Chromosome 6p22 Locus Associated with Clinically Aggressive NeuroblastomaMaris

Chromosome 6p22 Locus Associated with Clinically Aggressive NeuroblastomaMaris J. M., Mosse Y. P., Bradfield J. P., Hou C., Monni S., Scott R. H., Asgharzadeh S., Attiyeh E. F., Diskin S. J., Laudenslager M., Winter C., Cole K. A., Glessner J. T., Kim C., Frackelton E. C., Casalunovo T., Eckert A. W., Capasso M., Rappaport E. F., McConville C., London W. B., Seeger R. C., Rahman N., Devoto M., Grant S. F.A., Li H., Hakonarson H. Abstract FREE Full Text PDF N Engl J Med 2008; published at www.nejm.org on May 7, 2008 (10.1056/NEJMoa0708698).

ABSTRACT

Background Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known.
Methods We performed a genomewide association study by first genotyping blood DNA samples from 1032 patients with neuroblastoma and 2043 control subjects of European descent using the Illumina HumanHap550 BeadChip. Samples from three independent groups of patients with neuroblastoma (a total of 720 patients) and 2128 control subjects were then genotyped to replicate significant associations.
Results We observed a significant association between neuroblastoma and the common minor alleles of three consecutive single-nucleotide polymorphisms (SNPs) at chromosome band 6p22 and containing the predicted genes FLJ22536 and FLJ44180 (P=1.71x10–9 to 7.01x10–10; allelic odds ratio, 1.39 to 1.40). Homozygosity for the at-risk G allele of the most significantly associated SNP, rs6939340, resulted in an increased likelihood of the development of neuroblastoma (odds ratio, 1.97; 95% confidence interval, 1.58 to 2.45). Subsequent genotyping of the three 6p22 SNPs in three independent case series confirmed our observation of an association (P=9.33x10–15 at rs6939340 for joint analysis). Patients with neuroblastoma who were homozygous for the risk alleles at 6p22 were more likely to have metastatic (stage 4) disease (P=0.02), amplification of the MYCN oncogene in the tumor cells (P=0.006), and disease relapse (P=0.01).

Conclusions A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.

Source: http://content.nejm.org/cgi/reprint/NEJMoa0708698v2.pdf

Lytic Bone Lesions in Human Neuroblastoma Xenograft Involve Osteoclast Recruitment and Are Inhibited by Bisphosphonate

Yasuyoshi Sohara, Hiroyuki Shimada, Miriam Scadeng, Harvey Pollack, Shinya Yamada, Wei Ye,
C. Patrick Reynolds, and Yves A. DeClerck2

Abstract
Neuroblastoma is the second most common solid tumor in childhood and frequently metastasizes to the bone marrow and the bone matrix. The mechanism involved in bone metastasis and destruction in neuroblastoma is poorly understood. Using a model of bone invasion in immunodeficient mice, we demonstrated that neuroblastoma cells recruited osteoclasts to generate osteolytic lesions and invade the bone matrix. In further support of a contributory role for osteoclasts in neuroblastoma bone invasion, we demonstrated that treatment with the bisphosphonate compound, ibandronate, significantly delayed the progression of osteolytic lesions. The data suggest that bisphosphonates may be clinically effective in the treatment of bone metastases in neuroblastoma.

Source: http://cancerres.aacrjournals.org/cgi/reprint/63/12/3026.pdf

Curcumin induces apoptosis in human neuroblastoma cells via inhibition of NFkappaB.

