Experiments could lead to new treatments for neuroblastoma

August 18, 2008

Deadly cancer primarily strikes infants, kills more than 50 percent of victims

GALVESTON, Texas - Neuroblastoma is one of the most devastating diagnoses a child can receive. The cancer's victims average 2 years old when the disease is detected, most often by a parent feeling a lump in a child's abdomen. By then, the disease has often reached an advanced stage, and advanced neuroblastoma kills more than 50 percent of the children in whom it develops, despite aggressive treatment with surgery, chemotherapy and radiation.

Now, though, University of Texas Medical Branch at Galveston researchers believe they've found a critical weakness in the deadly cancer - one that could lead to the development of a lifesaving therapy. In a paper published this week in the "Proceedings of the National Academy of Sciences," a team led by associate professor of surgery Dr. Dai H. Chung describes cell-culture and animal experiments that demonstrate how shutting down a single biochemical signaling connection dramatically suppresses neuroblastoma tumor formation and slows the cancer's spread.

Their investigation centered on an intercellular signaling molecule known as gastrin-releasing peptide, or GRP, and the receptor molecule with which it docks on the cell's surface. GRP activates the production of gastrin, a hormone that among other things controls the release of gastric acid in the stomach; GRP is also produced by neuroblastoma cells and acts to accelerate their proliferation, a discovery made earlier by the UTMB group.

"We had previously demonstrated that GRP stimulates the growth of this particular cancer," said Chung. "This time we wanted to demonstrate the opposite effects by targeting GRP receptors in neuroblastoma, to see if we could make the cancer regress."

To "target" GRP, the researchers took a line of aggressive human neuroblastoma cells and added short-hairpin RNAs, tiny bits of genetic material specifically designed to keep cells from making particular proteins - in this case GRP receptor molecules. Experiments with the GRP-receptor-silenced human neuroblastoma cells revealed that they grew much less quickly than unaltered neuroblastoma cells, and showed less activity on a biochemical signaling pathway that is associated with abnormal cell proliferation.

The scientists then cultured the customized cells in soft agar, a gelatin-like material that gave them no surface to which they could attach themselves. Most cells need be solidly anchored to multiply and form colonies, but neuroblastoma cells (like other cancer cells) thrive in soft agar suspension

"In order for cells in a soft agar colony to proliferate and grow without adhering to a surface, they have to possess malignant properties, as in the original neuroblastoma cells," Chung said. "However, our GRP receptor-silenced neuroblastoma cells behaved like nonmalignant cells - their growth was significantly inhibited, and they formed fewer new colonies."

To further test what effect blocking GRP/GRP receptor binding would have on neuroblastoma in experimental animals, the researchers injected their GRP receptor-silenced neuroblastoma cells into immune-deficient mice. "We wanted to see how these neuroblastoma cells would behave, whether they would grow and/or metastasize to the liver," Chung said. "But instead, tumor growth was significantly attenuated." In control group mice, by contrast, "the cancer cells that expressed the GRP receptors behaved as we expected with rapid growth as well as aggressive liver metastases. The implication is that the metastatic behavior of this cancer is driven by GRP and its receptor."

Although researchers are discussing the use of short-hairpin RNA and other RNA interference techniques as potential therapies for patients with neuroblastoma and other cancers, Chung said, a compound that blocks the GRP receptor has already been approved by the FDA for adult use.

"With the publication of our data, we would like to propose an application involving a number of institutions to move forward with a phase 1 clinical trial using this FDA-approved GRP receptor antagonist for neuroblastoma," Chung said. "We hope to demonstrate the safety of targeting GRP receptors for effective inhibition of neuroblastoma growth and metastasis. This is just such a tragic disease, and with all the advances we're making, we ought to be able to make a dent in it."

University of Texas Medical Branch at Galveston

---

---

	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...
	The Neurology of Neuroblastoma: Neuroblastoma as a Neurobiological Disease by Nina Felice Schor (Author) 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,...