Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 15, Number 4, 2009


Contents


Angiogenesis Agents
Executive Editor: Cezary Marcinkiewicz



Editorial: Pp. 343-344


The Discovery of Antiangiogenic Molecules: A Historical Review Pp. 345-352
D. Ribatti
[Abstract] [Purchase Article] [PMID: 19199962 PubMed - indexed for MEDLINE]


Encountering and Advancing Through Antiangiogenesis Therapy for Gliomas Pp. 353-364
V. Martin, D. Liu and C. Gomez-Manzano
[Abstract] [Purchase Article] [PMID: 19199963 PubMed - indexed for MEDLINE]


Regulation of Angiogenesis by Macrophages, Dendritic Cells, and Circulating Myelomonocytic Cells Pp. 365-379
Z.M. Dong, A.C. Aplin and R.F. Nicosia
[Abstract] [Purchase Article] [PMID: 19199964 PubMed - indexed for MEDLINE]


PI-3 Kinase-PTEN Signaling Node: An Intercept Point for the Control of Angiogenesis Pp. 380-388
R.C. Castellino, C.R. Muh and D.L. Durden
[Abstract] [Purchase Article] [PMID: 19199965 PubMed - indexed for MEDLINE]


Angiogenic and Vascular Modulation by Extracellular Matrix Cleavage Products Pp. 389-410
F. Suhr, K. Brixius and W. Bloch
[Abstract] [Purchase Article] [PMID: 19199966 PubMed - indexed for MEDLINE]


Evolving Strategies in Manipulating VEGF/VEGFR Signaling for the Promotion of Angiogenesis in Ischemic Muscle Pp. 411-421
C. Uchida and T.L. Haas
[Abstract] [Purchase Article] [PMID: 19199967 PubMed - indexed for MEDLINE]


Treatment of Neuroblastoma: From Cellular to Molecular Therapy
Executive Editor: Gian Paolo Tonini


Editorial Pp. 422-423


Cellular Immunotherapy for Neuroblastoma: A Review of Current Vaccine and Adoptive T Cell Therapeutics Pp. 424-429
C.U. Louis and M.K. Brenner
[Abstract] [Purchase Article] [PMID: 19199969 PubMed - indexed for MEDLINE]


Apoptosis Pathways and Neuroblastoma Therapy Pp. 430-435
S. Fulda
[Abstract] [Purchase Article] [PMID: 19199970 PubMed - indexed for MEDLINE]


Targeting Histone Deacetylases in Neuroblastoma Pp. 436-447
O. Witt, H.E. Deubzer, M. Lodrini, T. Milde and I. Oehme
[Abstract] [Purchase Article] [PMID: 19199971 PubMed - indexed for MEDLINE]


Genome and Transcriptome Analysis of Neuroblastoma from Advanced Diagnosis to Innovative Therapy Pp. 448-455
S. Coco, G.P. Tonini, S. Stigliani and P. Scaruffi
[Abstract] [Purchase Article] [PMID: 19199972 PubMed - indexed for MEDLINE]


MicroRNA Involvement in the Pathogenesis of Neuroblastoma: Potential for MicroRNA Mediated Therapeutics Pp. 456-462
R.L. Stallings
[Abstract] [Purchase Article] [PMID: 19199973 PubMed - indexed for MEDLINE]




Abstracts


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Editorial: Angiogenesis Agents

