A cancer which claims the lives of thousands of children worldwide every year is a step closer to being cured thanks to a breakthrough by scientists at Newcastle University.
New research, published in the current edition of the American publication Clinical Cancer Research, could offer hope to parents whose children suffer relapses after being treated for neuroblastoma.
Neuroblastoma, a cancer mainly affecting children under the age of 5 years, arises from the sympathetic nervous system and can occur anywhere from the neck to the groin but is commonest in the abdomen.
It is the second biggest cancer killer of children in the world and it remains one of the most difficult childhood cancers to cure.
Every year in the UK 100 children will develop the disease and of those about half are in the high risk category.
High risk neuroblastomas have spread to distant sites when discovered in children over a year or 18 months of age, or have unfavourable genetics.
While most neuroblastomas initially respond to treatment, relapsed high risk neuroblastoma is very difficult to cure and in the UK about 30 children die every year from the disease.
But it is hoped the new discovery, which has identified abnormalities in a particular gene called p53, may be one reason why relapses are so hard to cure.
Pp53 is a tumor suppressor gene which activates cell death or stops cells reproducing after DNA damage, including that from cancer chemotherapy.
Abnormalities of the p53 gene pathway were detected in almost 1/2 of the 41 cases of relapsed neuroblastoma that were studied.
Experts hope they will now be able to develop new types of therapies that target the rogue gene which prevents the resurgent cancer being successfully treated.
Dr Deborah Tweddle, Clinical Senior Lecturer at the Northern Institute for Cancer Research at Newcastle University and Honorary Consultant Pediatric Oncologist at Newcastle upon Tyne Hospitals NHS Trust, who led the research, said: “Over half of all children who get high risk neuroblastoma will relapse and the chances of surviving a relapse are at present very small.
“This research is one of the first to investigate the cause of relapsed neuroblastoma and finding this link is an important breakthrough in developing new treatments”.
“We are currently developing drugs that reactivate the p53 gene at Newcastle University and elsewhere these types of drugs are now going into clinical trials and may help patients with neuroblastoma”.
“By understanding more about the biology of neuroblastoma at relapse we may be able to prevent it and reduce the deaths of many young children, with its devastating effect on families.
”The funding for this project came from a National Institute for Health Research Clinician Scientist Fellowship to Dr Tweddle with additional running costs from the North of England Children’s Cancer Research Fund.
Source: Newcastle University
Neuroblastoma, a malignant tumor that primarily affects infants and young children, is a leading cause of death for children with cancer. When amplification of the MYCN oncogene is found in the tumor, it usually indicates an aggressive tumor with rapid progression of the disease and a poor outcome. Thus MYCN amplification has come to be used as a prognostic indicator.
However, sometimes a favorable outcome can be achieved even if MYCN amplification is present. A study reported in the current issue of the journal Pediatric and Developmental Pathology focuses on four such cases.
Four patients were diagnosed with neuroblastoma between the ages of 6 and 13 months and were treated with high-dose therapy and autologous stem cell rescue. Three of the patients are alive and well, having survived from 19 months to 7 years following treatment. One patient, with stage 4 disease, died eight months after being diagnosed.
Although MYCN amplification was confirmed in all four patients, it was not expressed in some of the common ways. Fluorescence in situ hybridization was used to identify the gene amplification in these cases. MYCN protein expression was not detected through immunohistochemistry.
Tumors with MYCN amplification typically have an undifferentiated or poorly differentiated subtype with a high mitosis-karyorrhexis index. Large cell type and presence of prominent nucleoli also characterize MYCN amplification and indicate aggressive behavior of the tumor. In the four cases examined in this study, the tumors all showed a poorly differentiated subtype and a low mitosis-karyorrhexis index. They also did not qualify as a large cell type and lacked prominent nucleoli.
These cases display a unique combination of unfavorable and favorable prognostic indicators for neuroblastoma. The authors speculate that a lack of excess MYCN protein expression despite gene amplification could cause this rare genotype-phenotype discordance. The findings could indicate that MYCN amplification does not automatically mean a poor prognosis.
In a newly published study, Swedish and American scientists show how the Omega-3 fatty acid DHA can serve as both sword and shield in the fight against certain forms of cancer. The new findings on the mechanisms behind this two-sided effect give hope of one day using DHA as a complement to cytostatics in the treatment of children with neural cancer.
