Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 4, No. 3, 2004
Contents
Endocrinology
Meets Molecular Oncology: Beyond Radioactive Iodine
Guest
Editor: Robert C. Smallridge
The Sodium-Iodide Symporter Pp.167-174
Redifferentiation Therapy in Advanced Thyroid
Cancer Pp.175-180
Bryan
R. Haugen
AKT: A Potential Target for Thyroid Cancer Therapy Pp.181-185
Faiza
Kada, Motoyasu Saji and Matthew D. Ringel
Molecular Elements of Apoptosis-Regulating
Pathways in Follicular Thyroid Cells: Mining for Novel Therapeutic Targets in
the Treatment of Thyroid Carcinoma Pp.187-198
N.J.
Sarlis and L. Gourgiotis
Targeting the ERK Pathway: Novel Therapeutics
for Thyroid Cancer Pp.199-220
Sandra
F. Williams and Robert C. Smallridge
The PAX8/PPARg Fusion Oncogene as a Potential Therapeutic
Target in Follicular Thyroid Carcinoma Pp.221-234
Bryan
McIver, Stefan K.G. Grebe and Norman L. Eberhardt
Viral Mediated Gene Therapy for the Management
of Metastatic Thyroid Carcinoma Pp.235-244
Leslie
J. DeGroot and Rusheng Zhang
Dendritic Cell-Based Immunotherapy in Thyroid
Malignancies Pp.245-251
Matthias
Schott, Werner A. Scherbaum and Jochen Seissler
Telomerase as Drug and Drug Target for the
Treatment of Thyroid Cancer Pp.253-256
M.A.
Zeiger and A.K. Meeker
Abstracts
[Back to top] The Sodium-Iodide Symporter
C.H.
Baker and J.C. Morris
The sodium-iodide
symporter (NIS) is an intrinsic plasma membrane protein that mediates active
transport of iodide in the thyroid gland and several other extra-thyroidal
tissues. This activity has been utilized for many years for imaging the thyroid
gland and for treatment of thyroid disease both benign and malignant. Cloning
and characterization of NIS has more recently allowed research into its use in
nonthyroidal cancers through gene transfer for both diagnosis and treatment.
[Back to top] Redifferentiation Therapy in Advanced Thyroid
Cancer
Bryan
R. Haugen
Thyroid cancer is a
relatively common malignancy with an estimated prevalence of 250, 000 in the U.S.
A minority of patients have poorly differentiated thyroid carcinoma that is
unresponsive to radioiodine therapy. Redifferentiation agents that ‘reprogram’
these tumors to concentrate radioiodine would be of great value in treating
patients with advanced thyroid cancer. The retinoid isotretinoin is the most
extensively studied of these agents. It appears that 20-40% of patients respond
to isotretinoin treatment by concentration of radioiodine in metastatic tumors,
but the clinical utility of this redifferentiation is still unclear. In
vitro studies suggest that the retinoid receptors (RARb and RXRg) are
required for this effect. Abnormal DNA methylation may be an early event in
thyroid tumorigenesis and methylation of the sodium iodide symporter (NIS) may
play a role in the loss of iodine concentration in these tumors. Inhibitors of
methylation (5- azacytidine, phenylacetate and sodium butyrate) have been shown
to increase NIS expression and iodine uptake in cell culture models, but
published trials in humans are not yet available. Histone acetylation is
required for efficient transcription of genes necessary for differentiated
function. Proteins that cause histone deacetylation inhibit gene transcription
and differentiated function. Inhibitors of histone deacetylation
(depsipeptide,
trichostatin A) have been shown to increase NIS expression and iodine uptake in
poorly differentiated and undifferentiated cell lines. Phase II human trials
are currently underway for depsipeptide. Finally, commonly used agents such as
thiazolidinediones (diabetes) and HMG-CoA reductase inhibitors
(hypercholesterolemia) have shown promise in preliminary in vitro studies in
advanced thyroid cancer cell lines. Development of these and other novel agents
for the treatment of advanced thyroid cancer is critical for us to treat an
uncommon progression of a common malignancy.
[Back to top] AKT: A Potential Target for Thyroid Cancer
Therapy
Faiza
Kada, Motoyasu Saji and Matthew D. Ringel
Thyroid cancer is a
heterogeneous disorder characterized by gene mutations that activate signaling
pathways, and also by abnormalities in tumor suppressor genes and cell cycle
proteins. Activation of the Akt/PKB signaling pathway appears to be an
important event in thyroid tumorigenesis and, perhaps, in tumor progression
too. Akt is activated in Cowden’s syndrome through inactivation of PTEN, a
negative regulator of Akt. Cowden’s syndrome is an autosomal dominant
multiorgan hamartoma syndrome characterized by benign and malignant thyroid
tumors, breast cancers, and colon cancers. In addition, the Akt pathway appears
to be activated in a significant proportion of sporadic thyroid cancers through
activation of growth factor pathways by thyroid oncogenes and/or receptor overexpression.
