Scientists close in on method to fight deadly childhood cancer

October 16, 2008

GAINESVILLE, Fla. - A multicenter team of researchers, including scientists from the University of Florida, has discovered a way to potentially block the growth of neuroblastoma, a type of cancer responsible for 15 percent of all cancer deaths in children.

Working with human cell lines and tissue samples, researchers describe in Thursday's (Oct. 16, 2008) online issue of Nature how they were able to short-circuit genetic processes that apparently contribute to neuroblastomas - tumors that arise from the developing nervous system in children and often appear in the abdomen, chest or neck.

Concentrating on a gene known as ALK, the scientists used a small-molecule inhibitor - a technique common to many drugs - to block abnormalities that apparently cause neuroblastomas.

Neuroblastomas are extremely rare, appearing in about 600 patients annually in the United States, according to the National Institutes of Health. About half of the patients with neuroblastoma are diagnosed before the age of 18 months. In 40 percent of cases, the cancer has spread to other parts of the body by the time doctors discover it.

Treatment usually involves surgery, chemotherapy and radiation, and transplantation for high-risk patients.

"We need to find a home run for these kids," said Wendy B. London, Ph.D., a research associate professor of epidemiology, biostatistics and health policy research at the UF College of Medicine and a member of the UF Shands Cancer Center. "A targeted therapy to treat patients with ALK mutations would be a real breakthrough."

Led by Dana-Farber Cancer Institute researchers Rani E. George, M.D., Ph.D., an assistant professor of pediatrics at Harvard Medical School, and A. Thomas Look, M.D., a professor of pediatrics at Harvard, the scientists analyzed the ALK gene in 94 tumors representative of general neuroblastomas and 30 neuroblastoma cell lines.

Scientists discovered that ALK abnormalities in a subset of neuroblastoma cells appear to interfere with the natural cell-death processes. Furthermore, they found some of the ALK mutations were sensitive to a tiny organic molecule known as TAE684, a discovery that may be useful in efforts to create drugs to staunch cancer growth.

In addition, researchers used gene-transfer techniques to initiate ALK-related cancer in rodent cells. These transduced neuroblastomas also appear vulnerable to the small molecule, known as an ALK inhibitor.

The tumor samples were obtained from the Children's Oncology Group Neuroblastoma Tumor Bank. COG is a NIH/National Cancer Institute cooperative research coalition that conducts pediatric cancer clinical and biological trials, including specimen collection and statistical analyses. The University of Florida is one of three sites of the COG Statistics and Data Center, where the study design, data collection and statistical analyses of the data take place.

The current findings dovetail with the recent discovery of the role of ALK mutations in both inherited and non-inherited versions of neuroblastoma published by researchers from The Children's Hospital of Philadelphia on Aug. 24 in Nature.

"This research group looked at neuroblastoma in a totally different and complementary way to ours and came up with similar results, validating the role of ALK mutations," said pediatric oncologist Yael P. Mosse, M.D., of The Children's Hospital of Philadelphia. "A unique aspect of their work is they proved in a model system that these mutations can indeed be cancer-causing."

With samples they had collected from families for the past 15 years, as well as additional data from the COG, Children's Hospital of Philadelphia scientists traced the genetic roots of many neuroblastomas to ALK mutations - findings that open the door to genetic screenings for the disease as well as possible therapies.

Ultimately, researchers hope drug treatments can be developed to disrupt the cancer cell-signaling process. They are designing a clinical trial that would test small molecules against the cancer-causing mutations in the gene.

"This is the epitome of translational research," said London, who is also the principal investigator of the COG Statistics and Data Center at UF. "We will use what we have learned about the sensitivity of ALK mutations to an ALK inhibitor and attempt to translate this knowledge to the development of targeted therapy for treatment of neuroblastoma patients in the clinic."

University of Florida

Neuroblastoma
by Nai-Kong V. Cheung (Editor), Susan L. Cohn (Editor)

Neuroblastoma is a medical enigma. As a childhood neoplasm arising from neural crest cells, it is characterized by diverse clinical behaviors ranging from spontaneous remission to rapid tumor progression and death. Although clinical outcome can be predicted to a large extent by the stage of disease and the age at diagnosis, an in-depth understanding of its clinico-pathological behavior, now greatly aided by sophisticated molecular genetic profiling, will improve diagnostic precision and refine risk-based therapies. Comprehensive international efforts have advanced our understanding of tumor biology and improved the clinical management of children with neuroblastoma. This book reviews our current understanding of the genes and biological pathways that contribute to neuroblastoma...