Institut für Anatomie II: Experimentelle Morphologie, Universitätsklinikum Hamburg-Eppendorf 20246 Hamburg, Germany. c.freudlsperger@uke.uni-hamburg.de 2008 Jan-Feb;28(1A):209-14. Anticancer Res

BACKGROUND: Metastasised neuroblastoma is a largely incurable neoplasia in children over one year of age using current treatment protocols. After dissemination to the bone, the survival rate is <7%,>

MATERIALS AND METHODS: Proliferation of neuroblastoma cell lines Lan-5, SK-N-SH and Kelly under the treatment of curcumin over a broad concentration range (1 x 10(-5) to 1 x 10(2) microM) was assessed using XTT cell proliferation assays. Possible induction of apoptosis through curcumin treatment was assessed by detection of DNA fragmentation. To investigate the effect of curcumin on NFkappaB activation, the protein levels of the NFkappaB subunit p65 of curcumin-treated cells were compared to untreated cells using Western blots.

RESULTS: Curcumin showed a significant dose-dependent antiproliferative effect on all three neuroblastoma cell lines starting at a concentration of 1 x 10(-3) microM. The highest concentration of 1 x 10(2) microM significantly reduced the viable cell count to 8-48% depending on the cell line. This antiproliferative effect was mediated through an increased induction of apoptosis by inhibition of NFkappaB, corroborating earlier findings indicating an antiapoptotic effect of NFkappaB.

CONCLUSION: Our results suggest that curcumin might hold promise in the treatment of patients suffering from neuroblastoma

Source: Meryl Witmer [meryl@EAGLECAPITAL.NET]; The Neuroblastoma (Cancer) Online Support Group [N-BLASTOMA@LISTSERV.ACOR.ORG];
Date: Sat 4/5/2008 8:01 AM

Tumor-targeting viral therapy slows neuroblastoma, malignant peripheral nerve sheath tumors

Public release date: 15-Feb-2008[

Contact: Nick Miller 513-803-6035 Cincinnati Children's Hospital Medical Center
Tumor-targeting viral therapy slows neuroblastoma, malignant peripheral nerve sheath tumors

Study led by Cincinnati Children's suggests innovative therapy for hard-to-treat solid tumors
CINCINNATI –Researchers in a multi-institutional study led by Cincinnati Children’s Hospital Medical Center slowed the growth of two particularly stubborn solid tumor cancers – neuroblastoma and peripheral nerve sheath tumors –without harming healthy tissues by inserting instructions to inhibit tissue growth into an engineered virus, according to study results published in the February 15 Cancer Research.
“Malignant solid tumors are still very difficult to treat effectively, especially without causing harm to normal tissues, so we need to find innovative therapeutic approaches,” said Timothy Cripe, M.D., Ph.D., a physician and researcher at Cincinnati Children’s. “In our study, this tumor-targeting viral therapy enhanced anti-tumor activity by stimulating multiple biological processes, including directly killing the cancer cells and reducing the formation of blood vessels that fed the tumors. These data support continuing development and study of our tumor-targeted viral therapy to fight cancer.”
Previous research has documented that oncolytic herpes simplex virus (oHSV) and similar viruses can infect and kill human cancer cells without harming normal, healthy cells or causing disease. In their study, Dr. Cripe and his colleagues genetically armed oHSV with a gene that carries instructions for a cancer-fighting protein, human tissue inhibitor of metalloproteinase 3 (TIMP3). TIMP3 blocks enzymes that aid the development and progression of cancer, called matrix of metalloproteinases (MMP). Specifically, MMPs help break down molecules that are important for the structural support and normal development of cells, organs and maintenance of tissues. When MMP activity becomes unbalanced, the enzyme plays a well-documented role in the formation of invasive and metastatic cancers, including pediatric neuroblastoma, the most common solid cancer tumor in childhood.
Researchers dubbed the tumor-targeted viral therapy created by combining of TIMP and oHSV as rQT3. In laboratory studies involving human cancer cells and mice designed to develop neuroblastoma or peripheral nerve sheath tumors, rQT3 reduced new blood vessel development and increased toxicity to both kinds of tumor cells. In addition, rQT3 treatment resulted in longer life spans in mice compared to mouse models receiving just saline or other treatments.
Dr. Cripe said the researchers also discovered that rQT3 reduced the number of circulating endothelial progenitors (CEP). CEPs are derived from blood marrow and circulate in the blood. They have the ability to become cells that line blood vessels to promote blood flow.
“Our findings suggest that therapeutic viruses can act systemically by limiting the mobilization and recruitment of bone-barrow derived progenitors, both CEPs and others, that contribute to the tumor microenvironment and growth, resulting in the restriction of new blood vessel growth that can feed tumors,” Dr. Cripe said.
Neuroblastoma is a solid tumor cancer that begins in the sympathetic nervous system and most often strikes children younger than 5 years old. For children younger than 2, or those with a single mass tumor, the combination of surgery and chemotherapy has led to cure rates of 90 to 95 percent. In older children or those with metastatic disease, neuroblastoma is a much harder to fight. Tumor cells are often able to survive ordinary doses of chemotherapy and radiation, leading to relapses that are difficult to cure. During the last three decades, Cincinnati Children’s has been a leader in developing high-dose chemotherapy used in combination with bone marrow transplants and other drug treatments to help improve outcomes for patients with high-risk neuroblastoma. Malignant peripheral nerve sheath tumors are cancers affecting the connective tissue surrounding nerves. The first-line treatment is surgical removal with chemotherapy or radiotherapy used as auxiliary therapies.
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The study included the University of Cincinnati College of Medicine and the Dardinger Laboratory for Neuro-Oncology and Neurosciences/Department of Neurological Surgery and Comprehensive Cancer Center at Ohio State University. Other researchers in the study include, Yonatan Y. Mahller, Sachin S. Vaikunth, Maria C. Ripberger, William H. Baird, Yoshinaga Saeki, Jose A. Cancelas and Timothy M. Crombleholme. Funding support came from the National Institutes of Health and Cincinnati Children’s Division of Hematology/Oncology.
Cincinnati Children's, one of the top five children's hospitals in the nation according to Child magazine, is a 475-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to providing care that is timely, efficient, effective, family-centered, equitable and safe. For its efforts to transform the way health care is provided, Cincinnati Children's received the 2006 American Hospital Association-McKesson Quest for Quality Prize®. Cincinnati Children's ranks second nationally among all pediatric centers in research grants from the National Institutes of Health and is a teaching affiliate of the University of Cincinnati College of Medicine. The Cincinnati Children's vision is to be the leader in improving child health.