Neural cancer (neuroblastoma) in young children is the most common solid tumour form in this age group. The prognosis is very poor and some 40 per cent of patients die of the disease. However, it is known that fatty acids can protect healthy nerve cells from dying, and at the same time kill several types of cancer cells. In the current study, the scientists were interested in exploring what happens to DHA, an Omega-3 fatty acid found mainly in oily fish (e.g. salmon and mackerel), inside the cancer cell.
Using an advanced method called liquid chromatography combined with mass spectrometry, the researchers looked at the products that were formed on the breakdown of DHA and which of them have a lethal effect on the cancer cell. They also tried to identify the enzymes involved in the breakdown process.
“We observed that DHA forms hydroperoxy fatty acids and hydroxy fatty acids inside the cancer cell,” says Helena Gleissman, researcher at Karolinska Institutet and the study´s principal author. “These fatty acids are oxidised through the agency of enzymes called 5- and 15-lipoxygenase, but they can also be oxidised spontaneously. Hydroperoxy fatty acids are particularly involved in apoptosis.”
DHA can be converted into these cell-killing oxidised fatty acids in healthy neurons, but they are then converted further into substances called resolvins and protectins, thus avoiding the accumulation of cytolethal oxidised fatty acids in the cell. Protectins are particularly effective at protecting nerve cells from dying, which from a future treatment perspective makes it especially interesting that neither resolvins nor protectins are formed in neuroblastoma cells.
“While DHA kills cancer cells in the nervous system via hydroperoxy fatty acids, it protects healthy nerve cells from dying via protectins,” says Dr Gleissman. “If we can find a way of controlling this process, there is a good chance that DHA can serve as both sword and shield in neuroblastoma patients and act as a complement to cytostatic therapy.”
The study was based on a collaboration between Professor Per Kogner´s research group at Karolinska Institutet and Professor Charles N Serhan´s group at Harvard Medical School. The researchers will now be looking into how DHA can be applied most effectively in the treatment of cancer. The research was funded by the Swedish Children´s Cancer Foundation, Swedish Research Council, Swedish Cancer Society, Erik and Edith Fernström´s Foundation for Medical Research, Cystic Fibrosis Foundation, and NIH.
Helena Gleissman, Rong Yang, Kimberly Martinod, Magnus Lindskog, Charles N. Serhan, John Inge Johnsen & Per Kogner
Docosahexaenoic acid metabolome in neural tumors: identification of cytotoxic intermediates
The FASEB Journal, print issue March 2010. Abstract
High doses of the hormone progesterone can kill neuroblastoma cells while leaving healthy cells unscathed, scientists at Emory University School of Medicine have found in laboratory research.
The results, published in the journal Molecular Medicine, suggest that progesterone could be used to fight neuroblastoma, the most common form of cancer affecting small children.
More research is necessary to determine the optimal dose, how long progesterone treatment should last and if it should be used alone or in combination with radiation or chemotherapy. Emory scientists are also exploring whether it can stop the growth of other brain cancer types such as glioblastoma and astrocytoma. Progesterone has also been reported to slow growth of several other types of cancers in the laboratory, but has not been used clinically against neuroblastoma.
The first author in the team of researchers is Fahim Atif, PhD, instructor in emergency medicine, with senior author Donald G. Stein, PhD, Asa G. Candler professor of emergency medicine and director of Emory’s Department of Emergency Medicine Brain Research Laboratory. Daniel Brat, MD, PhD, professor of pathology and laboratory medicine in Emory School of Medicine was a collaborator on the research team.
The discovery grew out of studies of progesterone’s protective effects in brain injury. Based on Stein’s pioneering work, medical centers across the country are now testing progesterone in the setting of acute traumatic brain injury in a phase III clinical trial. While investigating how to enhance progesterone’s effectiveness, Atif and his colleagues observed that it could protect healthy neurons from stress but caused cells from a tumor cell line to die.
In a mouse model, progesterone treatment cut tumor growth in half over eight days, while no drug toxicity was seen with healthy neurons or in live animals. The researchers showed that progesterone can decrease the levels of proteins produced by tumor cells that attract new blood vessel growth and help tumor cells invade other tissues.
“This fits with what we know about one of progesterone’s roles during pregnancy, which is to regulate the growth of placenta,” Atif says. “Placental cells behave in a way that resembles tumor cells, invading the uterine wall and tapping into the mother’s blood vessels.”
In studies performed elsewhere, doses of progesterone that were lower than the most effective dose in the Emory study actually accelerated cancer growth. Based on their results, the Emory researchers propose that for fighting certain types of cancer, high doses of progesterone may be better than low doses.