Disruption of PI3-kinase activity pharmacologically or disruption of Akt
signaling using dominant negative cDNA expression have demonstrated salutary
effects on several cancer models in vitro. Therefore, Akt represents an
attractive target for pharmaceutical development for a variety of malignancies,
including thyroid cancer.
[Back to top] Molecular Elements of Apoptosis-Regulating
Pathways in Follicular Thyroid Cells: Mining for Novel Therapeutic Targets in
the Treatment of Thyroid Carcinoma
N.J.
Sarlis and L. Gourgiotis
Apoptosis or
programmed cell death occurs in both normal and pathological conditions,
including cancer. Dysregulation of apoptosis allows transformed cells to
continually and uninhibitedly enter the cell cycle, thus perpetuating the
sequence of mutation, genomic instability and, finally, oncogenesis. The cell
death machinery includes cell surface receptors, adaptor molecules, proteolytic
enzymes, such as caspases, and a variety of mitochondrial proteins, which
interact with each other in a complex fashion. In addition, extensive
“cross-talk” exists between the apoptotic pathways and several other signaling
systems that govern growth and differentiation. Recent advances in molecular
techniques have shed light upon elements of the above pathways in assorted
malignancies, including non-medullary thyroid carcinoma (ThyrCa). A subgroup of
ThyrCa patients is (or becomes over time) refractory to standard treatment
modalities and eventually succumbs to their disease. For such patients with
clinically aggressive ThyrCa, novel therapeutic agents are urgently needed.
Changes in the sensitivity of cells to apoptosis have clear implications for
the treatment of any malignancy. In this review, we outline the main molecular
targets that play a role in apoptosis in ThyrCa cells, and discuss various
options for promoting apoptosis, either by pharmacologic or gene transfer
therapeutic interventions.
[Back to top] Targeting the ERK Pathway: Novel Therapeutics
for Thyroid Cancer
Sandra
F. Williams and Robert C. Smallridge
Over the past two
decades significant progress has been made in elucidating the pathogenesis of
thyroid cancer. The ongoing identification of mutations in cellular signaling
pathways has revolutionized the field of thyroid cancer biology and has led to
the development of novel new therapeutic agents. One of the signaling cascades
implicated in the oncogenic process is the ERK pathway that normally functions
to transmit mitogenic signals from the cell membrane to the nucleus. Genetic
alterations of key components of this cascade, namely RET, Ras and Raf, are
thought to result in constitutive activation of the pathway and subsequent
thyroid tumorigenesis. Targeting of these components with pharmaceutical agents
holds the potential of providing newer and more effective treatment modalities
for thyroid cancer. Several such drugs are currently being developed to inhibit
RET, Ras, Raf, as well as other factors impacted by the ERK pathway. These
include a vast array of agents such as antisense compounds, small molecule
inhibitors as well as inhibitors of farnesyl transferase, heat shock proteins,
matrix metalloproteinases and histone deacetylases. Some of these drugs have
already entered preclinical and clinical testing with promising anti-tumor
effects. These as well as even newer agents may offer exciting possibilities
for the future treatment of thyroid cancer.
[Back to top] The PAX8/PPARg Fusion Oncogene as a Potential Therapeutic
Target in Follicular Thyroid Carcinoma
Bryan
McIver, Stefan K.G. Grebe and Norman L. Eberhardt
Follicular thyroid
carcinoma (FTC) accounts for approximately 20% of all thyroid cancers, and up
to 40% of the deaths associated with this disease. Current treatment approaches
include surgery, followed by radioactive iodine therapy. However, a significant
proportion of locally advanced and metastatic FTC fails to concentrate iodine.
Because traditional chemotherapeutic agents have not been shown to alter
outcomes in this disease, novel therapeutic strategies are needed for advanced
disease. Recently, a genomic rearrangement has been identified in up to 50% of
FTC, involving a translocation event between chromosome regions 3p25 and 2q13.
This translocation fuses the thyroid-specific transcription factor PAX8 gene
with the PPARg gene, a ubiquitously expressed transcription
factor. We have confirmed that this Pax8 / PPARg
fusion gene (designated PPFP) is an oncogene, which accelerates cell growth,
reduces rates of apoptosis and permits anchorage independent and contact
uninhibited growth of a thyroid cell line. The action of PPFP arises, at least
in part, through its activity as a dominant-negative inhibitor of the wild-type
PPARg transcription factor. Although the mechanism by
which PPFP impairs PPARg activity remains unknown at
this time, it is likely to be mediated by competition for the genomic PPARg response elements, the endogenous ligand, or
various cofactors, including the Retinoid X Receptor (RXR). Consequently,
modulation of PPFP activity might be possible through the use of PPARg agonists, RXR-agonists, or specific modulators
of PPFP itself. Alternatively, modulation of several down-stream regulatory
pathways may become possible, as the consequences of PPARg inhibition become better known. PPFP represents
a potential novel target for the management of advanced FTC.
