Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 16, Number 11, 2010

Contents

Molecularly Targeted Therapies in Breast Cancer Bone Metastases
Executive Editor: Philippe Clézardin


Editorial Pp. 1260-1261
[PMID: 20298163 PubMed - indexed for MEDLINE]


Bisphosphonates as Treatment of Bone Metastases Pp. 1262-1273
Ingunn Holen and Robert E. Coleman
[Abstract] [Purchase Article]


Targeting RANK/RANKL in the Treatment of Solid Tumours and Myeloma Pp. 1274-1283
C.H. Buckle, H.L. Neville-Webbe, P.I. Croucher and M.A. Lawson
[Abstract] [Purchase Article]


The CXCR4/SDF-1 Chemokine Axis: A Potential Therapeutic Target for Bone Metastases? Pp. 1284-1290
A.C. Hirbe, E.A. Morgan and K.N. Weilbaecher
[Abstract] [Purchase Article]


Bone Morphogenetic Proteins and its Receptors; Therapeutic Targets in Cancer Progression and Bone Metastasis? Pp. 1291-1300
Jeroen T. Buijs, Maj Petersen, Geertje van der Horst and Gabri van der Pluijm
[Abstract] [Purchase Article]


TGF-β Pathway as a Therapeutic Target in Bone Metastases Pp. 1301-1312
Patricia Juárez and Theresa A. Guise
[Abstract] [Purchase Article]


General Article

Identification of Molecular Targets Associated with Ethanol Toxicity and Implications in Drug Development Pp. 1313-1355
Lin-Lin Wang, An-Kui Yang, Shu-Ming He, Jun Liang, Zhi-Wei Zhou, Yong Li and Shu-Feng Zhou
[Abstract] [Purchase Article]




Abstracts


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Bisphosphonates as Treatment of Bone Metastases
Ingunn Holen and Robert E. Coleman

Accelerated bone loss is a common clinical feature of advanced breast cancer, and anti-resorptive bisphosphonates are the current standard therapy used to reduce the number and frequency of skeletal-related complications experienced by patients. Bisphosphonates are potent inhibitors of bone resorption, acting by inducing osteoclast apoptosis and thereby preventing the development of cancer-induced bone lesions. In clinical use bisphosphonates are mainly considered to be bone-specific agents, but anti-tumour effects have been reported in a number of in vitro and in vivo studies. By combining bisphosphonates with chemotherapy agents, growth and progression of breast cancer bone metastases can be virtually eliminated in model systems. Recent clinical trials have indicated that there may be additional benefits from bisphosphonate treatment, including positive effects on recurrence and survival when added to standard endocrine therapy. Whereas the ability of bisphosphonates to reduce cancer-induced bone disease is well established, their potential direct anti-tumour effect remain controversial. Ongoing clinical trials will establish whether bisphosphonates can inhibit the development of bone metastases in high-risk breast cancer patients. This review summarizes the main studies that have investigated the effects of bisphosphonates, alone and in combination with other anti-cancer agents, using in vivo model systems of breast cancer bone metastases. We also give an overview of the use of bisphosphonates in the treatment of breast cancer, including examples of key clinical trials. The potential side effects and future clinical applications of bisphosphonates will be outlined.


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Targeting RANK/RANKL in the Treatment of Solid Tumours and Myeloma
C.H. Buckle, H.L. Neville-Webbe, P.I. Croucher and M.A. Lawson

Cancers which damage the human skeleton include multiple myeloma, where the primary tumour colonises bone directly, or breast and prostate cancer, where malignant cells travel from the primary tumour to form clonal outgrowths within the bone. Owing to the interaction of tumour cells with those normally found in the bone microenvironment, such as osteoclasts and osteoblasts, these cancers affect the closely linked processes of bone formation and resorption. As a result, these twin processes contribute to the clinical manifestations of cancer metastasis, including bone pain and pathological fractures. A critical component of physiologically normal bone remodelling, the RANK/RANKL/OPG pathway, has been implicated in the formation of osteolytic, and possibly osteoblastic, lesions, which characterise the bone disease associated with these malignancies. In these cancers that affect the skeleton in this way the abnormally regulated RANK/RANKL system appears to be the final effector pathway. As a result, there has been much research focused upon targeting these molecules using OPG constructs, peptidomimetics, soluble receptor constructs and antibodies to RANKL, in pre-clinical studies. The success of these studies has paved the way for a clinical programme, the success of which is likely to lead to a new therapeutic approach to treating cancers that develop in the skeleton.


