Current
Cancer Drug Targets
ISSN: 1568-0096
OPEN ACCESS PLUS
Contents
Strategies for Overcoming Inherent and Acquired Resistance
to EGFR Inhibitors by Targeting Downstream Effectors in the
RAS/PI3K Pathway, 2010, 10, 824-833
A.J. Weickhardt, N.C. Tebbutt and J.M. Mariadason
[Abstract] [Full
Text Article]
Dexamethasone Synergizes with Lenalidomide to Inhibit Multiple
Myeloma Tumor Growth, But Reduces Lenalidomide-Induced Immunomodulation
of T and NK Cell Function, 2010, 10, 155-167
A.K. Gandhi, J. Kang, L. Capone, A. Parton, L.
Wu, L.H. Zhang, D. Mendy, A. Lopez- Girona, T. Tran, L. Sapinoso,
W. Fang, S. Xu, G. Hampton, J.B. Bartlett and P.
Schafer
[Abstract] [Full
Text Article]
Potential Uses of MicroRNA in Lung Cancer Diagnosis, Prognosis,
and Therapy, 2009, 9, 572-594
Qi Zhao Wang, William Xu, Nagy Habib and
Ruian Xu
[Abstract] [Full
Text Article]
S100A8 and S100A9 Overexpression Is Associated with Poor Pathological
Parameters in Invasive Ductal Carcinoma of the Breast,
2008, 8, 243-252
Kazumori Arai, Sachiko Takano, Takumi Teratani,
Yasuhiro Ito, Toshihiro Yamada and Ryushi Nozawa
[Abstract]
[Full
Text Article]
Nutritional Modulation of Terminal End Buds: Its Relevance
to Breast Cancer Prevention, 2007, 7, 465-474
Leena Hilakivi-Clarke
[Abstract] [Full
Text Article]
Mechanisms Used by Human Papillomaviruses to Escape the Host
Immune Response, 2007, 7, 79-89
Shreya Kanodia, Laura M. Fahey and W. Martin Kast
[Abstract]
[Full
Text Article]
Ribonucleotide Reductase Inhibitors and Future Drug Design,
2006, 6, 409-431
J. Shao, B. Zhou, Bernard Chu and Y. Yen
[Abstract] [Full
Text Article]
Liposomal Muramyl Tripeptide Phosphatidylethanolamine: Targeting
and Activating Macrophages for Adjuvant Treatment of Osteosarcoma,
2006, 6, 123-133
A. Nardin, M.-L. Lefebvre, K. Labroquère,
O. Faure and J.-P. Abastado
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Strategies for Overcoming Inherent and Acquired Resistance
to EGFR Inhibitors by Targeting Downstream Effectors in the
RAS/PI3K Pathway
A.J. Weickhardt, N.C. Tebbutt and J.M. Mariadason
[Full
Text Article]
Mutations in K-Ras are observed in approximately
40% of colon tumours. This has significant implications for
predicting likelihood of response to the antibody-based EGFR
inhibitors, cetuximab and panitumumab, with K-Ras
mutant patients now clearly shown to be inherently resistant
to these agents. Alternative treatment strategies for K-Ras
mutant patients are therefore urgently needed. Farnesyltransferase
inhibitors, developed to inhibit K-Ras, have to-date
been largely unsuccessful. However, a number of agents which
target signaling components in the MAPK and PI3K
pathways downstream of mutant K-Ras are currently
being evaluated in clinical trials and will be discussed.
A further clinical concern is that K-Ras wild type
patients who initially respond to EGFR inhibitors eventually
develop acquired resistance to these agents and experience
tumour progression. Studies from the use of related agents
in other disease settings as well as pre-clinical studies
provide important insights into mechanisms by which this may
occur. While no evidence presently exists for somatic mutations
as a basis for acquired resistance to EGFR inhibitors in colon
cancer, several studies implicate upregulation and signaling
via other Her family members, c-Met, IGFR and Src. Upregulation
of the pro-angiogenic factor, VEGF, is also a possible mechanism
of acquired resistance. This review discusses drugs currently
in clinical trials that may potentially achieve more efficient
and prolonged targeting of the EGFR pathway by overcoming
these mechanisms of resistance.