[Back to top] Viral Mediated Gene Therapy for the
Management of Metastatic Thyroid Carcinoma
Leslie
J. DeGroot and Rusheng Zhang
Thyroid cancers are of
special interest in gene therapy, since it is possible to direct gene
expression specifically to the thyroid derived cells by using promoters with limited
expression, and secondly, because destruction of the normal tissue by
introduction of a toxic gene would have no important adverse effect. A variety
of methods for gene delivery are available. Adenovirus is a well studied and
widely used vector and is useful for targeting genes because it infects many
cell types, including differentiated thyroid cancer and medullary thyroid
cancer cells. Strategies that have been employed successfully in animal models
include adenoviral mediated expression of thymidine kinase under control of a
thyroglobulin promoter, similarly expression of the cytokine IL-2, and perhaps
most effectively, expression of IL-12. Combinations of vectors expressing
thymidine kinase and IL-12 under control of a strong but non-tissue specific
CMV promoter effectively destroy a model anaplastic thyroid tumor in Wistar
rats. Replicating adenoviruses, in contrast to the non-replicating form
commonly used, have also been used to infect tumor cells and express P-53
protein, leading to apoptosis of tumor cells.
Medullary thyroid
cancer provides a target much like differentiated thyroid cancer because it is
possible to address gene expression specifically to the medullary thyroid cells
by the use of a modified calcitonin promoter. Animal models of this tumor are
available in a mouse and Wag/Rij rat model. In the latter system, treatment
with adenoviruses expressing genes under control of the modified calcitonin
promoter and expressing thymidine kinase or IL-12 leads to destruction of
growing medullary thyroid cancer tumors, destroy distant tumors after injection
in one tumor, and cause induction of long lasting immunity to subsequent tumor
development in the animals.
There are many ongoing
studies of gene therapy in humans using various genes such as thymidine kinase,
IL-2, and now IL-12. Although none of these trials to date shows complete
eradication of metastatic tumors in humans, there are reports showing
distinctly that the viral mediated gene therapy approach can effectively
destroy human tumors after in vivo administration. Tumors that have been
treated include melanomas, glioblastomas, breast tumors, and prostate
carcinomas. In the latter studies, it has been possible to show objective
responses documented by a fall in serum PSA levels of 50% or more that are
sustained for prolonged periods.
Gene therapy using the
adenoviral vectors appears to be safe in studies reported so far. A problem is
prior or induced immunity to adenoviral proteins, but direct injection of the
vector into a tumor nodule largely circumvents this problem. New genes and new
vectors under development will certainly lead to the established use of these
methods in the therapy of human thyroid carcinomas in the near future.
[Back to top] Dendritic Cell-Based Immunotherapy in Thyroid Malignancies
Matthias Schott, Werner A. Scherbaum and Jochen
Seissler
A new approach for
anti-tumor immunotherapy is to use dendritic cells (DCs) as adjuvants in order
to actively immunize cancer patients with antigens specifically expressed in
tumor cells. DCs possess a unique capacity to effectively activate CD4+ T
helper cells and CD8+ cytotoxic T cells. During the last years, several
clinical trials in various malignancies demonstrated that immunizations with tumor
antigen pulsed DCs could break the tolerance of the immune system against
antigens expressed by the tumor cells resulting in partial or complete
remission in some cases. This review describes the most important findings on
the interaction between DCs and T cells as well as natural killer cells and
summarizes recent data on DC vaccination of endocrine and non-endocrine
malignancies. The results from current pilot studies suggest that DC
vaccination may represent a promising strategy for the development of an
anti-cancer vaccine to treat chemotherapy and radioresistant endocrine
malignancies.
[Back to top] Telomerase as Drug and Drug Target for the Treatment of Thyroid Cancer
M.A. Zeiger and A.K. Meeker
Telomerase is known to
be activated in almost all cancer cells and is quiescent in almost all normal
cells. Therefore, it follows that therapeutic strategies directed against
cancer would include the targeting of telomerase, as well as the use of
telomerase. Several approaches have been used both in vitro and in
vivo and include the following: 1) antisense; 2) immunotherapy directed
against hTERT; and 3) the use of telomerase promoter to direct cytotoxic
therapy. Herein we review these approaches and discuss their potential applicability
against thyroid cancer.