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The CXCR4/SDF-1 Chemokine Axis: A Potential Therapeutic Target for Bone Metastases?
A.C. Hirbe, E.A. Morgan and K.N. Weilbaecher

Chemokines and chemokine receptors play diverse roles in homeostasis. The chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 have critical functions in the immune, circulatory, and central nervous systems and have also been implicated in tumor biology and metastasis. Here we review the current data regarding the role of the CXCR4/SDF-1 chemokine axis in the development of bone metastases, derived from tumor models of breast or prostate cancers. There is substantial evidence that CXCR4 and SDF-1 directly influence the survival and proliferation of tumor cells. In regards to bone metastases, the CXCR4/SDF-1 axis also appears to facilitate tumor cell recruitment to the bone marrow microenvironment via a homing mechanism. This makes disruption of the chemokine axis an attractive therapeutic target for the prevention of tumor cell spread to bone. However, within the bone microenvironment, SDF-1 and CXCR4 appear to have conflicting roles. While genetic disruption of CXCR4 enhances osteoclast activity and therefore stimulates tumor cell growth in the bone - likely via release of bone-derived growth factors - SDF-1 has been shown to have either a stimulatory effect or no effect on osteoclasts. In short, the effects of the CXCR4/SDF-1 axis on tumor cell growth within the bone are not yet fully defined. Further, there are theoretical risks that blockade of this chemokine axis could impair immune function or mobilize tumor cells leading to other sites of metastasis. As such, caution should be taken when designing therapeutic strategies targeting this chemokine axis.


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Bone Morphogenetic Proteins and its Receptors; Therapeutic Targets in Cancer Progression and Bone Metastasis?
Jeroen T. Buijs, Maj Petersen, Geertje van der Horst and Gabri van der Pluijm

Breast and prostate cancer are osteotropic cancers, i.e., carcinomas that have a special predilection to form bone metastases. At postmortem examination, ~70% of patients dying of these cancers have evidence of metastatic bone disease.

Bone Morphogenetic Proteins (BMPs) were first identified by their ability to induce ectopic bone formation in vivo. Since prostate cancer cells express several BMPs, BMPs have been implicated in the osteoblastic phenotype of bone metastases. In addition to their osteogenic function, BMPs turned out to be multifunctional proteins regulating cell growth, differentiation, migration, and apoptosis in various target cells, including breast and prostate cancer cells. Especially in the last decade, studies have focused on the role of several BMPs in osteotropic cancers. In this review, the role of BMPs, particularly that of BMP7, in breast and prostate cancer will be discussed.


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TGF-β Pathway as a Therapeutic Target in Bone Metastases
Patricia Juárez and Theresa A. Guise

Breast and prostate cancer frequently metastasizes to the skeleton and causes bone destruction. In skeletal tissue, transforming growth factor-β (TGF-β) is a major bone-derived factor responsible for driving a feed-forward vicious cycle of breast cancer growth in bone. TGF-β is released from bone in active form by osteoclastic resorption and increases the tumor secretion of factors, which stimulate osteolytic destruction of the bone adjacent to the tumor. Moreover it activates epithelial-mesenchymal transition and tumor cell invasion, increases angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between tumor and bone offers a target for therapeutic intervention to decrease skeletal metastasis. Here we summarize the current knowledge of TGF-β in bone metastases, the use of TGF-β inhibitors and its potential for clinical use and consequences.


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Identification of Molecular Targets Associated with Ethanol Toxicity and Implications in Drug Development
Lin-Lin Wang, An-Kui Yang, Shu-Ming He, Jun Liang, Zhi-Wei Zhou, Yong Li and Shu-Feng Zhou

Alcohol dependence is a major disease burden of adults in modern society worldwide. There is no cure for alcohol dependence. In this study, we have examined the molecular targets of ethanol-induced toxicity in humans based on a systematic review of literature data and then discussed current and potential therapeutic targets for alcohol abuse and dependence. Using human samples with ethanol exposure, microarray analyses of gene expression have shown that numerous genes are up- and/or down-regulated by alcohol exposure. The ethanol-responsive genes mainly encode functional proteins such as proteins involved in nucleic acid binding, transcription factors, selected regulatory molecules, and receptors. These genes are also correlated with important biological pathways, such as angiogenesis, integrin signaling pathway, inflammation, wnt signaling pathway, platelet-derived growth factor signaling pathway, p53 pathway, epidermal growth factor receptor signaling pathway and apoptosis signaling pathway. Currently, only three medications were approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol abuse and alcohol dependence, including the aldehyde dehydrogenase inhibitor disulfiram, the μ-opioid receptor antagonist naltrexone, and the N-methyl-D-aspartate (NMDA) receptor inhibitor acamprosate (oral and injectable extended-release formulations). In addition, a number of agents are being investigated as novel treatments for alcohol abuse and dependence. These include selective 5-HT reuptake inhibitors (e.g. fluoxetine), 5-HT₁ receptor agonists (e.g. buspirone), 5-HT₂ receptor antagonists (e.g. ritanserin), 5-HT3 receptor antagonists (e.g. ondansetron), dopamine receptor antagonists (e.g. aripiprazole and quetiapine), dopamine receptor agonists (e.g. bromocriptine), GABAB receptor agonists (e.g. baclofen), and cannabinoid-1 (CB₁) receptor antagonists. Some of these agents have shown promising efficacy in initial clinical studies. However, further randomized studies with larger samples are warranted to establish their efficacy and safety profiles in the treatment of alcohol dependence.