[Back to top]
Dexamethasone Synergizes with Lenalidomide to Inhibit
Multiple Myeloma Tumor Growth, But Reduces Lenalidomide-Induced
Immunomodulation of T and NK Cell Function
A.K. Gandhi, J. Kang, L. Capone, A. Parton, L.
Wu, L.H. Zhang, D. Mendy, A. Lopez- Girona, T. Tran, L. Sapinoso,
W. Fang, S. Xu, G. Hampton, J.B. Bartlett and P.
Schafer
[Full
Text Article]
To determine the effect of dexamethasone on the antimyeloma
effects of lenalidomide, we tested in vitro proliferation,
tumor suppressor gene expression, caspase activity, cell cycling,
and apoptosis levels in a series of multiple myeloma (MM)
and plasma cell leukemia cell lines treated with lenalidomide
and dexamethasone, alone or in combination. The effect of
dexamethasone on the immunomodulatory activities of lenalidomide
such as T cell and natural killer (NK) cell activation was
measured via interleukin [IL]-2 production, and interferon-γ
and granzyme B production respectively. Lenalidomide inhibited
proliferation in most cell lines tested, and this effect was
enhanced by dexamethasone. This effect was observed in MM
cells containing the high-risk cytogenetic abnormalities t(4;14),
t(14;16), del17p, del13, and hypodiploidy. Mechanistically,
lenalidomide plus dexamethasone synergistically induced expression
of the tumor suppressor genes Egr1, Egr2, Egr3, p15, p21,
and p27 in MM cell lines and MM patient cells. The
combination activated caspases 3, 8, and 9 and induced cell
cycle arrest and apoptosis. Lenalidomide alone increased T
cell production of IL-2, and NK cell production of interferon-γ
and granzyme B. Notably, dexamethasone antagonized these immunostimulatory
effects of lenalidomide in a dose-dependent manner. These
data further elucidate the mechanism of action of lenalidomide
and dexamethasone in MM, and suggest that use of low-dose
dexamethasone with lenalidomide may retain the antiproliferative
effect of lenalidomide while permitting greater immunomodulatory
effects of this combination regimen.
[Back to top]
Potential Uses of MicroRNA in Lung Cancer Diagnosis,
Prognosis, and Therapy
Qi Zhao Wang, William Xu, Nagy Habib and
Ruian Xu
[Full
Text Article]
Lung cancer is the leading cause of death from cancer in the
world. Although the molecular network of lung carcinogenesis
has been partly known at the levels of genes and proteins,
and personalized therapy based on the genetic changes has
made considerable progress in the last decade, the high mortality
rate is not markedly changed. MicroRNAs (miRNAs), a class
of short endogenous RNAs, acting as post-transcriptional regulators
of gene expression, are similar with siRNAs in both the biosynthesis
and the function steps. While, miRNAs mostly silence gene
expression by binding imperfectly matched sequences in the
3' UTR of target mRNA, which is different with siRNAs by targeting
ORF of mRNA with a perfectly complementary manner. miRNAs
have multiple functions in lung development, and abnormal
expression of miRNAs could lead to lung tumorigenesis. The
different expression profiles of miRNAs in lung cancer, and
the stability of miRNAs in serum, all together make them as
new potentially clinical biomarkers for diagnosis and prognosis.
Moreover, miRNAs may serve as either novel potential targets
acting directly as oncogenes (e.g. miR-17-92 cluster)
or directly therapeutic molecules working as tumor suppressor
genes (e.g. let-7 family). RNAi technology based
on miRNAs has many advantages over siRNAs, such as in
vivo stability, highly RNA promoter-compatibility and
no overt toxicity. Eventually, it might overcome the present
disadvantages and become a good candidate for lung cancer
therapy.