Angiogenesis is a complex process of development of new vessels from pre-existing vasculature. In human pathology, neovascularization is associated with excessive or insufficient vessel growth that results in initiation and development of a variety of diseases. The major pharmacological approach for the investigation of excessive angiogenesis is directed to designing new pharmaceutics to inhibit pathological vessel growth. In this context, blocking of the vascularization process in cancer progression gets the most attention. This type of biomedical research resulted in FDA approval of an anti-VEGF therapy in metastatic colorectal cancer by the humanized monoclonal antibody, bevacizumab, which is also in clinical trials for other types of tumors such as malignant gliomas. Surface receptors that are expressed on endothelial cells are also considered as a potential target for angiostatic therapy. Much attention is devoted to growth factor receptors, as well as certain integrins. In these cases, the most advanced clinical studies ongoing are with VEGFRs and αvβ3 integrin, although FGFRs and α5β1,α1β1 and α2β1 integrins are also in consideration. Targeting of intracellular signaling molecules in angiogenesis also has a long history of investigation. The pharmacological blocking of pro-angiogenic factors is mainly achieved by using humanized monoclonal antibodies or low molecular weight, synthetic compounds. Use of these compounds in therapy is usually associated with balancing of effectiveness and side effects, as well as their half-life time in the blood of patients. In the case of brain tumors, penetration of the blood brain barrier by these anti-angiogenesis agents is also very important. Analogical strategy is applied for developing pharmaceutics that will be useful in the promotion of angiogenesis. This treatment is essential for human diseases, in which insufficient angiogenesis is an important factor for progression of pathology. In this context, the most investigated are heart diseases, which require restoration of vasculature. The review articles included to this issue of Current Pharmaceutical Design, summarize recent information from the field of pharmacology of angiogenesis that may be useful for readers working in basic biomedical science and for clinicians to update information about the trends in modern cancer and heart disease therapies.

In the first paper [1], the author summarizes the major approaches that were investigated during a history of angiogenesis research. Targeting vessel growth in developing solid cancers was initially proposed by Judah Folkman in the early seventies of XX century. As a surgeon he observed an increased vascularization ratio of tumor in comparison with adjacent non pathologically affected tissue. Following his ideas, angiogenesis generated a lot of attention in biomedical laboratories around the word, and each year reveals new knowledge about this process including explanation of a basic mechanism, as well as the discovery of new pharmaceutical compounds that positively or negatively regulate neovascularization. The past almost four decades of angiogenesis research definitely proved its importance for tumor growth, and showed that other diseases such as autoimmune are strongly affected by this process. In this paper the author presents all major endogenous regulators of angiogenesis with special attention to the therapy of cancer.

The next outstanding review by Marin et al. [2] is focused on the application of angiostatic therapy on a specific type of brain tumor, glioma. Glioma is considered as one of the most vascularized tumor, and although it does not metastasize out of the primary organ its treatment is extremely difficult resulting in a high mortality of patients. The authors discuss the newest findings in the field of blocking angiogenesis and the application of combination cytotoxic therapy in the most malignant gliomas. The very interesting and logical description of the transition of basic discoveries in laboratories to clinical trails is one of many attributes of this paper. The authors also discuss a very interesting paradigm stating that angiostatic therapy may have also increased the sensitivity of cancer stem cells, which reside in vascular niches. Further studies on the role of endothelial cells on the survival of tumor stem cells may successfully move forward the therapy of glioblastoma.

Another aspect of inhibition of angiogenesis is discussed by Ming et al. [3]. This review is devoted to the pro-inflammatory macrophages and dendritic cell-based angiostatic therapies. These types of cells significantly stimulate or down-regulate angiogenesis in response to inflammatory infiltration of cancer tissue. Authors excellently present the current knowledge about mechanisms that are involved in regulation of angiogenesis by macrophages and dendritic cells not only in pathology related to cancer, but also in other inflammatory-dependent tissue remodeling such as wound healing or adipose. The perspectives in modulation of activity of these cell types in tumor immunotherapy are very promising and may bring a new view and be supportive for traditional cancer treatment.

The involvement of cell signaling molecules in angiostatic cancer therapy is discussed by Castellino et al. [4]. The authors focused on the elements of the PTEN/PI-3 kinase/AKT signaling node as potential targets to modulate pathological vessel growth. This signaling system includes a variety of positive and negative regulators of angiogenesis and it may function as a controller of the angiogenic switch in normal and pathological states. The authors proposed an interesting concept to pulse angiogenic signals within the cell, instead of blocking single cell surface receptors such as VEGFR2. This strategy may be much effective, because a number of pro-angiogenic cell surface molecules are not affected by selective receptor therapy. However, a significant disadvantage of inhibiting downstream signaling pathways is lack of a selectivity among the cells. Therefore, this therapy may be very toxic and affect several systems crucial for the proper functioning of a variety of organs.

