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Therapy Reduces Dangerous Side-effects of Cancer Treatment in Children
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.”
Notes:
*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.
Source: http://insciences.org/article.php?article_id=9316
ALK gene discovered by St. Jude scientists associated with FDA approved adult cancer drug
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
Progesterone Could Fight Against Neuroblastoma
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
Source: http://www.news-medical.net/news/20110714/Progesterone-could-fight-against-neuroblastoma.aspx?page=2
Omega-3 Possible Weapon Against Neural Tumors in Children
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.
Publication:
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
MYCN Amplification Can Serve As a Favorable Prognostic Indicator for Neuroblastoma
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.
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