Current Cancer Drug Targets

ISSN: 1568-0096

Current Cancer Drug Targets
Volume 7, Number 6, September 2007

Contents


Nuclear Imaging of Hormonal Receptor Status in Breast Cancer: A Tool for Guiding Endocrine Treatment and Drug Development Pp. 510-519
E.F.J. de Vries, M.G. Rots and G.A.P. Hospers
[Abstract]


Energetics of Quadruplex-Drug Recognition in Anticancer Therapy Pp. 520-540
B. Pagano and C. Giancola
[Abstract]


Myelodysplastic Syndromes: Review of Pathophysiology and Current Novel Treatment Approaches Pp. 541-558
E.D. Warlick and B.D. Smith
[Abstract]


Transglutaminase-Mediated Activation of Nuclear Transcription Factor- κB in Cancer Cells: A New Therapeutic Opportunity Pp. 559-565
Amit Verma and Kapil Mehta
[Abstract]


Targeting Microtubules to Inhibit Angiogenesis and Disrupt Tumour Vasculature: Implications for Cancer Treatment Pp. 566-581
Eddy Pasquier, Nicolas André and Diane Braguer
[Abstract]


Stem Cells, Cancer, Liver, and Liver Cancer Stem Cells: Finding a Way Out of the Labyrinth… Pp. 582-590
A.C. Piscaglia, T.D. Shupe, B.E. Petersen and A. Gasbarrini
[Abstract]


Cross-Talk between the Androgen Receptor and the Phosphatidylinositol 3-Kinase/Akt Pathway in Prostate Cancer Pp. 591-604
Yu Wang, Jeffrey I. Kreisberg and Paramita M. Ghosh
[Abstract]




Abstracts


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Nuclear Imaging of Hormonal Receptor Status in Breast Cancer: A Tool for Guiding Endocrine Treatment and Drug Development
E.F.J. de Vries, M.G. Rots and G.A.P. Hospers

Breast cancer is a commonly occurring disease in women and a major cause of morbidity and mortality. In the past decades, the development of medical endocrine therapies has led to a significant improvement in treatment outcome for this type of cancer. This therapy is targeting specific hormone receptors that are overexpressed by the tumor cells. In breast cancer, estrogen and progesterone receptors are important targets and therefore the receptor status of the tumor strongly determines treatment outcome. However, the receptor status can change during the course of the disease and consequently therapy resistance can occur. Therefore, insight in the current receptor status of the tumor is essential for optimal treatment. Nuclear imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT), could provide the means to monitor the receptor status of tumors and the receptor occupancy by medical endocrine drugs in a non-invasive manner. Thus, these imaging techniques could offer a tool to guide therapy management in the individual patient. Nuclear imaging techniques for some of the relevant receptors for treatment of breast cancer are currently available. These imaging techniques could also aid the development of novel treatment strategies like modulation of hormone receptor expression. This review will address the role of hormone receptors in breast cancer treatment, the available nuclear imaging methods for monitoring the receptor status, the potential role of nuclear imaging in therapy management and drug development.


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Energetics of Quadruplex-Drug Recognition in Anticancer Therapy
B. Pagano and C. Giancola

Immortality of tumour cells is strictly correlated to telomerase activity. Telomerase is overexpressed in about 85% of tumour cells and maintains telomere length contributing to cell immortalisation, whereas in somatic cells telomeres progressively shorten until cell death occurs by apoptosis. Different drugs can promote telomeric G-rich overhangs which fold into quadruplex structures that inhibit telomerase activity. Detailed studies on drug-quadruplex complexes are essential to understand quadruplex recognition and address drug design. This review will discuss the energetic aspects of quadruplex-drug interactions with a particular attention to physico-chemical methodologies.


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Myelodysplastic Syndromes: Review of Pathophysiology and Current Novel Treatment Approaches
E.D. Warlick and B.D. Smith

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders of hematopoietic progenitors manifest by cytopenias, bleeding, infection, and potential for progression to acute myelogenous leukemia. The wide spectrum of clinical manifestations, including variability in illness severity and potential for progression, suggest that myelodysplastic syndromes encompass a multitude of disorders, likely involving numerous pathologic pathways. In fact, it is the effort to understand the underlying biology of these syndromes that has led to recent advances in treatment approaches, including the FDA approval of three new agents (5-azacitidine, decitabine, and lenalidomide) for the treatment of MDS. This review will present data supporting each of the current pathophysiologic pathways implicated in the development and progression of MDS; summarize the emerging clinical paradigms for treating patients with MDS; and offer insights into several novel approaches attempting to improve treatment options for future MDS patients.