The review paper presented by Bloch [5], overviews the current stage of knowledge about the endogenous regulators of angiogenesis processed from molecules of extracellular matrix proteins. A discussion of proteolytic enzymes involved in such degradation and cellular receptors such as integrins is also included. The negative and positive regulation of angiogenesis by fragments of ECM such as endostatin indicates that the physiological release of these macromolecules may be beneficial for protection against diseases that pathologically induce angiogenesis, as well as those that required the recovery of circulation in ischemic tissues. In this context, the author summarizes the effect of exercises on the level of ECM fragments in plasma in correlation with the activation of matrix metalloproteinases and cathepsins. The regulation of angiogenesis by ECM fragments appears to be very clinically promising, but further basic mechanistic studies are necessary. Disappointing clinical trials with endostatin and inhibitors of MMP suggest that this system requires a better understanding on a molecular level.

Although anti-angiogenic approaches in the cancer treatment are broadly discussed for clinical application, therapeutic angiogenesis is also an important issue for recovery of normal circulation. Uchida and Haas [6] provided an interesting review concerning pro-angiogenesis therapies for ischemic muscle. Special attention is directed to the VEGF receptors (VEGFR1 and VEGFR2) and signal transduction induced following ligand/receptor interaction. Stimulation of endothelial cells to induce a neovascularization process is an important issue for recovery of normal circulation in acute or chronic ischemia. The authors describe the existing non invasive therapies such as exercise, as well as pharmacological approaches and gene therapy. The limitations of ongoing treatment are pointed out and the perspective for therapeutic angiogenesis is also discussed.

References

[1] Ribatti D. The Discovery of Antiangiogenic Molecules: A Historical Review. Curr Pharm Des 2009; 15(4): 345-352.

[2] Martin V, Liu D, Gomez-Manzano C. Encountering and Advancing Through Antiangiogenesis Therapy for Gliomas. Curr Pharm Des 2009; 15(4): 353-364.

[3] Dong ZM, Aplin AC, Nicosia RF. Regulation of Angiogenesis by Macrophages, Dendritic Cells, and Circulating Myelomonocytic Cells. Curr Pharm Des 2009; 15(4): 365-379.

[4] Castellino RC, Muh CR, Durden DL. PI-3 Kinase-PTEN Signaling Node: An Intercept Point for the Control of Angiogenesis. Curr Pharm Des 2009; 15(4): 380-388.

[5] Suhr F, Brixius K, Bloch W. Angiogenic and Vascular Modulation by Extracellular Matrix Cleavage Products. Curr Pharm Des 2009; 15(4): 389-410.

[6] Uchida C, Haas TL. Evolving Strategies in Manipulating VEGF/VEGFR Signaling for the Promotion of Angiogenesis in Ischemic Muscle. Curr Pharm Des 2009; 15(4): 411-421.

Cezary Marcinkiewicz
Temple University, CST
Department of Biology
1900 N.12th Street
Philadelphia, PA 19122
USA


[Back to top] [Purchase Article] [PMID: 19199962 PubMed - indexed for MEDLINE]
The Discovery of Antiangiogenic Molecules: A Historical Review
D. Ribatti

In a landmark publication of 1971, Folkman proposed antiangiogenesis as a potential target in cancer biology [1]. Over the past 30 years most research on tumor angiogenesis has been aimed at inhibiting the process of tumor-induced vessel formation. The first angiogenesis inhibitor, bevacizumab, was approved by the Food and Drug Administration in 2004 for the treatment of metastatic carcinoma of the colon-rectum. Antiangiogenesis remains a dynamic and evolving field in oncology. New therapeutic targets continue to emerge followed by the rapid development of new therapeutic agents to be investigated in clinical trials.


[Back to top] [Purchase Article] [PMID: 19199963 PubMed - indexed for MEDLINE]
Encountering and Advancing Through Antiangiogenesis Therapy for Gliomas
V. Martin, D. Liu and C. Gomez-Manzano

Malignant gliomas, the most common subtype of primary brain tumor, are aggressive, highly invasive, and neurologically destructive. First-line treatment of gliomas consists of surgery and radiotherapy, followed by chemotherapy with temozolomide. However, even with this strong regimen, the prognosis of patients with the most malignant variant, glioblastoma multiforme is poor. Because of the lack of effective treatments and the high vascularity that characterizes these tumors, antiangiogenic therapy of gliomas is being studied. This approach is supported by encouraging preclinical data in both in vitro and in vivo models. Clinical studies have shown that these agents do not cause high toxicity; and due to the effect they exert on vessel permeability, patients can avoid the use of corticosteroids and their accompanying adverse. Moreover, in studies of these agents, we have observed improvements in several parameters normally used to measure therapy response. However, whether these parameters are reliable for understanding and measuring the anticancer effect of antiangiogenic molecules is unknown. In addition, resistance to angiogenic therapy is already evident, and in studies performed in animal models, this resistance was associated with the appearance of more invasive phenotypes. These models give us the opportunity to further understand what causes therapy resistance and will allow us to test new combination therapies. Future studies are directed to understand if it is possible to target not only the bulk of the tumor but also the putative tumor niche composed of tumor cells, vessels, and stroma.


