Current Cancer Drug Targets, Volume 5, No. 3, 2005
Contents
EphA2 Receptor Tyrosine Kinase as a Promising
Target for Cancer Therapeutics
Pp.149-157
Renee
C. Ireton and Jin Chen
Modulation of pRb/E2F Functions in the Regulation
of Cell Cycle and in Cancer
Pp.159-170
Lucy
L. Seville, Nita Shah, Andrew D. Westwell and Weng C. Chan
Molecularly Targeted Therapy for
Gastrointestinal Cancer
Pp.171-193
Marcus
W. Wiedmann and Karel Caca
Copper Lowering Therapy With
Tetrathiomolybdate as an Antiangiogenic Strategy in Cancer Pp.195-202
George
J. Brewer
Matrix Metalloproteinases as Therapeutic
Targets in Cancer Pp.203-220
Pia Vihinen, Risto Ala-aho and Veli-Matti Kahari
New Target Antigens for Cancer
Immunoprevention Pp.221-228
P.-L. Lollini, G. Nicoletti, L. Landuzzi, C. De Giovanni and P. Nanni
Abstracts
[Back to top] EphA2
Receptor Tyrosine Kinase as a Promising Target for Cancer Therapeutics
Renee C. Ireton and Jin Chen
Eph receptors are
a unique family of receptor tyrosine kinases (RTK) that play critical roles in
embryonic patterning, neuronal targeting, and vascular development during
normal embryogenesis. Eph RTKs and their ligands, the ephrins, are also
frequently overexpressed in a variety of cancers and tumor cell lines. In
particular, one family member, EphA2, is overexpressed in breast, prostate,
lung, and colon cancers. Unlike traditional oncogenes that often function only
in tumor cells, recent data show that Eph receptors mediate cell-cell
interactions both in tumor cells and in the tumor microenvironment, namely the
tumor stroma and tumor vasculature. Thus, EphA2 receptors are attractive
targets for drug design, as targeting these molecules could simultaneously
inhibit several aspects of tumor progression. This review focuses on the multiple
roles of EphA2 in cancer progression, the mechanisms by which EphA2 inhibition
may halt this progression, and the pre-clinical results of EphA2 inhibition in
various cancer model systems.
[Back to top] Modulation of pRb/E2F Functions in the
Regulation of Cell Cycle and in Cancer
Lucy
L. Seville, Nita Shah, Andrew D. Westwell and Weng C. Chan
Cell proliferation
is regulated by the cell cycle, and in order to divide the cell must enter a
mitotic state. Prior to mitosis the cell is required to pass through a number
of checkpoints, including the critical G1/S restriction point
governed by the successive phosphorylation of the retinoblastoma protein, pRb.
The various proteins and regulatory factors governing pRb phosphorylation have
been a major focus of study in recent years, given the central importance of G1/S
transition deregulation in cancer development.
This review
summarises the molecular biology around the G1/S transition,
focussing on the critical roles of the transcription factor family E2F and the
cyclin-dependent kinase (CDK) and cyclin families involved in E2F release from
pRb. Interestingly, E2F release from pRb is associated with cell proliferation;
however, above a certain threshold E2F has the potential to trigger apoptosis.
The review focuses
on the following topics: (i) how E2F and other substrates bind to pRb at the
molecular level; (ii) mechanisms by which pRb function is modulated within the
cell; (iii) mechanisms that inhibit or enhance cell proliferation via
the pRb/E2F pathway; (iv) how E2F can potentiate apoptotic pathways; and (v)
what controls whether E2F mediates cell proliferation or apoptosis. The case
for the development of agents that perturb pRb:E2F interactions will be made, as
a strategy to further inform the molecular biology around this important target
and as a therapeutic strategy against cancer.
[Back to top] Molecularly Targeted Therapy for
Gastrointestinal Cancer
Receptor and
non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug
target molecules for treating gastrointestinal cancer. Imatinib mesilate
(STI-571, GleevecTM), an inhibitior of bcr-abl TK, which was
primarily designed to treat chronic myeloid leukemia is also an inhibitor of
c-kit receptor TK, and is currently the drug of choice for the therapy of
metastatic gastrointestinal stromal tumors (GISTs), which frequently express
constitutively activated forms of the c-kit-receptor. The epidermal growth
factor receptor (EGFR), which is involved in cell proliferation, metastasis and
angiogenesis, is another important target. The two main classes of EGFR
inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, IressaTM)
has been on trial for esophageal and colorectal cancer (CRC) and erlotinib
(OSI-774, TarcevaTM) on trial for esophageal, colorectal,
hepatocellular, and biliary carcinoma. In addition, erlotinib has been
evaluated in a Phase III study for the treatment of pancreatic cancer.
Cetuximab (IMC-C225, ErbituxTM), a monoclonal EGFR antibody, has
been FDA approved for the therapy of irinotecan resistant colorectal cancer and
has been tested for pancreatic cancer. Vascular endothelial growth factor
(VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis.
Bevacizumab (AvastinTM), a monoclonal antibody against VEGF, was
efficient in two randomized clinical trials investigating the treatment of
metastatic colorectal cancer. It is also currently investigated for the therapy
of pancreatic cancer in combination with gemcitabine. Other promising new drugs
currently under preclinical and clinical evaluation, are VEGFR2 inhibitor
PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777
(tipifarnib, ZarnestraTM), matrix metalloproteinase inhibitors,
proteasome inhibitor bortezomib (VelcadeTM), mammalian target of
rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet
derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC)
inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous
sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase
(HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora
kinase inhibitors, hedgehog inhibitors, and TGF-b
signalling inhibitors.
