News

Neuroblastoma Deploys Energy-Draining Weapon Against Immune System

Immune cells do their best to mount an efficient offensive campaign against menacing tumors, but much like soldiers barricaded within a stronghold, cancer cells deploy numerous weapons to keep immune cells from breaching the defenses.

Now, scientists funded by Cancer Research UK (CRUK), have discovered that neuroblastoma cells produce an enzyme that depletes a critical energy source for immune cells that are trying to attack the tumor.    

The investigators found that the neuroblastoma cells produced an abundance of the enzyme arginase II, which created a microenvironment that was immunosuppressive since the enzyme’s target, arginine, is a critical protein building block and an essential energy source for immune cells 

“We’ve known for a while that harnessing the power of the immune system could be an effective way to treat neuroblastoma,” explained lead author Francis Mussai, M.D., Ph.D., clinical senior lecturer in pediatric oncology at the Birmingham Children’s Hospital, UK “But we didn’t know why the immune cells were having such difficulty recognizing and destroying the tumor. Armed with this new knowledge about the role of arginine, we may be able to activate the immune system to attack cancer cells.”

The findings from this study were published recently in Cancer Research through an article entitled “Neuroblastoma Arginase Activity Creates an Immunosuppressive Microenvironment that Impairs Autologous and Engineered Immunity.”

Neuroblastomas are the most common extracranial tumor in children and even with newly developed immunotherapy drugs, survival rates still remain poor, especially for those with advanced disease.

Previously, researchers noticed that neuroblastoma cells have a molecule on their surface that differentiates them from healthy cells, leading to the hope that the immune system might be persuaded to recognize and destroy them. The current study, however, may explain why initial attempts to harness the immune system in this way have so far been unsuccessful.

“Now the challenge is to develop new drugs which stop neuroblastoma from using arginine, and may make immune therapy more effective,” noted senior author Carmela De Santo, Ph.D., CRUK new investigator fellow at the University of Birmingham.

Specifically, the CRUK scientists saw that neuroblastomas from both mouse and human were able to suppress T-cells through increased arginase activity. Furthermore, the team observed that the arginase activity inhibited myeloid cell activation and suppressed bone marrow CD34+ progenitor proliferation. Clinically, they noted that high arginase II expression correlated with poor survival for neuroblastoma patients

“These findings could have huge implications for treating neuroblastoma. Better understanding the role of arginine could help us to boost the body’s immune cells and we hope this could lead to more effective treatments,” stated Eleanor Barrie, senior science information manager at CRUK. “We recently launched Cancer Research UK Kids and Teens as part of our commitment to bringing forward the day when no young lives are lost to cancer. Our target is to find more cures and kinder treatments for children with the disease so that, in the future, every child with cancer can go on to live a long and healthy life.”

FDA Approves First Therapy For High-Risk Neuroblastoma

The U.S. Food and Drug Administration today approved Unituxin (dinutuximab) as part of first-line therapy for pediatric patients with high-risk neuroblastoma, a type of cancer that most often occurs in young children.

Neuroblastoma is a rare cancer that forms from immature nerve cells. It usually begins in the adrenal glands but may also develop in the abdomen, chest or in nerve tissue near the spine. Neuroblastoma typically occurs in children younger than five years of age. According to the National Cancer Institute, neuroblastoma occurs in approximately one out of 100,000 children and is slightly more common in boys. There are an estimated 650 new cases of neuroblastoma diagnosed in the United States each year. Patients with high-risk neuroblastoma have a 40 to 50 percent chance of long term survival despite aggressive therapy.

Unituxin is an antibody that binds to the surface of neuroblastoma cells. Unituxin is being approved for use as part of a multimodality regimen, including surgery, chemotherapy and radiation therapy for patients who achieved at least a partial response to prior first-line multiagent, multimodality therapy.

“Unituxin marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Unituxin fulfills a critical need by providing a treatment option that prolongs survival in children with high-risk neuroblastoma.”.

The FDA granted Unituxin priority review and orphan product designation. Priority review shortens the timeframe for review of drug applications by four months, compared to standard reviews, and is granted to drugs that, if approved, will provide a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan product designation is given to drugs intended to treat rare diseases. With this approval, the FDA also issued a rare pediatric disease priority review voucher to United Therapeutics, which confers priority review to a subsequent drug application that would not otherwise qualify for priority review. This is the second rare pediatric disease priority review voucher granted by the FDA since inception of the rare pediatric disease review voucher program, which is designed to encourage development of new therapies for prevention and treatment of certain rare pediatric diseases.