Progesterone’s effects on cancer are known to be complex. There may be differences between progesterone, the natural hormone, and synthetic progestins. The National Institutes of Health’s Women’s Health Initiative study showed that women who received hormone replacement therapy with combined estrogen and progestins had an increased risk of heart disease and breast cancer, although some studies have identified a potential “safe period” if hormone replacement therapy lasts less than two years.
Progesterone has a long history as a treatment designed to prevent preterm birth. If progesterone is to be used with small children, any potential effects on development must be weighed against the risks of standard treatments.
Source: Emory University
A drug recently approved by the U.S. Food and Drug Administration for treatment of an adult cancer targets a malfunctioning gene discovered more than a decade earlier at St. Jude Children’s Research Hospital. The story highlights how scientific findings from St. Jude can be translated into therapies and tests that in addition to helping children, also help adults.
The drug is Xalkori (crizotinib). The FDA approved Xalkori in August as the first targeted therapy for patients with ALK-positive non-small cell lung cancer (NSCLC) that is locally advanced or metastatic. Xalkori is manufactured by the pharmaceutical company Pfizer.
The ALK gene was discovered by St. Jude scientists searching for genes affected by a chromosomal change common in the cancer cells of patients with anaplastic large cell lymphoma (ALCL).The blood cancer accounts for 10 to 30 percent of pediatric non-Hodgkin lymphoma. In 1994 Stephan Morris, M.D., then a St. Jude junior faculty member; Thomas Look, M.D., then chair of a St. Jude department; and their colleagues, published the first of several reports detailing the discovery of ALK and the gene’s pivotal role in driving the cancer. ALK is short for anaplastic lymphoma kinase, the name investigators gave the protein whose assembly instructions the gene carried.
ALK is now widely recognized as a potent promoter of several adult and childhood cancers, including ALCL and neuroblastoma, a childhood tumor of certain nerve cells. The work done by Morris, Look and their colleagues in a fifth-floor laboratory of the Danny Thomas Research Center eventually helped to launch a new targeted cancer treatment.
Hiroyuki Mano, M.D., of the University of Tokyo, led the 2007 research into the molecular drivers of NSCLC. The study showed some NSCLC tumors were driven by an ALK rearrangement. Following this discovery, Pfizer expanded a Phase I clinical trial of Xalkori to include patients with ALK-positive advanced NSCLC. Xalkori blocks the cancer-causing activity of the ALK protein. Additional clinical trials with the drug are now underway in other cancers, including neuroblastoma and ALCL, the lymphoma that launched the search.
The ALK discovery and related later research led to five U.S. patents for St. Jude. The patented work includes methods for detecting the chromosomal rearrangements that unleash the cancer-causing ability of the ALK gene as well as tools to identify and characterize drugs for cancers caused by ALK deregulation. Morris, Look and their colleagues also worked with another pharmaceutical company to design a diagnostic assay to identify patients with the ALK mutation. The test, a fluorescence in situ hybridization (FISH) assay, has been marketed for more than a decade. In August, it won FDA approval as a diagnostic test for use with Xalkori.
Dr. William E. Evans, St. Jude director and chief executive officer, said the ALK story captures an important aspect of the hospital’s commitment. “Our focus is on finding cures for pediatric diseases, but our discoveries often provide insights that can be building blocks for advances in other diseases, including adult cancers. We are committed to facilitating this so that the most good can come from our discoveries,” he said.
Working through the St. Jude Office of Technology Licensing, Pfizer obtained licenses to the hospital’s patented research tools. Several other companies have executed licenses with St. Jude to use these patent rights.
This year about 210,000 new cases of lung cancer will be diagnosed in the U.S. Current estimates are that approximately 3 to 5 percent, or 6,500 to 11,000 patients with non-small cell lung cancer, carry the ALK rearrangement and may be candidates for treatment with Xalkori.
Today, Morris is a member of the St. Jude Pathology and Oncology departments. Look is a professor of pediatrics at Harvard Medical School and the Dana-Farber Cancer Center in Boston. Morris is still asking questions about ALK, including the protein’s normal functions. He said he is thrilled that his work offers new hope for thousands of lung cancer patients. “We knew in 1994 when we initially discovered ALK that it was an outstanding drug-development target,” Morris said. “It is heartening to now see patients benefiting from our research.”
Source St. Jude Children’s Research Hospital
Children given a hormone growth factor alongside chemotherapy for the aggressive cancer neuroblastoma are less likely to suffer a potentially deadly side-effect, according to a major international study published today in the Journal of Clinical Oncology*.