[Back to top]
S100A8 and S100A9 Overexpression Is Associated with Poor Pathological
Parameters in Invasive Ductal Carcinoma of the Breast
Kazumori Arai, Sachiko Takano, Takumi Teratani,
Yasuhiro Ito, Toshihiro Yamada and Ryushi Nozawa
[Full
text article]
S100 protein A8 and A9 naturally form a stable heterocomplex.
Recently, we have proved that S100A9 overexpression in various
adenocarcinomas is associated with poor tumor differentiation.
In this study, we examined the relationship between the expression
of each protein and the pathological parameters that reflect
the aggressiveness of carcinoma, in invasive ductal carcinoma
(IDC) of the breast. Serial paraffin-embedded tissue sections
from 101 IDC cases were immunostained with respective monoclonal
antibodies, and the results were as follows: 1) A positive
correlation of immunoreactivity between S100A8 and S100A9
was noticed (r=0.873 and P<0.0001); 2) The percentage of
S100A9-positive tumor cells was higher than that of S100A8-positive
tumor cells (P<0.001), and S100A8 alone was not detected
in any case; 3) Overlap between S100A8 and S100A9 staining
patterns was found in the corresponding tissue areas, but
S100A9 positivity was also observed in S100A8-negative tumor
cells; 4) The immunopositivity for each protein also correlated
with the mitotic activity, MIB-1 index, HER2 overexpression,
node metastasis, and poor pT categories and pStage (P<0.05);
5) Co-expression of both proteins was associated with poor
tumor differentiation, vessel invasion, node metastasis, and
poor pStage (P<0.05). Furthermore, co-expression of the
proteins was also observed in MCF-7 cells, and it was suggested
that the immunolocalization is related with cell cycle. Our
conclusions are as follows: 1) It is suggested that S100A8
is S100A9-dependently expressed and acquires the protein stability
by S100A8/A9 heterocomplex formation; 2) S100A8 and S100A9
overexpression should be considered marker of poor prognosis
in IDC.
[Back to top]
Nutritional Modulation of Terminal End Buds: Its Relevance
to Breast Cancer Prevention
Leena Hilakivi-Clarke
[Full
text article]
Findings with experimental rodent models reveal
that exposures to dietary factors during the in utero and
pubertal periods when the mammary gland is undergoing extensive
modeling and re-modeling, alter susceptibility to develop
mammary tumors. Similar observations have been made in humans:
childhood exposure to genistein in soy or to some other bioactive
food components reduces later breast cancer risk, although
they may have no effect if consumed during adulthood. Thus,
food components may be more effective in affecting cancer
risk in some periods of life than others. Many of these dietary
exposures modify fetal and postnatal hormonal environment,
including changing the concentrations of estrogens and leptin.
The hormonal alterations then may induce persistent epigenetic
changes by affecting gene promoter regions or by inducing
histone modifications that affect chromatin transcription.
The targets of epigenetic changes are likely to be the terminal
end buds (TEBs), the structures where carcinogen-induced mammary
tumors in rats and mice are initiated. More specifically,
the site of these changes in TEBs may be the stem cells and
their niche; this might explain how an exposure early in life
affects the risk of breast cancer decades later. Similar structures
in women, called terminal ductal lobular units, are the sites
where most human breast cancers rise. According to this hypothetical
model, cancer is initiated only when the epigenetically altered
cells are exposed to carcinogens/radiation, etc. during adult
life. In a “normal” stem cell or its niche, cancer
initiating exposures do not necessarily cause cancer, because
the cells can either repair the damage or undergo apoptosis.
Thus, the most likely molecular targets of early life dietary
exposures are genes that regulate DNA adduct formation, repair
DNA damage or induce apoptosis, such as genes affecting cellular
metabolism, tumor suppressor genes or genes promoting cell
survival. It is possible that some of these epigenetic changes
also explain why the number of TEBs generally, but not always,
correlates with breast cancer risk. This hypothesis may imply
that adult intake of some bioactive dietary components reduces
cancer risk increased by early life dietary exposures or inhibits
tumor growth by reversing epigenetic changes in various molecular
targets.