The safety and efficacy of Unituxin were evaluated in a clinical trial of 226 pediatric participants with high-risk neuroblastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Participants were randomly assigned to receive either an oral retinoid drug, isotretinoin (RA), or Unituxin in combination with interleukin-2 and granulocyte-macrophage colony-stimulating factor, which are thought to enhance the activity of Unituxin by stimulating the immune system, and RA.

Three years after treatment assignment, 63 percent of participants receiving the Unituxin combination were alive and free of tumor growth or recurrence, compared to 46 percent of participants treated with RA alone. In an updated analysis of survival, 73 percent of participants who received the Unituxin combination were alive compared with 58 percent of those receiving RA alone.

Unituxin carries a Boxed Warning alerting patients and health care professionals that Unituxin irritates nerve cells, causing severe pain that requires treatment with intravenous narcotics and can also cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Unituxin may also cause other serious side effects including infections, eye problems, electrolyte abnormalities and bone marrow suppression.

The most common side effects of Unituxin were severe pain, fever, low platelet counts, infusion reactions, low blood pressure, low levels of salt in the blood (hyponatremia), elevated liver enzymes, anemia, vomiting, diarrhea, low potassium levels in the blood, capillary leak syndrome (which is characterized by a massive leakage of plasma and other blood components from blood vessels into neighboring body cavities and muscles), low numbers of infection-fighting white blood cells (neutropenia and lymphopenia), hives, and low blood calcium levels.

Unituxin is marketed by Silver Spring, Maryland-based United Therapeutics.

 

Another Gene Linked

Researchers at Children’s Cancer Institute have uncovered, for the first time, another gene linked to the cause of one of the most aggressive forms of childhood cancer – that could provide new targets for cancer therapy and change the way we treat the disease.

The Institute’s work shows that noncoding or ‘junk’ DNA can cause childhood cancer and contributes to the malignant nature of neuroblastoma – the most common solid cancer found in infants and young children that often presents as an aggressive, incurable disease.

The study, published in the prestigious US Journal of the National Cancer Institute, was led by Dr Tao Liu, Group Leader for Histone Modification at Children’s Cancer Institute and his colleague Professor Glenn Marshall, Head of Molecular Carcinogenesis Program at Children’s Cancer Institute, Director of the Kids’ Cancer Alliance and Director of the Kids’ Cancer Centre at Sydney Children’s Hospital.

It has been known for some time that the aggressive nature of neuroblastoma is often driven by a cancer-causing gene called MYCN. Each neuroblastoma cell carries many copies of MYCN, but the results of Dr Liu’s study reveal that DNA containing MYCN also contains ‘passenger DNA’, which dramatically adjusts the levels of MYCN in neuroblastoma cells and further fuels the cancer.

By uncovering a new long noncoding RNA (a type of RNA molecule) that plays a critical part in neuroblastoma tumor formation, Dr Liu’s research suggests that noncoding DNA is in fact not ‘junk’ at all. It actually plays a major role in regulating the levels of genes – including cancer-causing genes.

“I attended a conference a few years ago where it was suggested that long noncoding RNAs may also affect the occurrence of cancer,” says Dr Liu. “When I returned to the lab, I decided to study this further.

“I started researching one particular long noncoding RNA that didn’t yet have a name – as it had never been studied before. We called it lncUSMycN.”

Dr Liu’s team discovered that when lncUSMycN was blocked in neuroblastoma cells growing in the laboratory, the MYCN oncogene was ‘switched off’ by almost 90 per cent. Moreover, a study of large neuroblastoma tumors showed a direct link between poor survival rates and a higher level of lncUSMycN, independent of MYCN.

This is the first time it has been discovered that a long noncoding RNA can impact the progression of neuroblastoma, revealing that MYCN is not the only gene that contributes to the disease.

“Dr Liu’s study has improved our understanding of what leads to the development of neuroblastoma, and uncovered another potential target for this rare but devastating disease,” says Children’s Cancer Institute’s Head of Translational Research, Prof Glenn Marshall AM.

“Side-effects associated with conventional chemotherapy used to treat kids with cancer are a significant clinical problem. Research results such as these will help us discover new treatments, specifically designed for children, to ensure they experience the highest possible quality of life – and support further work to uncover other junk DNA targets for cancer therapy.”