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Transglutaminase-Mediated Activation of Nuclear Transcription Factor- κB in Cancer Cells: A New Therapeutic Opportunity
Amit Verma and Kapil Mehta

The nuclear factor κB (NF-κB) plays an important role in tumorigenesis by affecting processes such as tumor initiation, promotion, growth, and metastasis. NF-κB induces the expression of genes that are known to confer resistance to apoptosis. Therefore, its activation has been associated with the development of chemo- and radiation resistance in cancer cells. NF-κB is constitutively activated in many types of tumor cells by mechanisms that are not well understood. Like NF-κB, tissue-type transglutaminase (TG2), the most diverse and ubiquitous member of the calcium-dependent transglutaminase family of enzymes, is also aberrantly overexpressed in many human cancer types, blocks apoptosis, and promotes drug resistance and metastatic phenotypes. In this review, we will discuss the current understanding of the mechanisms thought to participate in constitutive activation of NF-κB. Particular focus is given to the implications of increased TG2 expression in NF-κB activation and its contributions to the development of drug resistance and metastatic phenotypes in cancer cells.


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Targeting Microtubules to Inhibit Angiogenesis and Disrupt Tumour Vasculature: Implications for Cancer Treatment
Eddy Pasquier, Nicolas André and Diane Braguer

Anticancer agents that interfere with tubulin functions are widely used in the clinic and have a broad spectrum of activity against both haematological malignancies and solid tumours. These Microtubule-Targeting Agents (MTAs), such as the taxanes and Vinca alkaloids, bind to the β subunit of α/β tubulin and disrupt microtubule dynamics in tumour cells, ultimately leading to mitotic block and subsequent cell death. Recently, MTAs have received considerable interest as potential tumour-selective anti-angiogenic and vascular-disrupting agents. Angiogenesis is a keystone of tumour progression and metastasis and targeting the formation of new blood vessels within the tumour is therefore regarded as a promising strategy for cancer therapy. In this regard, conventional MTAs can be given on daily schedules at non-toxic doses (metronomic dosing) to disturb tumour angiogenesis. Some MTAs can also act as vascular-disrupting agents. After briefly reviewing the classical mechanisms involved in the anti-tumour action of MTAs, we will focus on the latest studies investigating the molecular and cellular processes underlying the anti-angiogenic and the vascular-disrupting properties of these agents. We will also review and discuss the potential clinical development and the limitations of MTAs used as tumour-specific anti-vascular molecules.


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Stem Cells, Cancer, Liver, and Liver Cancer Stem Cells: Finding a Way Out of the Labyrinth…
A.C. Piscaglia, T.D. Shupe, B.E. Petersen and A. Gasbarrini

Subsequent to an initiating event, tumor promotion requires sustained cell proliferation to allow for progressive accumulation of pro-oncogenic mutations. The unique characteristics of stem cells would seem to implicate these cells as particularly suitable targets for carcinogens. Several lines of evidence suggest that tumors harbor a small population of cancer stem cells (CSC) which both give rise to the bulk of the tumor and are tumorigenic in experimental models. Mounting evidence suggests that these cells are responsible for re-growth of a tumor following unsuccessful treatment and for the establishment of metastases. The concept of CSC has been demonstrated in several human cancers including leukemia, breast, prostate, lung, and brain tumors. Taken together, the properties of CSC suggest that they are appropriate targets for cancer therapies. Such treatments would require a deep understanding of the CSC origin, molecular profile, and interaction with the local microenvironment. This report will summarize what is currently known regarding CSC, with particular emphasis on hepatic cancers, the cellular origin of liver tumors, and the role of liver stem cells and their niche in hepatocarcinogenesis.


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Cross-Talk between the Androgen Receptor and the Phosphatidylinositol 3-Kinase/Akt Pathway in Prostate Cancer
Yu Wang, Jeffrey I. Kreisberg and Paramita M. Ghosh

Prostate cancer is initially dependent on androgens for growth; hence, recurrent prostate is treated with androgen ablation which may result in progression to androgen independence characterized by a resistance to such therapy. Androgens bind to and activate the androgen receptor (AR), a member of the nuclear steroid receptor family of transcription factors, which regulates prostate cancer cell proliferation and survival in androgen-independent, as well as –dependent, tumors. Another pathway regulating proliferation and survival is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Here we analyze reports in the literature indicating that these two pathways cooperate to regulate prostate tumor development and progression. Studies show that AR transcriptional activity and expression are regulated by Akt. In addition, androgens regulate the Akt pathway by both genomic and non-genomic effects. This explains why prostate tumors subjected to androgen ablation experience an increase in Akt phosphorylation, and suggest that the tumor compensates for the loss of one pathway with another. Different modes of interaction between the two pathways, including direct interaction, or regulation via downstream intermediates, such as the wnt/GSK-3β/β-catenin pathway, NF-κB, and the FOXO family of transcription factors, will be discussed. In addition, we will discuss the role of Akt in the interaction of the AR with upstream regulators of Akt phosphorylation, such as receptor tyrosine kinases of the EGF and IGF-1 receptor families and the tumor suppressor PTEN.