[Back to top] [Purchase Article] [PMID: 19199964 PubMed - indexed for MEDLINE]
Regulation of Angiogenesis by Macrophages, Dendritic Cells, and Circulating Myelomonocytic Cells
Z.M. Dong, A.C. Aplin and R.F. Nicosia

Angiogenesis during reactive and pathologic processes is characteristically associated with inflammation. Macrophages and dendritic cells present in the inflammatory infiltrate contribute to the angiogenic process by multiple mechanisms. Macrophages produce a broad array of angiogenic growth factors and cytokines, generate conduits for blood flow through proteolytic mechanisms, and promote the remodeling of arterioles into arteries. They can also inhibit angiogenesis and cause reabsorption of neovessels by inducing endothelial cell death. Dendritic cells can stimulate or inhibit angiogenesis depending on their activation status and subset specificity. Dendritic cells stimulate angiogenesis by secreting angiogenic factors and cytokines, promoting the proangiogenic activity of T lymphocytes, and trans-differentiating into endothelial cells. Inflammatory infiltrates associated with angiogenesis also contain Tie2+, VEGFR2+, and GR1+ myelomonocytic cells which actively regulate the angiogenic process through paracrine mechanisms. In this paper we review our current knowledge of this field and discuss how recent advances have provided the rationale for novel therapeutic approaches against cancer.


[Back to top] [Purchase Article] [PMID: 19199965 PubMed - indexed for MEDLINE]
PI-3 Kinase-PTEN Signaling Node: An Intercept Point for the Control of Angiogenesis
R.C. Castellino, C.R. Muh and D.L. Durden

Angiogenesis is tightly regulated by opposing mechanisms in mammalian cells and is controlled by the angiogenic switch. Other review articles have described a central role for the PTEN/PI-3 kinase/AKT signaling node in the coordinate control of cell division, tumor growth, apoptosis, invasion and cellular metabolism [1, 2]. In this review, we focus on literature that supports the PTEN/PI-3 kinase/AKT signaling node as a major control point for the angiogenic switch in both the on and off positions. We also discuss the rationale for designing small molecule drugs that target the PTEN/PI-3 kinase/AKT signaling node for therapeutic intervention. Our hypothesis is that, instead of inhibiting one cell surface receptor, such as VEGFR2 with bevacizumab (Avastin^®), thereby leaving a significant number of receptors free to pulse angiogenic signals, a more effective strategy may be to regulate signaling through an intercept node where redundant cell surface receptor signals converge to transmit important signaling events within the cell. This therapeutic configuration brings coordinate control over multiple cell surface receptors in concert with a physiologic response which may combine arrest of cell cycle progression with growth inhibition and the induction of genes involved in specialized functions such as movement, which are all required for the complex process of angiogenesis to occur in a temporal-spatial paradigm.


[Back to top] [Purchase Article] [PMID: 19199966 PubMed - indexed for MEDLINE]
Angiogenic and Vascular Modulation by Extracellular Matrix Cleavage Products
F. Suhr, K. Brixius and W. Bloch

In the last fifteen years different extracellular matrix proteins and cleavage products have been identified. These molecules possess the ability to regulate vascular development, repair and function. However, the concept is still inconsistent and only partially understood. In this review, we will focus on angiogenesis regulation by extracellular matrix processing. Therefore, possible regulatory mechanisms in vascular biology controlled by different cleavage products of basement membrane proteins (e.g. endostatin and tumstatin, endorepellin), their activation by proteases and inhibitors, such as matrix metalloproteases (MMPs), cathepsins, tissue inhibitors of MMPs and cystatin, will be reviewed. Up to now there is only limited knowledge about the situations, under which different ECM cleavage products will be released and produced by proteases. Beside vascular growth and the formation of new blood vessels, it is also important to pay attention to the implication of the mentioned proteins in the vascular repair process. Physical exercise and its angio-regulatory potentials have become in the focus in recent years. We will therefore discuss physical exercise and its effects on the mentioned molecules regarding angiogenic inductions. Until today it remains to be clearly stated, which impact might be achieved by matrix cleavage products with respect to the regulation of vascular progenitor cells and their possible therapeutical role in support of vascular repair mechanisms. Furthermore, the current knowledge of the functional role of ECM in the vascular system is highlighted.