SOURCE: http://www.eurekalert.org/pub_releases/2008-02/cchm-tvt021208.php

Serum Neuron-Specific Enolase as a Marker Useful for Monitoring the Effectiveness of Therapy in Patients with Neuroblastoma

Serum Neuron-Specific Enolase as a Marker Useful for Monitoring the Effectiveness of Therapy in Patients with Neuroblastoma as Compared with Urinary Catecholamine Metabolites

KUMIKO HASHIMOTO1), YOH-ICHI GOTOH1) and KEIYA TADA1)

1) Department of Pediatrics, Tohoku University School of Medicine


HASHIMOTO, K., GOTOH, Y. and TADA, K. Serum Neuron-Specific Enolase as a Marker Useful for Monitoring the Effectiveness of Therapy in Patients with Neuroblastoma-as Compared with Urinary Catecholamine Metabolites. Tohoku J. exp. Med., 1986, 149 (1), 25-30-Neuron-specific enolase (NSE) in sera of 3 patients with neuroblastoma (Stage IV) were measured by radioimmunoassay, as compared with urinary catecholamine metabolites (vanillyl-mandelic acid (VMA) and homovanillic acid (HVA)) during the course of chemotherapy, radiation, and second look operation. In Case 1(Stage IV B) and Case 3 (Stage IV A), NSE level on admission was found to be elevated to 51.0ng/ml and 25.5ng/ml, respectively. VMA and HVA were also elevated. In Case 2 (Stage IV A), NSE on admission was elevated to 128.0ng/ml., HVA was high, but VMA was within normal range. From 1 to 3 weeks after chemotherapy and radiation, high levels of urinary VMA and/or HVA in patients promptly decreased within normal range. The size of primary tumor masses either showed no marked change or slightly decreased by radiological examinations. After intensive chemotherapy, high levels of serum NSE decreased within normal range. At that time, second look operations were carried out. The size of primary tumors was reduced (3.6×2.7×2.1cm in average) and almost all masses had scarred over. These data suggest that serum NSE levels correlate very well with residual tumor burdens.