The hormone, called granulocyte colony-stimulating factor (GCSF), was already known to boost production of white blood cells. But this Cancer Research UK-funded study is the first large randomised trial to show it can reduce the complications associated with low white blood cell count in children treated for advanced forms of neuroblastoma.
Around 100 children are diagnosed with neuroblastoma** every year in the UK, usually under the age of five. Overall six out of ten children are successfully treated, but for children with advanced forms of the cancer it is very difficult to treat successfully.
Children diagnosed with advanced forms of neuroblastoma are given particularly intense treatment that combines surgery, radiotherapy and chemotherapy.
But this treatment often carries the side-effect of ‘neutropenia’ – a low white blood cell count. As white blood cells are key components of the immune system, patients who develop neutropenia during treatment are more susceptible to other diseases and complications.
Professor Andy Pearson, lead author of the paper and Cancer Research UK’s professor of paediatric oncology at The Institute of Cancer Research (ICR) and The Royal Marsden NHS Foundation Trust in Sutton, said: “Patients given GCSF immediately after chemotherapy treatment had fewer problems associated with neutropenia, such as fever, infections, days spent in hospital or on antibiotics and gastrointestinal issues.
“Our team previously identified the high dose chemotherapy regimen that is already saving the lives of many children with high risk neurobastoma, and in this study we report finding a new therapy to reduce side-effects for these patients.
“On the strength of these new trial results, all children receiving intense chemotherapy to treat high-risk neuroblastoma will now be given GCSF.”
The work builds on promising results from an earlier study, also funded by Cancer Research UK and led by Professor Pearson at the ICR , which found that giving doses of five chemotherapy drugs – cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide – more frequently offered the best hope of a cure.
This therapy is now being taken forward as the treatment for children in Europe through the International Society of Paediatric Oncology, Europe Neuroblastoma Group (SIOPEN)***.
Kate Law, Cancer Research UK’s director of clinical trials, said: “The results of this promising trial mean that children across Europe diagnosed with neuroblastoma will receive a more effective treatment for this disease.
“Cancer Research UK is the largest single funder of children’s cancer research in the country and is at the heart of an international research effort leading to rapid improvements in children surviving cancer with the fewest possible side effects.”
*Ladenstein et al., Journal of Clinical Oncology (2010), Randomised trial of prophylactic granulocyte colony stimulating factor during rapid COJEC induction in paediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study.
** Neuroblastoma is a form of childhood cancer which starts in the child’s developing nerves and often appears as a tumour in the abdomen, adrenal glands or the nerve tissue at the back of the abdomen. About one hundred children are diagnosed in the UK each year, mostly before the age of five, and the high-risk form of the disease is one of the main causes of cancer-related deaths in children.
*** The SIOPEN Group led by Dr Ruth Ladenstein at St Anna Children’s Hospital in Vienna, Austria and Professor Pearson at the ICR carried out a Cancer Research UK-funded trial in 16 European countries that assessed the clinical benefit of prophylactic GCSF use. The scientists monitored side-effects of rapid, intense chemotherapy in 119 patients who were routinely given GCSF with 120 patients who were only given GCSF if a severe infection developed.
St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project and Memorial Sloan-Kettering Cancer Center discover first gene alteration associated with patient age and neuroblastoma outcome
MEMPHIS, Tenn., March 13, 2012 /PRNewswire/ — Researchers have identified the first gene mutation associated with a chronic and often fatal form of neuroblastoma that typically strikes adolescents and young adults. The finding provides the first clue about the genetic basis of the long-recognized but poorly understood link between treatment outcome and age at diagnosis.
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The study involved 104 infants, children and young adults with advanced neuroblastoma, a cancer of the sympathetic nervous system. Investigators discovered the ATRX gene was mutated only in patients age 5 and older. The alterations occurred most often in patients age 12 and older. These older patients were also more likely than their younger counterparts to have a chronic form of neuroblastoma and die years after their disease is diagnosed.
The findings suggest that ATRX mutations might represent a new subtype of neuroblastoma that is more common in older children and young adults. The work is from the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP). The study appears in theMarch 14 edition of the Journal of the American Medical Association.
If validated, the results may change the way doctors think about this cancer, said co-author Richard Wilson, Ph.D., director of The Genome Institute atWashington University School of Medicine in St. Louis. “This suggests we may need to think about different treatment strategies for patients depending on whether or not they have the ATRX mutation,” he said.
Neuroblastoma accounts for 7 to 10 percent of all childhood cancers and about 15 percent of pediatric cancer deaths. In about 50 percent of patients, the disease has already spread when the cancer is discovered.
