| Current
Cancer Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 9, Number 7, November 2009
Contents
Target Therapy of Bone Metastases and Tumours
Guest Editors: M. Caraglia and D. Santini
Editorial Pp. 789-790
Cutting the Limits of Aminobisphosphonates: New Strategies
for the Potentiation of their Anti-Tumour Effects
Pp. 791-800
M. Marra, A. Abbruzzese, R. Addeo, S. Del Prete, P. Tassone,
G. Tonini, P. Tagliaferri, D. Santini and M. Caraglia
[Abstract] [Purchase
Article]
Integrins in Bone Metastasis Formation
and Potential Therapeutic Implications Pp. 801-806
P. Clézardin
[Abstract] [Purchase
Article]
Anti-Tumour Effects of Bisphosphonates
- What have we Learned from In Vivo Models? Pp.
807-823
H.K. Brown and I. Holen
[Abstract] [Purchase
Article]
Bisphosphonates in the Prevention of Disease Recurrence: Current
Results and Ongoing Trials Pp. 824-833
M. Gnant
[Abstract] [Purchase
Article]
Denosumab: The Era of Targeted Therapies
in Bone Metastatic Diseases Pp. 834-842
D. Santini, M.E. Fratto, B. Vincenzi, N. Napoli, S. Galluzzo,
M. Tantardini, A. Abbruzzese, M. Caraglia and G.
Tonini
[Abstract] [Purchase
Article]
Targeted Therapies in Bone Sarcomas Pp. 843-853
K. Scotlandi, P. Picci and H. Kovar
[Abstract] [Purchase
Article]
Challenging the Current Approaches to Multiple Myeloma-Related
Bone Disease: From Bisphosphonates to Target Therapy Pp.
854-870
P. Tassone, P. Tagliaferri, M. Rossi, T. Calimeri, A.
Bulotta, A. Abbruzzese, M. Caraglia and P. Neri
[Abstract] [Purchase
Article]
Association of p53 with Bid Induces Cell Death in
Response to Etoposide Treatment in Hepatocellular Carcinoma
Pp. 871-880
G. Song, G.G. Chen, J.-P. Yun and P.B.S. Lai
[Abstract] [Purchase
Article]
HIF-1α
and Calcium Signaling as Targets for Treatment of
Prostate Cancer by Cardiac Glycosides Pp. 881-887
J. Lin, S. Denmeade and M.A. Carducci
[Abstract] [Purchase
Article]
Abstracts
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Cutting the Limits of Aminobisphosphonates: New Strategies
for the Potentiation of their Anti-Tumour Effects
M. Marra, A. Abbruzzese, R. Addeo, S. Del Prete, P. Tassone,
G. Tonini, P. Tagliaferri, D. Santini and M. Caraglia
Therapy with aminobisphosphonate (N-BPs), and zoledronic
acid (ZOL) especially, has become a standard of care for patients
with malignant bone disease. In addition, preclinical and
preliminary clinical data suggest that N-BPs exert their direct
or indirect anti-tumour effects on cancer growth factor release,
cancer cell adhesion, invasion and viability, cancer angiogenesis
and cancer cell apoptosis. Here, we will discuss the molecular
mechanisms of the antitumour effects induced by ZOL. Despite
their well-established in vitro anti-tumour effects
N-BPs have not clear in vivo anti-tumour activity
in humans. The bases of these discrepancies will be discussed
in the text with a special focus on the pharmacokinetic limits
of N-BPs. Moreover, the following molecular and pharmacological
strategies in order to overcome N-BPs limitations will be
described: i) development of pharmacological combinations
with other biological agents; ii) finding of new molecular
targets of N-BPs; iii) development of new pharmacological
formulations of N-BPs. Finally, a new scenario of integrated
bio-medicine and pharmacology will be depicted in order to
drive the optimization of anti-cancer activity of N-BPs.
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Integrins in Bone Metastasis Formation
and Potential Therapeutic Implications
P. Clézardin
Integrins constitute a family of cell surface receptors
that are heterodimers composed of noncovalently associated
α and
β subunits.
Integrins bind to extracellular matrix proteins and immunogobulin
superfamily molecules. They exert a stringent control on cell
migration, survival and proliferation. However, their expression
and functions are often deregulated in cancer, and many lines
of evidence implicate them as key regulators during progression
from primary tumor growth to metastasis. Here, we review the
role of integrins in bone metastasis formation and present
evidence that the use of integrin-targeted therapeutic agents
may be an efficient strategy to block tumor metastasis.
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Anti-Tumour Effects of Bisphosphonates
- What have we Learned from In Vivo Models?