Download Paper:
http://www.journalarchive.jst.go.jp/jnlpdf.php?cdjournal=tjem1920&cdvol=149&noissue=1&startpage=25&lang=en&from=jnlabstract

Children's Cancer Institute Australia for Medical Research, "Scientists find cancer causing protein", Tuesday, 13 November 2007

A team of researchers have discovered a completely new pathway in which a cell protein causes two common forms of cancer, neuroblastoma and breast cancer.
In neuroblastoma, the most common tumour of infants, and breast cancer, levels of the Myc proteins are commonly elevated in tumour cells. High levels of the protein are also associated with poor treatment outcomes. However, the way in which these proteins cause cancer has remained unknown.
For the first time, researchers at Children’s Cancer Institute Australia for Medical Research (CCIA), and collaborators in Italy, describe how the Myc proteins lead to tumour formation.
"Our results show that Myc proteins cause cancer by switching off genes involved in cancer prevention, such as transglutaminase 2 (TG2)," says Professor Glenn Marshall, Head of CCIA’s Molecular Carcinogenesis Program and Director of the Centre for Children’s Cancer and Blood Disorders at Sydney Children's Hospital.
"In addition to this, we have also shown that when the neuroblastoma and breast cancer cells are treated with a new class of anti-cancer drugs called histone deacetylase inhibitors (HDACIs), they are able to turn the TG2 gene back on, which then inhibits tumour growth."
The results, which will be published in the prestigious Proceedings of the National Academy of Science USA journal, describe in detail the complex interaction between the Myc protein, TG2 gene and HDACI drug within tumour cells.
"This work highlights the importance of HDACIs for the treatment of cancers caused by the high levels of Myc proteins," says Professor Marshall.
"More importantly, we identify TG2 as a potential drug development target for the treatment of these cancers.
"We believe that TG2 mimetics, combined with HDACIs in cancer therapy, will have potent anticancer effects in cells driven by Myc proteins."

Source: Ellen, Sat 3/29/2008 9:01 PM, The Neuroblastoma (Cancer) Online Support Group Mailing List[N-BLASTOMA@LISTSERV.ACOR.ORG]

Anti-GD2 monoclonal antibody immunotherapy: a promising strategy in the prevention of neuroblastoma relapse

In spite of the satisfactory frequency of clinical response to first-line therapy in neuroblastoma (NB), complete eradication of NB cells is rarely achieved. As a consequence, the majority of patients with advanced stage NB undergo relapse, which is often resistant to conventional treatment and rapidly overwhelming. Thus, after induction of the apparent remission, new therapeutic strategies are needed to completely eradicate the small number of surviving NB cells and to prevent relapse. We explored the potential of different doses of the anti-GD2 monoclonal antibody (mAb) 14G2a in an experimental metastatic model where a limited number of HTLA-230 human NB cells are injected i.v. into nude mice, leading to extensive metastases and death of animals within 7–8 weeks. Treatment with 14G2a mAb (1–4 mg/kg cumulative dose given as five i.v. daily administrations) dramatically reduced the metastatic spread of NB cells and prolonged the long-term survival of treated mice in a dose-dependent manner. Neither macrophages nor NK cells appeared to contribute to the protective effect of antibody treatment in vivo, suggesting either an involvement of granulocytes or a complement-mediated cytotoxicity towards NB cells. Whatever the effecting mechanism(s) involved, these results strongly support the clinical use of anti-GD2 mAbs after first-line induction regimens.

Reference: Anti-GD2 monoclonal antibody immunotherapy: a promising strategy in the prevention of neuroblastoma relapse