Media enquiries: Catherine Arnott, Media & Communications Advisor; 02 9385 8879; carnott@ccia.org.au

Drug Targets Cancer Cells to Self-Destruct

A new chemotherapy drug targets the structures that hold cancer cells together, potentially causing all types of cancerous tumors to self-destruct.

Researchers at the University of New South Wales (UNSW) in Australia have developed a new drug that may be a cancer cure-all. The drug, called TR100, works by attacking the proteins that form the structure of cancer cells, while leaving healthy cells alone. Their study, which involved tests on lab rats, was published this month in Cancer Research.

Like a building, cells need support structures in order to hold their shape. Two proteins called actin and myosin give cancer cells their structure; they are like long, tough, interlocking cables. 

Healthy human muscle cells, including the cells that form the heart, also employ actin and myosin. For this reason, most researchers had abandoned actin and myosin as targets for chemotherapy, and the development of drugs targeting these proteins stalled for nearly 25 years.

But world myosin specialist Dr. Peter Gunning pressed on, and now his work has yielded results. He and other researchers were able to isolate two specific types of myosin, called tropomyosins, which cancer cells use but healthy muscle cells don’t. He worked with Dr. Justine Stehn, the paper’s lead author, to develop TR100.

Programmed Cell Death: Making Tumors Implode

“We’ve really gone after the core component of the internal scaffold or structure of the cancer cell,” said Stehn, a research fellow in the Oncology Research Unit at the UNSW School of Medical Sciences, in an interview with Healthline. “[When] the cell senses that there’s something fundamentally wrong with its architecture, it will undergo programmed cell death.”

Programmed cell death is a genetic time bomb lurking inside each cell in the human body. If a cell is damaged, infected, or otherwise no longer working properly, the body can signal it to self-destruct. “It’s like when you see a building collapse,” said Stehn. “If you take out the structure and the scaffolds, the building will fall in on itself.”  

Programmed death causes the cell to break itself down into tidy little packets of material that other cells can absorb, recycle, and reuse.

TR100 appears to trigger this progress in cancer cells by destroying the two tropomyosins that cancer uses. However, stem cells also rely on this form of tropomyosin. Stem cells are active in a developing embryo, generating all of the new cells that will eventually form a healthy baby. 

“When a cell is proliferating or growing, tropomyosin is really important,” said Stehn. “When a cell differentiates and becomes a heart cell, a lung cell, or a brain cell, it’s no longer growing, and the role of tropomyosin changes and targeting it with [TR100] is no longer toxic.”

Human Trials Slated for 2015

This means that TR100 could also affect parts of the human body where stem cells are still active after birth. Stem cells are active in bone marrow where they produce new red blood cells, in the brain where they produce nerve cells to form new memories, and elsewhere.

Stehn tested the drug on heart cells, liver cells, and brain cells in the lab, and all were unharmed.

Stehn then tested TR100 on two types of cancer, neuroblastoma and melanoma, and in both cases, the TR100 killed the cancerous cells while leaving healthy cells alone. She’s confident that it should work on other types of cancer, too. “What we’ve found is that every tumor cell we’ve looked at relies heavily on this tropomyosin,” she said. “We haven’t found a tumor cell that doesn’t express the tropomyosin proteins we target.”

Her research was made possible by The Kids’ Cancer Project, which was willing to fund a study into a technique that the research community had abandoned as a hopeless cause. “Our priority is focused on children’s cancer,” Stehn said. “We have developed these compounds with the intent of treating hard-to-treat childhood cancers, like neuroblastoma.”

Pictured above is two-year-old Zoe Emin and her mother Alison Emin. The Emins took a trip to visit Peter Gunning and Justine Stehn at UNSW. Zoe is currently in remission from neuroblastoma, a hard-to-treat pediatric brain cancer.

Stehn’s new drug, which will hopefully begin clinical trials in 2015, could help save the lives of children like Zoe. For now, she will be working with Dr. Timothy Cripe at the Nationwide Children’s Hospital as he fine-tunes the drug. 

“We know that it’s not a silver bullet; it’s going to be used in combination with other therapies in the clinic,” Stehn said. “This is a major step forward and provides, for the first time, a new class of anti-cancer drug which can be used in the war against cancer.”