H.K. Brown and I. Holen
Bisphosphonates are extensively used to treat cancer-induced
bone disease in a range of solid tumours and multiple myeloma,
where they reduce the incidence of skeletal related events
and improve patients’ quality of life. Recent reports
indicate that bisphosphonates may also prevent recurrence
of breast cancer at peripheral sites, suggesting that these
drugs may have anti-tumour effects outside the skeleton. Anti-tumour
effects of several bisphosphonates have been reported in a
range of tumour cell types in vitro. These positive
results have subsequently been supported by investigations
of effects of bisphosphonates on tumour growth in vivo,
both in bone and at peripheral sites. A reduction of tumour
burden and also in cancer-induced bone disease has been reported
following bisphosphonate treatment in several model systems,
including breast and prostate cancer, osteosarcoma and multiple
myeloma. In addition, bisphosphonates have been shown to significantly
reduce growth of human tumour cells (including breast, prostate,
lung and mesothelioma) implanted subcutaneously in immunocompromised
mice. However, the majority of in vivo studies showing
a reduction in bone disease and reduced tumour burden have
used high doses and frequent administration of bisphosphonates,
and the clinical relevance of these data have therefore been
the subject of considerable debate. Bisphosphonates may hold
greater promise as anti-tumour agents when used in combination
with cytotoxic drugs, and several in vivo studies
have reported substantial increased inhibition of tumour growth
and improved survival when bisphosphonates have been added
to standard chemotherapy regimens. This review will summarise
the published data on anti-tumour effects of bisphosphonates
from in vivo models, alone and in combination with
other anti-cancer agents, and highlight the main lessons learned
and future challenges in this field.
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Bisphosphonates in the Prevention of Disease Recurrence: Current
Results and Ongoing Trials
M. Gnant
Bisphosphonates are the standard of care for preventing
skeletal morbidity and treating hypercalcemia of malignancy
in patients with bone metastases. Zoledronic acid (intravenous;
4 mg monthly) is approved to prevent skeletal-related events
(SREs) in patients with bone metastases from several tumor
types, and can improve survival in some subsets of patients
with skeletal metastases and high baseline bone turnover.
In the adjuvant setting, bisphosphonates have shown clinical
efficacy for preventing cancer treatment-induced bone loss
and promise for reducing disease recurrence. For example,
early studies of clodronate showed the potential for bisphosphonates
to prevent bone metastases and prolong survival, but results
with clodronate have been inconsistent. Recently, the more
active bisphosphonate zoledronic acid (4 mg every 6 months)
prevented bone loss and significantly reduced the risk of
disease-free survival events by 36% (P = .01) compared
with adjuvant endocrine therapy alone in a large phase III
trial (N = 1,803) in premenopausal women with early breast
cancer. Notably, these benefits were not limited to bone,
because the addition of zoledronic acid reduced disease recurrence
at all sites. Similarly, twice-yearly zoledronic acid has
reduced disease recurrence in large phase III trials in more
than 1,600 postmenopausal women with early breast cancer.
Several ongoing trials (involving more than 20,000 patients
altogether) are evaluating the efficacy of bisphosphonates
for prevention of metastases in breast, prostate, and lung
cancers; and multiple myeloma. Results from these studies
are likely to expand the role of bisphosphonates, especially
zoledronic acid, in the adjuvant therapy setting.
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Denosumab: The Era of Targeted Therapies
in Bone Metastatic Diseases
D. Santini, M.E. Fratto, B. Vincenzi, N. Napoli, S. Galluzzo,
M. Tantardini, A. Abbruzzese, M. Caraglia and G.
Tonini
This system constituted of the Receptor Activator of
nuclear Factor-kB Ligand (RANKL), the Receptor Activator of
Nuclear Factor-kB (RANK) and by the decoy Receptor Osteoprotegerin
(OPG) plays a central role in bone resorption. Denosumab (AMG
162) is an investigational fully human monoclonal antibody
with a high affinity and specificity for RANKL.This review
will critically describe and discuss the recent results of
clinical trial investigating denosumab in different settings
of medical oncology. In particular, we will report the recently
published data of clinical trials investigat-ing denosumab
in prevention of cancer treatment induced bone loss (CTIBL),
in prevention of skeletal related events (SREs) in bone metastatic
patients and the ongoing studies in prevention of disease
recurrence in the adjuvant setting of solid tumours. The clinical
data that will be reported in this review represent the first
step in a path that will conduct us to explore new horizons
in the field of bone health care in cancer patients.
