MEN2B and some sporadic MTCs. RET mutations in certain inherited forms of MTC, as in
codon 804 and 806, seem to confer resistance to Vandetanib” (Maryse Brassard
and Geneviève Rondeau).
Clinical Studies
In the preclinical trails, Vandetanib was shown to be
successful in vitro by inhibiting VEGF cell growth and inhibiting the RET proto-oncogenic kinase and RET-dependent
thyroid tumor cell proliferation. However, throughout the three phases of the clinical studies, the amount of adverse events patients experienced is
significantly high. In all phases of the clinical studies, most patients
experienced symptoms such as diarrhea, fatigue, rash, and nausea. The
majority of patients would acquire an adverse event on the suggested dosage of 300mg/day. There were
unusual adverse events as well. For example, there was a case of reversible cerebral
vasoconstriction syndrome and a case of development of vortex keratopathy. However,
after not taking Vandetanib, these patients were not encountering the previous
symptoms.
Conclusion
Now, Vandetanib has become the new typical treatment for
patients with metastatic medullary thyroid cancer in the United States.
However, as mentioned above the toxicity of Vandetanib is very high, and it is
strictly regulated.
Discussion
After reading the article, many questions came to mind. I
was speculating on why so many patients were experiencing similar adverse
events and why these particular symptoms? Also I wanted to know what is causing
these symptoms in the molecular level? I was also speculating in rather this type of treatment is more effective than chemotherapy or external-beam radiation. One must do extra research to understand preciously what is really happening in the molecular level of this new treatment. Overall, I do believe this therapy is effective since it is the only FDA-approved medication for metastatic medullary thyroid.
Works Cited
Brassard, Maryse, and Geneviève Rondeau. "Role of Vandetanib in the Management of
Medullary Thyroid Cancer." Pub Med Central 6 (2012): 59-66. Online.
Medullary Thyroid Cancer." Pub Med Central 6 (2012): 59-66. Online.
"National Cancer Institute." Genetics of Medullary Thyroid Cancer (PDQ®) -. Web. 19 Apr. 2012.
-Marytza