Dendritic Cell Vaccine for Relapsed Neuroblastoma

At the beginning of 2013, the newswires and social networks lit up with the news that a vaccine targeted to kill neuroblastoma cells had put a patient into remission.  The case study was published in the high-impact journal “Pediatrics”. This work built on five years of pre-clinical research, resulting in some very promising new immunological targets for neuroblastoma.  The project was partially funded by a joint grant from the Andrew McDonough B+ Foundation, Pierce Phillips Charity and Solving Kids’ Cancer.

As much as this is encouraging, it is also valuable to understand some details of the case.  Most importantly, this report is about only one patient in the larger study that is currently ongoing at University of Louisville (Kosair Children’s) and at Dana-Farber (Boston Children’s).  The paper is a “case report” which is distinct from clinical research reports that discuss results of all patients on a study. Evidence-based medicine in clinical research is built on the results of many patients, and conclusions from single case studies should be taken as anecdotal.

Immune cells (dendritic cells) were collected from the patient, pulsed with CT (cancer testes) antigens, and grown in the laboratory to return to the patient as a vaccine injection in several doses. The dendritic cells “teach” the patient’s T cells to recognize the neuroblastoma cells with the CT antigens.  Before receiving the vaccine, the patient was treated with chemotherapy (decitabine) to increase the expression of the CT antigens on the neuroblastoma cancer cells (Krishnadas et al, 2013).  This type of immunotherapy is different from other approaches using antibodies such as ch14.18 that target GD2 which is also found on the surface of neuroblastoma tumor cells.

This case is about one patient who was diagnosed with neuroblastoma (unfavourable, not MYCN amplified) at 3 years of age with a primary tumor, bone marrow involvement, and bony metastases (found by PET scan); however, HVA/VMA and MIBG scans were negative.  The patient did not respond completely to frontline therapy (COG- ANBL0532 protocol), and at the end of treatment which included ch14.18 immunotherapy, the patient’s final tests showed disease in the bone marrow.  This disease persisted even after three cycles of irinotecan and temozolomide.

The patient had his “peripheral blood mononuclear cells collected via apheresis for the culture of dendritic cells” (Krishnadas et al. 2013, p. e338) and then began the decitabine chemotherapy.  The patient received 3 cycles of the protocol: decitabine for 5 days, followed by 2 weekly vaccines (with imiquimod given before and after the vaccination), and one week of rest.  After the third cycle the patient experienced a decline in neutrophil and platelet counts, and an elevated alkaline phosphatase level.

At the end of the 3 cycles of decitabine and the vaccine, the patient had no evidence of neuroblastoma in his bone marrow aspirates and biopsies. On the one year anniversary of the patient’s last vaccination, the patient’s bone marrow continued to remain free of neuroblastoma, including clear CT scans. The decitabine/dendritic cell vaccine therapy shows some great promise and is certainly worthy of future study.  Future research in this area will involve (Krishnadas et al, 2012, p. e340):

1. Continuing this study with a larger number of patients to determine if there is a significant response rate to this therapy.

2. Examining if patients with bulky disease would also benefit from this therapy, and not just patients with a minimal disease profile.

3. Establishing a detailed understanding on how the neuroblastoma cells are being killed.

4. Determining if there are subsequent immune responses towards any disease after the vaccine treatment is completed.

 

Reference

Krishnadas, D.K., Shapiro, T. And Lucas, K. (2013). Complete Remission Following Decitabine/Dendritic Cell Vaccine for Relapsed Neuroblastoma. Pediatrics, Vol 131, No 1.

Immunotherapy Effective Against Neuroblastoma in Children

New therapy improves chances of living disease-free with difficult-to-treat childhood cancer.

A phase III study has shown that adding an antibody-based therapy that harnesses the body’s immune system resulted in a 20 percent increase in the number of children living disease-free for at least two years with neuroblastoma. Neuroblastoma, a hard-to-treat cancer arising from nervous system cells, is responsible for 15 percent of cancer-related deaths in children. The researchers reported their findings – the first to show that immunotherapy could be effective against childhood cancer – online May 14, 2009 on the American Society of Clinical Oncology website in advance of presentation June 2.

“This establishes a new standard of care for a traditionally very difficult cancer in children,” said lead author Alice Yu, MD, PhD, professor of pediatric hematology/oncology at the University of California, San Diego School of Medicine and the Moores UCSD Cancer Center. “High-risk neuroblastoma has always been a frustrating cancer to treat because, despite aggressive therapy, it has a high relapse rate.”