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Targeted Therapies in Bone Sarcomas
K. Scotlandi, P. Picci and H. Kovar
The treatment of sarcoma urgently requires new, innovative
therapeutic strategies. The most recent improvements in the
cure of patients with localized disease have been achieved
by dose-intensification, in turn paying the price of acute
severe toxicity and secondary malignancies. Keeping side-effects
to a minimum is an important goal for pediatric patients and
this may be achieved by combining standard cytotoxic chemotherapy
with targeted approaches. In addition, after first-line therapy,
very limited treatment options remain for patients with disease
progression, who, like patients with metastasis at diagnosis,
are in urgent need of more effective drugs. The present review
highlights key examples of target identification in bone sarcomas,
including chimeric oncoproteins, insulin-like growth factor
receptor (IGF-IR), and tumor/microenvironment interactions.
The review identifies questions and concerns that still need
to be addressed before proceeding to safe clinical trials
with agents against these promising new targets.
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Challenging the Current Approaches to Multiple Myeloma-Related
Bone Disease: From Bisphosphonates to Target Therapy
P. Tassone, P. Tagliaferri, M. Rossi, T. Calimeri, A.
Bulotta, A. Abbruzzese, M. Caraglia and P. Neri
Bone disease (BD) is the hall-mark clinical feature of multiple
myeloma (MM), accounting up to 60% of patients with bone pain
at diagnosis and 60% with a pathologic fracture during the
course of their disease. Experimental models, which recapitulate
in vivo the human bone marrow microenvironment (HBMM)
in immunodeficient mice have been recently developed as valuable
tool for the study of MM pathophysiology as well as the experimental
treatment of BD. At present, bisphosphonates are the mainstay
treatment of MM-related BD. The growing information on the
cellular and molecular bases of BD as well as the availability
of novel anti-resorptive agents, such as the IgG1-anti-RANKL
(AMG 161) Deno-sumab, are now depicting a new scenario
where the treatment will be afforded by the use of different
agents. Furthermore the availability of highthroughput molecular
profiling approaches, including DNA microarrays and proteomics,
is likely to provide new platforms for patients stratification
and treatment individualization on specific targets. It is
now the right time for a therapeutical approach which is rationally
based on the complexity of the biopathology of MM-related
BD.
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Association of p53 with Bid Induces Cell Death in
Response to Etoposide Treatment in Hepatocellular Carcinoma
G. Song, G.G. Chen, J.-P. Yun and P.B.S.
Lai
Appropriate subcellular localization of proteins is crucial
for regulating their functions. Both p53 and the BH3-only
Bid play roles in the development and the treatment of hepatocellular
carcinoma (HCC). They both participate in the cross talk of
cell cycle arrest and apoptosis in response to DNA damage.
However, some important issues related to their pathways are
not yet resolved. Bid genomic loci contain p53-binding DNA
response elements and Bid can mediate p53-dependent transactivation.
Here, we showed that etoposide-induced DNA damage could significantly
induce p53 and Bid nuclear export. When cells were stimulated
by etoposide, p53 could, through the association with Bid,
cause translocation of Bid from the nucleus to the cytoplasm
and on to its ultimate location in the mitochondria. p53 was
physically associated with Bid, and both p53 and Bid cooperatively
promoted cell death induced by etoposide. Knockdown of Bid
expression notably attenuated cell death induced by etoposide
and also released p53 from the mitochondria. These findings
reveal a novel mechanism by which p53 is associated with Bid
in the nucleus to facilitate exportation of Bid to the mitochondria
and induce apoptosis in response to etoposide-induced DNA
damage in HCC.
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HIF-1α
and Calcium Signaling as Targets for Treatment of
Prostate Cancer by Cardiac Glycosides
J. Lin, S. Denmeade and M.A. Carducci
Prostate cancer possesses its unique feature of low proliferation
rate and slow growth. Ca2+-induced
apoptosis is not dependent on cell cycle progression and targeting
this pathway could circumvent the problems encountered using
current cytotoxic chemotherapies for prostate cancer. Hypoxia-inducible
factor 1a (HIF-1α)
is another novel cancer drug target and inhibitors of hypoxia-response
pathway are being developed. Digoxin and other cardiac glycosides,
known inhibitors of the alpha-subunit of sarcolemmal Na+K+-ATPase,
were recently found to block tumor growth via the
inhibition of HIF-1α
synthesis. Thus, cardiac glycosides disrupt two important
cellular pathways and, therefore, may be useful as an anticancer
therapy. This review will focus on HIF-1α
and calcium signaling as novel cancer drug targets in prostate
cancer. The possible application of digoxin and other cardiac
glycosides in cancer therapeutics especially in prostate cancer
is discussed.
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