For patients whose disease has spread, age has long been a powerful but perplexing predictor of treatment outcome. Currently 88 percent of patients age 18 months and younger become long-term survivors, compared to 49 percent of those ages 18 months through 11 years and only 10 percent of patients age 12 and older.
“Until now there was no understanding of the basis of this age-related risk, and no treatment has had an impact on the outcome,” said Michael Dyer, Ph.D., a member of the St. Jude Department of Developmental Neurobiology and a Howard Hughes Medical Institute Early Career Scientist. He is the study’s corresponding author. “The mutation we found is associated with patients in the older age group, but it also identifies for the first time a subset of younger patients who turned out to have an indolent form of neuroblastoma.”
Researchers must now determine whether tumors with ATRX mutations behave the same way in both children and young adults, following a similarly indolent but often deadly course, said Nai-Kong Cheung, M.D., Ph.D., first author and head of the Neuroblastoma Program at New York’s Memorial Sloan-Kettering Cancer Center.
St. Jude investigators have begun screening the hospital’s library of federally approved drugs looking for evidence of activity against neuroblastoma cells with the ATRX mutation. Availability of more targeted therapies would likely spur efforts for early identification of patients with the ATRX mutation who have a chronic form of neuroblastoma and are unlikely to benefit from current therapies.
The ATRX mutation is the latest discovery from the PCGP. The three-year project aims to sequence the complete matched normal and cancer genomes of 600 patients with some of the most poorly understood and aggressive childhood cancers. Investigators believe the findings will lay the foundation for a new generation of clinical tools.
This study involved whole-genome sequencing of the complete normal and cancer genomes of 40 neuroblastoma patients. To validate those results, an additional 64 neuroblastoma tumors were also sequenced. The normal and tumor tissue samples were all donated by Memorial Sloan-Kettering Cancer Center patients. The human genome includes a chemical alphabet that stretches more than 3 billion characters in length and provides the instructions to build and sustain life.
The genome data from this and other published PCGP studies are available at no cost to the global scientific community at the PCGP Explore website. To access Explore, go to http://explore.pediatriccancergenomeproject.org.
Researchers found the ATRX gene was mutated in 44 percent of the 32 patients with neuroblastoma age 12 and older. The gene was altered in 17 percent of the 54 patients 18 months through 11 years, although the changes were found only in patients age 5 and older. None of the 18 patients in youngest treatment group, those age 17 months and younger, had ATRXmutations.
Although this is the first study linking changes in ATRX to neuroblastoma, mutations in the gene have been found in cancers of the pancreas, kidney and ovaries. In pancreatic neuroendocrine tumors, patients with ATRX mutations have a better prognosis while neuroblastoma patients with the altered gene fall into the age group with a poor prognosis. The ATRX mutations associated with neuroblastoma include deletions in the gene not found in other tumors.
Evidence in this study suggests ATRX mutations contribute to neuroblastoma cell survival in several ways, including a mechanism called alternative lengthening of telomeres (ALT). Telomeres are the strands of DNA at the end of chromosomes that limit the number of times a cell can divide. By lengthening the telomere, ALT contributes to the unchecked cell division that is a hallmark of cancer and likely makes cancer cells less vulnerable to chemotherapy or radiation therapy. The human genome is encoded in DNA and organized into chromosomes.
Researchers suspect ATRX is also involved in regulating the activity of other genes through epigenetic mechanisms that alter gene activity without changing the underlying DNA sequence. This is in keeping with previous discoveries at St. Jude that retinoblastoma and glioma cancer progression may be driven by epigenetic processes.
The paper’s other first authors are Jinghui Zhang of St. Jude and Charles Lu ofWashington University. The other authors are Matthew Parker, Armita Bahrami, Alberto Pappo, Sara Federico, James Dalton, Jianmin Wang, Xiang Chen, Jared Becksfort, Jianrong Wu, Catherine Billups, David Ellison andJames Downing, all of St. Jude; Satish Tickoo, Adriana Heguy and Irene Cheung, all of Memorial Sloan-Kettering Cancer Center; and Li Ding, Bob Fulton, and Elaine Mardis, all of Washington University in St. Louis.
The research was funded in part by the Pediatric Cancer Genome Project, including Kay Jewelers, a lead project sponsor; the National Cancer Institute, the National Institutes of Health, the Catie Hoch Foundation, the Robert Steel Foundation and ALSAC.
Washington University School of Medicine
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
Memorial Sloan-Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center is the world’s oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide. For more information, go to www.mskcc.org.
SOURCE St. Jude Children’s Research Hospital
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