The therapy targets a specific glycan (a complex sugar chain found on the surface of cells) on neuroblastoma cells called GD2, which inhibit the immune system from killing cancer cells. The antibody – ch14.18 – binds to this glycan, enabling various types of immune cells to attack the cancer.

Neuroblastoma – in which the cancer cells arise from nerve cells in the neck, chest, or abdomen – is the most common cancer diagnosed in the first year of life. Approximately 650 new cases of neuroblastoma are diagnosed in this country every year, and about 40 percent of patients have high-risk neuroblastoma. These high-risk patients are usually treated with surgery, intensive chemotherapy with stem cell rescue (in which patients’ adult stem cells, removed before treatment, are returned after chemotherapy to restore the blood and immune system), and radiation therapy. Still, only 30 percent of patients survive.

Yu and her colleagues compared both the percentage of patients who were still alive without experiencing a recurrence after two years as well as overall survival in two groups of 113 patients each. Patients began the trial when they were newly diagnosed with high-risk neuroblastoma. After conventional treatment with surgery, chemotherapy, stem cell rescue and radiotherapy, one group was given the standard treatment (retinoic acid) plus immunotherapy (the antibody plus immune-boosting substances), while 113 similar patients received the standard treatment alone.

After two years, 66 percent of individuals in the immunotherapy group were living free of cancer compared to 46 percent in the standard treatment group. Overall survival improved significantly as well. The trial patient randomization was halted early because of the benefit seen, and all patients enrolled in the trial will receive immunotherapy plus standard treatment.

Yu noted that the two-year mark is especially important because past trials have shown that those neuroblastoma patients who live without disease for two years after a stem cell transplant will most likely be cured.

“This is the first time in many years that we have been able to improve the ‘cure rate’ for neuroblastoma patients,” she said. “This new therapy can help us improve care and perhaps offer new hope to many patients and families.”

Yu and her team conducted the early phase I and phase II trials at the General Clinical Research Center at UC San Diego Medical Center.

Other co-authors include Andrew Gilman, Carolinas Medical Centre; M. Fevzi Ozkaynak, New York Medical College; Susan Cohn, University of Chicago; John Maris, Children’s Hospital of Philadelphia; Paul Sondel, University of Wisconsin; W. B. London, University of Florida; S. Kreissman, Duke University; H.X. Chen, National Cancer Institute; and K.K. Matthay, UCSD. Local patients were seen in San Diego at Rady Children’s Hospital.

The Moores UCSD Cancer Center is one of the nation’s 41 National Cancer Institute-designated Comprehensive Cancer Centers, combining research, clinical care and community outreach to advance the prevention, treatment and cure of cancer.

Source: University of California, San Diego, UCSD Medical Center

Genetic Finding Could Lead To Targeted Therapy For Neuroblastoma

GAINESVILLE — Researchers have identified a genetic glitch that could lead to development of neuroblastoma, a deadly form of cancer that typically strikes children under 2.

Two University of Florida scientists are part of the multicenter team of researchers that made the discovery, which could pave the way for better treatments that target the disease, according to findings published Wednesday in the journal Nature.

“What makes our study so important is that although neuroblastoma accounts for 7 percent of childhood cancers, it is responsible for 15 percent of deaths in children with cancer,” said Wendy London, 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. “This paper adds yet another gene in the pathway that could lead to tumorigenesis (tumor formation) of neuroblastoma.”

Neuroblastoma forms in developing nerve cells, with tumors most often found on a child’s adrenal gland. It’s the most common form of cancer in babies and the third most common childhood cancer, according to the American Cancer Society.

Led by Dr. John J. Maris, director of the Cancer Center at The Children’s Hospital of Philadelphia, researchers performed what’s known as a genome-wide association study to uncover errors in DNA that could be associated with neuroblastoma.

To do this, researchers analyzed the genetic makeup of 846 patients with neuroblastoma, whose samples were derived from the Children’s Oncology Group Neuroblastoma Tumor Bank, and 803 healthy patients in a control group.

On the basis of their initial findings, the researchers performed a second validation analysis, pinpointing that a glitch called a “copy number variation” in a single chromosome is associated with neuroblastoma. Copy number variation has to do with the gain, loss or duplication of snippets of DNA.