[Back to top] [Purchase Article] [PMID: 19199967 PubMed - indexed for MEDLINE]
Evolving Strategies in Manipulating VEGF/VEGFR Signaling for the Promotion of Angiogenesis in Ischemic Muscle
C. Uchida and T.L. Haas

Peripheral artery disease is characterized by reduced blood flow to the lower limb, resulting in chronic ischemia in these muscles, which can lead to eventual amputation of the affected limb. Stimulation of angiogenesis in the ischemic region would be of therapeutic benefit; however, attempts to increase angiogenesis through delivery of vascular endothelial growth factor (VEGF) largely have been unsuccessful. Recent studies have shown that VEGF signaling through its receptors, VEGFR1 and VEGFR2, is much more complex than previously appreciated. This review will examine current research into the function of VEGFR1 and -2 signaling pathways, and evidence of cross-talk between these two receptors. The potential impact of endothelial cell co-stimulation via other growth factors/cell surface receptors (such as angiopoietins and ephrins) on angiogenesis also will be discussed. Evidence suggesting deficiencies in VEGF pathway signaling in individuals with chronic ischemia and diabetes will be discussed. Numerous pro-angiogenic therapies for ischemia have been employed. The successes and limitations of these therapies will be illustrated, emphasizing more recent angiogenesis therapies that focus on activating co-ordinated patterns of pro-angiogenic genes as the most promising direction in the treatment of ischemic muscle tissue in peripheral artery disease.


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Editorial: Treatment of Neuroblastoma: From Cellular to Molecular Therapy

Neuroblastic Tumors is a group of pediatric cancers with a high incidence in the preschool age. Neuroblastic Tumors are classified in several histological categories but neuroblastoma, composed by undifferentiated cell without stromal tissue is the most aggressive disseminated tumor occurring in patients over 18 months of age. Neuroblastoma attracted the attention of scientists since the middle century because metastatic tumor in infants very often regressed while in older patients was very aggressive. In 1973 Biedler and coworkers established cell cultures from human metastatic neuroblastoma tissues and opened a new era in biological and pharmacological study of this cancer. Afterwards several human cell lines were established and transplanted in mice giving the opportunity to study the effect of drug both in vitro and in vivo. Meantime patients were carefully managed and risk of relapse was assessed by age, extension of disease, biological and genomic factors. Furthermore, specimens of primary tumors were accurately stored and biological repositories go a long way towards studying biological and molecular aspects of neuroblastoma.

Although the great advances in tumor biology, patients with metastatic stage 4 disease still have the worst prognosis. From several years the Children’s Oncology Group (COG) and Societé Internationale Oncologie Pédiatrique Européenne Neuroblastoma (SIOPEN) have reduced therapy for children with localized disease in which surgery is the most effective approach to improve patient survival. Risk of patients with localized disease is increased by the presence of MYCN gene amplification in tumor cells and these patients receive chemotherapy. Conversely, high-dose therapy and retinoic acid administered after bone marrow ablation are used for patients with advanced disease.

Unfortunately, about 6% of patients with localized tumors and more than 50% of patients with disseminated aggressive tumor have a disease progression and died. So, new therapeutic approaches are urgently necessary.

Meanwhile, COG and SIOPEN groups are working to define new genetic/biological markers in order to perform a therapy more precise in children with neuroblastoma. Information on the MYCN copy number, the most important oncogene associated with tumor progression in neuroblastoma, has gained central importance in decision- making process concerning patients’ treatment. The absence or presence of MYCN amplification represents frequently the only criterion which prompts clinicians to choose between a ‘wait and see strategy’ or an aggressive cytotoxic treatment.