[Back to top]
Mechanisms Used by Human Papillomaviruses
to Escape the Host Immune Response
Shreya Kanodia, Laura M. Fahey and W. Martin Kast*
[Full
text article]
The greatest risk factor for the development of
cervical and other cancers that have been linked to the human
papillomavirus (HPV) family is the persistence of the virus.
To persist for the decades required to develop HPV-related
cancers, the virus must escape host immunity. HPV is a simple
DNA virus that has evolved to escape immune attack by a combination
of stealth and interference. This review focuses on the mechanisms
by which HPV can evade recognition by the host immune system.
[Back to top]
Ribonucleotide Reductase Inhibitors and Future Drug Design
J. Shao, B. Zhou, Bernard Chu and Y. Yen
[Full
text article]
Ribonucleotide reductase (RR) is a multisubunit
enzyme responsible for the reduction of ribonucleotides to
their corresponding deoxyribonucleotides, which are building
blocks for DNA replication and repair. The key role of RR
in DNA synthesis and cell growth control has made it an important
target for anticancer therapy. Increased RR activity has been
associated with malignant transformation and tumor cell growth.
Efforts for new RR inhibitors have been made in basic and
translational research. In recent years, several RR inhibitors,
including Triapine, Gemcitabine, and GTI-2040, have entered
clinical trial or application. Furthermore, the discovery
of p53R2, a p53-inducible form of the small subunit of RR,
raises the interest to develop subunit-specific RR inhibitors
for cancer treatment. This review compiles recent studies
on (1) the structure, function, and regulation of two forms
of RR; (2) the role in tumorigenesis of RR and the effect
of RR inhibition in cancer treatment; (3) the classification,
mechanisms of action, antitumor activity, and clinical trial
and application of new RR inhibitors that have been used in
clinical cancer chemotherapy or are being evaluated in clinical
trials; (4) novel approaches for future RR inhibitor discovery.
[Back to top]
Liposomal Muramyl Tripeptide Phosphatidylethanolamine:
Targeting and Activating Macrophages for Adjuvant Treatment
of Osteosarcoma
A. Nardin, M.-L. Lefebvre, K. Labroquère,
O. Faure and J.-P. Abastado
[Full
text article]
About one third of osteosarcoma patients develop lung metastasis
refractory to chemotherapy. Recent studies indicate that biological
response modifiers activating the patient’s immune system
may help controlling minimal residual disease via pathways
distinct from those used by cytotoxic drugs, and therefore
prove effective against tumor resistance. Muramyl tripeptide
phosphatidylethanolamine (MTP-PE) is a synthetic lipophilic
glycopeptide capable of activating monocytes and macrophages
to a tumoricidal state. When intercalated in multilamellar
liposomes (L-MTP-PE) and injected intravenously, it targets
lung, liver, and spleen macrophages. Therapeutic activity
of L-MTP-PE was demonstrated in several preclinical models
of experimental lung metastasis and in clinical trials in
dogs with osteosarcoma. Although macrophage activation was
shown to be directly involved in the in vivo anti-metastatic
activity of this molecule, cytokine and chemokine secretion
by activated macrophages could induce recruitment and stimulation
of other immune cells, which may in turn indirectly contribute
to the anti-tumor effect. L-MTP-PE has undergone clinical
development in humans. In early trials, most side effects
of L-MTP-PE were minimal. L-MTP-PE showed signs of efficacy
in treatment of patients with recurrent osteosarcoma and the
encouraging results from phase II studies led to a phase III
trial conducted by the Children’s Oncology Group in
patients with newly diagnosed high-grade osteosarcoma. Patients
were treated with or without L-MTP-PE in combination with
multi-drug chemotherapy in adjuvant setting; significantly
higher overall survival and disease free survival were observed
in the group receiving L-MTP-PE.
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