[Back to top] Copper Lowering Therapy With Tetrathiomolybdate
as an Antiangiogenic Strategy in Cancer
George J. Brewer
Tetrathiomolybdate
(TM) is a novel anticopper agent under development for use in Wilson’s disease.
It acts by forming a stable tripartite complex with serum albumin and copper,
rendering the complexed copper unavailable for cellular uptake. TM is a very
potent anticopper agent and has an excellent safety profile. It has been shown
that normal copper levels are required for optimal angiogenesis. Based on this
background, we decided to evaluate TM as an anticancer agent. TM treatment of
Her/2neu mice, genetically programmed to develop breast cancer,
completely prevented the development of visible mammary cancers, although
avascular microscopic clusters of cancer cells were present in the breasts of
TM treated animals. Controls developed grossly visible tumors. TM was able to
strongly inhibit tumor growth in six other rodent models. In a phase 1/2
clinical trial of advanced and metastatic cancers, freedom from progression
averaged 11 months, and some individual results were quite dramatic. Eight
phase 2 studies of specific cancers have been launched.
TM’s hypothesized
mechanism of action is inhibition of angiogenic cytokines. Unlike other current
approaches to antiangiogenic therapy which target single agents, we hypothesize
that TM inhibits multiple angiogenic cytokines. Part of this effect appears to
stem from inhibition of nuclear factor kappa B (NFKB), which in turn
controls transcription of many angiogenic and other cytokines. However, there
are probably multiple mechanisms, in that some angiogenic cytokines appear to
have separate mechanisms of copper dependence. The inhibition of multiple
angiogenic cytokines gives TM the potential to be a more global inhibitor of
angiogenesis.
[Back to top] Matrix Metalloproteinases as Therapeutic
Targets in Cancer
Pia
Vihinen, Risto Ala-aho and Veli-Matti Kahari
Degradation of
extracellular matrix is crucial for malignant tumor growth, invasion,
metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of
zinc-dependent neutral endopeptidases collectively capable of degrading
essentially all matrix components. Elevated levels of distinct MMPs can be
detected in tumor tissue or serum of patients with advanced cancer, and their
role as prognostic indicators in cancer has been widely examined. In addition,
therapeutic intervention in tumor growth and invasion based on inhibition of
MMP activity is under intensive investigation and several MMP inhibitors
(MMPIs) are in clinical cancer trials. Even though results of the first
clinical trials in advanced cancer have been mostly disappointing, there are
also positive results. Recent observations show, that certain MMPs limit tumor
growth. Therefore, identification of proper MMPs for therapeutic intervention
with array-based molecular classifications of tumors and targeting these with
more specific MMPIs in combination with conventional chemotherapy is expected
to provide a feasible approach for cancer therapy. MMPIs represent a totally
different therapeutic modality from proven anti-cancer drugs and thus traditional
approaches to evaluate drug efficiency cannot be used without modification. In
this review, we discuss the current view on the feasibility of MMPs as targets
for therapeutic intervention in cancer.
[Back to top] New Target Antigens for Cancer
Immunoprevention
P.-L.
Lollini, G. Nicoletti, L. Landuzzi, C. De Giovanni and P. Nanni
Prevention of
cancer through the activation of the immune system has been explored in recent
years in preclinical systems thanks to the availability of several new
transgenic mouse models that closely mimic the natural history of human tumors.
The most thoroughly investigated model of cancer immunoprevention is the
mammary carcinoma of HER-2/neu transgenic mouse. In this system it has clearly been
shown that the activation of immune defences in healthy individuals can
effectively prevent the subsequent onset of highly aggressive mammary
carcinomas. A complete prevention was obtained using a combination of three
signals (the so called “triplex” vaccine) that included the specific antigen
(p185, the product of HER-2/neu) and nonspecific signals like allogeneic
histocompatibility antigens and interleukin 12. The analysis of protective
immune responses in models of cancer immunoprevention revealed some unexpected
features, in particular the central role of antibodies in immunoprevention, at
variance with conventional immunotherapy which is firmly based on cytotoxic T
cells. In the HER-2/neu system anti-p185 antibodies, in addition to
immunological functions leading to tumor cell lysis, inhibit p185 dimerization
and induce its internalization, resulting in the inhibition of mitogenic
signaling. Most current tumor antigens appear to be unsuitable targets for
cancer immunoprevention. An ideal antigen should have a crucial pathogenetic
role in tumor growth to avoid the selection of antigen loss variants.
Downregulation of major histocompatibility complex (MHC) expression during
tumor progression frequently limits antigen recognition by MHC-restricted T cells.
Thus an ideal antigen for cancer immunoprevention should be recognized both by
T cells and by antibodies. Antibody binding to cell surface oncogenic
determinants, in addition to complement- and cell-mediated tumor cell lysis,
can block mitogenic signaling and induce internalization, resulting in tumor
growth arrest. A search for new tumor antigens should be conducted among
molecules that are directly involved in neoplastic transformation and are
recognizable by the immune response also in MHC loss variants. Novel tumor
antigens fulfilling both conditions will be crucial for the development of
cancer immunoprevention and will provide new targets also for cancer
immunotherapy.