Recently, the genome wide analysis by high density oligonucleotide Comparative Genomic Hybridzation is used to identify numerical and structural chromosome abnormalities in tumor. This type of analysis allows us to study tumor chromosome profile. Patients are classified in Type 1, 2, 3, …, n according to the severity of tumor chromosome aberrations and the therapy is tailored according to the risk classification.

The present review wants to show some of the most recent studies to improve the cure of neuroblastoma. Louis and Brenner [1] attend to the role of immunotherapy in neuroblastoma by ganglioside GD2 monoclonal and indicate the way for the use of CAR (chimeric antigen receptor) T cell engineering in adaptive cell transfer therapy. Since evasion of apoptosis is one of the main feature of tumor cell, pharmacologically induction of apoptosis is a tool to reduce tumor. Fulda [2] reports a detailed analysis of apoptosis in neuroblastoma cells and the role of Inhibitor of Apoptosis Proteins (IAPs). It is interesting to note that Survivin, a protein whose gene is located at the 17q chromosome very often gained in neuroblastoma, plays a crucial role in apoptosis regulation. Survivin is one of the IAPs interfering with caspase activation. Fulda, also reports that some protopyc molecules such as ABT-263 have been evaluated in Pediatric Preclinical Testing.

Histone deacetylases (HDAC) inhibitors, an emerging field in neuroblastoma has been reported by Witt [3]. Vorinostat was the first HDAC inhibitor used in oncology while several HDAC inhibitors are used in neuroblastoma, in vitro. Valproic acid has been recently used in trial evaluation of young patients with refractory central nervous system tumors by COG.

Scaruffi and coworkers [4] show the use of genome-wide analysis as tool to classify risk of patients who could be treated by advanced therapies. Genome-wide analysis and the use of gene expression signature are now widely accepted to evaluate the risk of patient’s relapse. As mentioned above both COG and SIOPEN studies have introduced the genome-wide analysis to differentiate patients’ treatment.

Finally, Stallings [5] reports the fascinating discovery of microRNA in neuroblastoma and the possibility to control microRNA by antagomir opening a new horizon to cure neuroblastoma.

References

[1] Louis CU, Brenner MK. Cellular immunotherapy for neuroblastoma: A review of current vaccine and adoptive T cell therapeutics. Curr Pham Des 2009; 15(4): 424-429.

[2] Fulda S. Apoptosis pathways and neuroblastoma therapy. Curr Pham Des 2009; 15(4): 430-435.

[3] Witt O, Deubzer HE, Lodrini M, Milde T, Oehme I. Targeting histone deacetylases in neuroblastoma. Curr Pham Des 2009; 15(4): 436-447.

[4] Coco S, Tonini GP, Stigliani S, Scaruffi P. Genome and transcriptome analysis of neuroblastoma from advanced diagnosis to innovative therapy. Curr Pham Des 2009; 15(4): 448-455.

[5] Stallings RL. MicroRNA involvement in the pathogenesis of neuroblastoma: Potential for microRNA mediated therapeutics. Curr Pham Des 2009; 15(4): 456-462.

Gian Paolo Tonini


[Back to top] [Purchase Article] [PMID: 19199969 PubMed - indexed for MEDLINE]
Cellular Immunotherapy for Neuroblastoma: A Review of Current Vaccine and Adoptive T Cell Therapeutics
C.U. Louis and M.K. Brenner

Immunotherapy is an attractive option for patients with high risk neuroblastoma due to their poor long-term survival rates after conventional treatment. Neuroblastoma cells are derived from the embryonic neural crest and therefore express tumor antigens not widely seen in normal cells, making them potential targets for immunologic attack. There is already considerable experience with monoclonal antibodies that target these tumor associated antigens, and in this review we focus on more exploratory approaches, using tumor vaccines and adoptive transfer of tumor-directed T cells.


[Back to top] [Purchase Article] [PMID: 19199970 PubMed - indexed for MEDLINE]
Apoptosis Pathways and Neuroblastoma Therapy
S. Fulda

Evasion of apoptosis, the cell’s intrinsic death program, is a hallmark of human cancers including neuroblastoma. Also, failure to undergo apoptosis may cause treatment resistance, since the cytotoxic activity of anticancer therapies commonly used in the clinic, e.g. chemotherapy, γ-irradiation or immunotherapy, is predominantly mediated by triggering apoptosis in tumor cells. Therefore, a better understanding of the signaling pathways and molecules that govern apoptosis in neuroblastoma cells is expected to open new avenues for the design of molecular targeted therapies for neuroblastoma.