“This is part of series of papers that creates the bigger picture, an understanding of the genetic mechanisms that lead to neuroblastoma,” saidLondon, the principal investigator for the Children’s Oncology Group Statistics andDataCenterat UF. “We are searching for genetic targets to treat with therapy.”

The researchers reported additional genetic links in Nature Genetics in May. The team discovered that on the gene called BARD1, six single-nucleotide polymorphisms — variations in tiny pieces of DNA — were also associated with neuroblastoma.

“Only two years ago we had very little idea of what causes neuroblastoma,” said Maris, who led both studies. “Now we have unlocked a lot of the mystery of why neuroblastoma arises in some children and not in others.”

Although neuroblastoma is one of the more common childhood cancers, it is relatively rare overall when compared with more common adult cancers, which has proved to be a challenge for researchers trying to uncover its causes, said Dr. Peter Zage, an assistant professor of pediatrics at the Children’s Cancer Hospital at the University of Texas M.D. Anderson Cancer Center.

“Dr. Maris’ group has been able to collect a relatively large number of cases for a neuroblastoma study and so has been able to identify these genetic variations and specific genes to provide us with some new avenues for therapy that we probably would not have been able to identify looking at the smaller cohorts of patients we each see at our individual institutions. In that sense, it’s certainly an amazing leap forward in our understanding of the disease.”

The discovery does hold promise for developing treatments, butLondoncautions that these potential “targeted therapies” won’t work on all neuroblastoma patients. Not all neuroblastoma patients have this particular genetic anomaly, and not all children with this anomaly will develop neuroblastoma. Development of neuroblastoma is complicated and can occur because of multiple reasons, arising after a complex chain of events,Londonsaid.

“What’s amazing is there are so many different ways for tumorigenesis to occur,”Londonsaid. “That’s the reason it is so hard to treat and cure cancer, or even to understand why it happens and how it happens.”

All the researchers involved in the study are members of the Children’s Oncology Group, the only National Institutes of Health/National Cancer Institute pediatric cancer cooperative group. The group performs clinical trials, collects specimens and performs statistical analysis related to pediatric cancers. UF is one of three institutions with a COG Statistics andDataCenter, where study design, data collection and statistical analysis for COG research occurs.

Gene Findings Unlocking Reasons for Neuroblastoma Risk

PHILADELPHIA, PR Newswire-US Newswire — Two new studies from The Children’s Hospital of Philadelphia advance the search for genetic events that result in neuroblastoma, a puzzling, often-deadly type of childhood cancer.

Originating in the peripheral nervous system, neuroblastoma is the most common solid cancer of early childhood and causes 15 percent of all childhood cancer deaths.

“Only two years ago we had very little idea of what causes neuroblastoma,” said study leader John M. Maris, M.D., chief of Oncology and director of the Cancer Center at The Children’s Hospital of Philadelphia. “Now we have unlocked a lot of the mystery of why neuroblastoma arises in some children and not in others.”

In the largest gene study to date in pediatric oncology, Maris’s study team performed a genome-wide association study to discover that common variants in the gene BARD1 increase a child’s susceptibility to a high-risk form of neuroblastoma.

A second genome-wide study found that a copy number variation (CNV) — a missing stretch of DNA — along a structurally weak location on chromosome 1 plays an important role in the development of neuroblastoma. Although CNVs have received much attention from genetics researchers over the last several years, this study was the first example of a specific CNV that predisposes people to cancer.

The BARD1 study was published online in Nature Genetics on May 3, while the CNV study appeared in the June 18 issue of Nature. The researchers made use of highly automated gene-analyzing technology at the Center for Applied Genomics at Children’s Hospital, directed by Hakon Hakonarson, M.D., Ph.D., a co-author of both studies. They used specimens collected from around the world through the Children’s Oncology Group.

The BARD1 gene had already attracted attention from oncology researchers because it is associated with the gene BRCA1, which was the first discovered familial breast cancer gene. “Researchers have suspected that variants in BARD1 also increased the risk of breast cancer, but no one has found compelling evidence of this,” said Maris. “Instead, surprisingly, our genome-wide association studies found that BARD1 is a susceptibility gene for neuroblastoma, and perhaps other cancers as well.”

Maris added that researchers are now working to understand the mechanism by which BARD1 gene variants act on developing nervous system cells to give rise to cancer during fetal or early childhood development.