Neuroblastoma (Pediatric Cancer: Diagnosis, Therapy, and Prognosis, Vol. 1)
by M.A. Hayat (Editor)

Introduction of new technologies and their applications to neuroblastoma diagnosis, treatment, and therapy assessment are explained. Role of molecular ghenetics in diagnosis and therapy for neuroblastoma patients is detailed. Molecular detection of minimal residual neuroblastoma is described. Magnetic resonance imaging and spectroscopy are detailed for diagnosing this solid, extracranial cancer. Targets for therapeutic intervention in neuroblastoma are identified, including targeting multidrug resistance in this cancer. Ornithine decarboxylase and polyamines are novel targets for therapeutic intervention. The effectiveness of chemotherapy with oral irinotecan and temozolomide is explained. The role of transcription factors (GATA) in neuroblastoma pregression is also included.

Olfactory neuroblastoma.(PATHOLOGY CLINIC)(Disease/Disorder overview): An article from: Ear, Nose and Throat Journal
by Lester D.R. Thompson (Author)

This digital document is an article from Ear, Nose and Throat Journal, published by Thomson Gale on September 1, 2006. The length of the article is 798 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser.

Citation Details
Title: Olfactory neuroblastoma.(PATHOLOGY CLINIC)(Disease/Disorder overview)
Author: Lester D.R. Thompson
Publication: Ear, Nose and Throat Journal (Magazine/Journal)
Date: September 1, 2006
Publisher: Thomson Gale
Volume: 85 Issue: 9 Page: 569(2)

Article Type: Disease/Disorder overview

Distributed by Thomson...

Advances Neuroblastoma Res (Progress in cancer research and therapy)
by Evans (Author)

The Official Parent's Sourcebook on Neuroblastoma: A Revised and Updated Directory for the Internet Age
by Icon Health Publications (Author)

This sourcebook has been created for parents who have decided to make education and Internet-based research an integral part of the treatment process. Although it gives information useful to doctors, caregivers and other health professionals, it also tells parents where and how to look for information covering virtually all topics related to neuroblastoma, from the essentials to the most advanced areas of research. The title of this book includes the word official. This reflects the fact that the sourcebook draws from public, academic, government, and peer-reviewed research. Selected readings from various agencies are reproduced to give you some of the latest official information available to date on neuroblastoma. Following an introductory chapter, the sourcebook is organized into three...

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Neuroblastoma is the single most common solid tumor of childhood. Although children with small primary neuroblastomas alone are almost always cured by surgery, 65% of children with neuroblastoma already have large bulky tumors or metastatic disease by the time of initial diagnosis. For these children, the 5-year survival rate is only somewhere between 5% and 20% with therapies including surgery, radiation, chemotherapy, and bone marrow transplantation. Dr Schor outlines a new approach to these tumors in order to make a difference for these children. There is much information to support the notion that neuroblastomas represent a developmental aberration of the nervous system, rather than a de novo abnormality in a previously normal cell. While the remote, paraneoplastic effects of...

Advances in neuroblastoma research: Proceedings of the Third Symposium on Advances in Neuroblastoma Research held in the Children's Hospital of ... in clinical and biological research)
by Liss (Publisher)

The Epidemiology of Neuroblastoma
by Stefano Parodi (Author), Riccardo Haupt (Author)

Neuroblastoma is a cancer of the sympathetic nervous system. It is the most common tumor in the first year of life and the most common solid extra-cranial cancer in childhood. Neuroblastoma represents an enigmatic disease, in that some cases, especially in infants, tend to spontaneously regress, even in advanced states, while many patients are refractary to any therapeutical approach and show an inexorable clinical course. As most of the other solid cancers in children, the distribution of Neuroblastoma risk worldwide is only partly known. In Western countries, its incidence varies between 7 and 16 cases per million children and it tends to decrease increasing the age.Besides, survival of patients affected by such disease, in relation with clinical and biological characteristics, have...

Cancer in the First Year of Life: Leukemias, Neuroblastomas, Soft Tissue Sarcomas (Contributions to Oncology)
by Germany) Italo-German Workshop on Pediatric Oncology 1989 (Braunfels (Author), L. Cordero Di Montezemolo (Author), A. Pession (Author), Fritz Lampert (Author), Fritz Lampert (Contributor)

Neuroblastomas: Webster's Timeline History, 1949 - 2007
by Icon Group International (Author)

Webster's bibliographic and event-based timelines are comprehensive in scope, covering virtually all topics, geographic locations and people. They do so from a linguistic point of view, and in the case of this book, the focus is on "Neuroblastomas," including when used in literature (e.g. all authors that might have Neuroblastomas in their name). As such, this book represents the largest compilation of timeline events associated with Neuroblastomas when it is used in proper noun form. Webster's timelines cover bibliographic citations, patented inventions, as well as non-conventional and alternative meanings which capture ambiguities in usage. These furthermore cover all parts of speech (possessive, institutional usage, geographic usage) and contexts, including pop culture, the arts,...