[Back to top] [Purchase Article] [PMID: 19199971 PubMed - indexed for MEDLINE]
Targeting Histone Deacetylases in Neuroblastoma
O. Witt, H.E. Deubzer, M. Lodrini, T. Milde and I. Oehme

Histone deacetylases (HDACs) are an emerging class of novel anti-cancer drug targets. Recently, studies in adult cancers and in neuroblastoma have shown that individual HDAC family members are aberrantly expressed in tumors and correlate with disease stage and prognosis. In neuroblastoma, knockdown of individual HDAC family members causes distinct phenotypes ranging from differentiation to apoptosis. HDACs are involved in controlling MYCN function and are upregulated in chemotherapy-resistant neuroblastoma cells. Treatment with unselective pan-HDAC inhibitors causes cell cycle arrest, differentiation, apoptosis, and inhibition of clonogenic growth of neuroblastoma cells, and restores susceptibility to chemotherapy treatment. The molecular mechanisms mediating the anti-cancer effects of HDAC inhibitors on neuroblastoma cells are incompletely understood and involve targeting of aberrant epigenetic repression of tumor suppressor genes, activation of developmental differentiation pathways, as well as changing the acetylation level and function of non-histone proteins. In neuroblastoma mouse models, unselective HDAC inhibitors demonstrate anti-tumoral effects. First phase I clinical trials in children with refractory cancers using HDAC inhibitors depsipeptide and the recently approved vorinostat are underway. This review summarizes our current knowledge about classical HDAC family members as novel drug targets for neuroblastoma therapy and discusses the potential role of next generation, selective HDAC inhibitors.


[Back to top] [Purchase Article] [PMID: 19199972 PubMed - indexed for MEDLINE]
Genome and Transcriptome Analysis of Neuroblastoma from Advanced Diagnosis to Innovative Therapy
S. Coco, G.P. Tonini, S. Stigliani and P. Scaruffi

Neuroblastoma is an extracranial solid tumor which occurs in infants and young children and accounts for 8% of pediatric cancers. It origins from neural crest cells of the sympathetic nervous system. Disease-free survival ranges from 95% for localized tumors to 30% for metastatic disease in children over 1 year of age and patients’ outcome depends on dissemination and tissue histology. Despite the most recent therapies, the overall survival for high risk patients is still low and the outcome is invariably fatal. Improvement of neuroblastoma treatment is one of the highest priorities in pediatric oncology and a major challenge to clinicians and researchers. Understanding the biology and genetics of pediatric malignancies will be the key to identify molecular targets for innovative treatments as well as to individual management of disease.

The success of human genome project and recent advances in technology have provided new tools to investigate cancer cells and to discover new tumor-associated genes. High-throughput efforts include array-based comparative genomic hybridization, single-nucleotide polymorphism arrays and expression microarrays. Here we present an overview on the most recent advances in wide-genome analysis of neuroblastoma. We also focus on the potential clinical application of genome and transcriptome information to the diagnosis, prognosis and neuroblastoma therapy.


[Back to top] [Purchase Article] [PMID: 19199973 PubMed - indexed for MEDLINE]
MicroRNA Involvement in the Pathogenesis of Neuroblastoma: Potential for MicroRNA Mediated Therapeutics
R.L. Stallings

Neuroblastoma arises from precursor cells of the sympathetic nervous system and presently accounts for 15% of all childhood cancer deaths. These tumors display remarkable heterogeneity in clinical behavior, ranging from spontaneous regression to rapid progression and resistance to therapy. The clinical behavior of these tumors is associated with many factors, including patient age, histopathology and genetic abnormalities such as MYCN amplification. More recently, the dysregulation of some miRNAs, including the miR-17-5p-92 cluster and miR-34a, has been implicated in the pathobiology of neuroblastoma. MiR-17-5p-92 family members act in an oncogenic manner while miR-34a has tumor suppressor functions. The evidence for the contribution of miRNAs in the aggressive neuroblastoma phenotype is reviewed in this article, along with exciting possibilities for miRNA mediated therapeutics.