Maris’s second study, spearheaded by Dr. Sharon Diskin, also of The Children’s Hospital of Philadelphia, found that an inherited CNV located at chromosome 1q21.1 is associated with neuroblastoma. The chromosome region contains a large family of genes that are involved in the development of the nervous system, and the CNV they discovered changes how much of one particular gene is made within normal nerve and neuroblastoma cells.

This study, Maris added, opens up a new area for studying the mechanisms of how CNVs may increase the risk of cancer.

The current findings build on 2008 studies by Maris’s lab, one identifying the ALK gene as the major gene predisposing patients to the rare familial form of neuroblastoma, and the other identifying a region of chromosome 6 that increases the risk of the nonhereditary form of the disease. The ALK gene discovery has already led to a clinical trial led by Dr. Yael Mosse of The Children’s Hospital of Philadelphia.

As gene studies continue to better define the genetic landscape of neuroblastoma, added Maris, pediatric oncologists can better develop more precise targeted treatments to improve survival and quality of life for children with this complex disease. The Cancer Center at Children’s Hospital has one of the nation’s largest research and clinical programs in pediatric oncology.

DNA samples for both studies were provided by the Children’s Oncology Group, a multi – center collaborative research organization in which Maris chairs the committee overseeing basic and clinical research in neuroblastoma. A variety of funding sources supported both studies, including the National Institutes of Health, the Alex’s Lemonade Stand Foundation, the Evan Dunbar Foundation, the Rally Foundation, the Andrew’s Army Foundation, the Abramson Family Cancer Research Institute and the Giulio D’Angio Endowed Chair.

Maris is also on the faculty of the University of Pennsylvania School of Medicine. Scientists from six other centers in addition to Children’s Hospital and the University of Pennsylvania contributed to the discovery or replication of the findings.

Source: The Children’s Hospital of Philadelphia

Engineered Virus Targets and Kills Apparent Cancer Stem Cells in Neuroblastoma

Treatment Blocked Deadly Nerve Cancer in Study Led by Cincinnati Children’s Hospital

After identifying an apparent population of cancer stem cells for neuroblastoma, researchers successfully used a reprogrammed herpes virus to block tumor formation in mice by targeting and killing the cells.

Published online Jan. 21 by PLoS (Public Library of Science) One, the study led by Cincinnati Children’s HospitalMedicalCenteradds to a growing body of evidence suggesting early stage cancer precursor cells with stem-cell-like properties may explain how some cancers form, are treatment resistant and prone to relapse. The study also underscores the increasing potential of targeted biological therapies to help people with stubborn cancers like neuroblastoma, which often recur and metastasize, said Timothy Cripe, MD, PhD, senior investigator and a physician / researcher in the Division of Hematology / Oncology at Cincinnati Children’s.

“The main finding of our study is that pediatric neuroblastomas seem to have a population of cells with stem-cell characteristics that we may need to target for therapy,” Dr. Cripe said. “We also show that one promising approach for targeted treatment is biological therapy, such as an engineered oncolytic virus that seeks out and kills progenitor cells that could be the seeds of cancers.”

Neuroblastoma’s solid tumors usually attack the sympathetic nervous system, part of the body’s autopilot mechanism that controls vital organ function and instinctive responses, like “fight or flight.” The disease can be thrown into remission by chemotherapy, radiation or surgery, but it’s also known for treatment resistance and a high rate of relapse and death. In patients with high-risk forms of the disease, long-term survival rates are less than 50 percent. The reasons for neuroblastoma’s tendency to relapse and spread still need to be proven, said Dr. Cripe, also professor of Pediatrics at the University of Cincinnati College of Medicine.

To further explore the cancer stem cell theory, the research team took human neuroblastoma cells and grew them in laboratory cultures. The cultures contained cells exhibiting biological properties of neural stem cells – which are specific to the nervous system and grow to form a variety of nerve tissue. The cultures generated cell colonies that acted like stem cells in the way they divided, grew and were capable of diverse, or multi-lineage, differentiation. Analysis showed the cells also carried known biological markers for nerve stem cells, such as the proteins CD133 and nestin.

The cells advanced into tumor-like cell spheres and were tumorigenic, meaning they had the potential to form tumors. Cells derived from these tumorspheres were relatively resistant to the chemotherapy agent doxorubicin, similar to that seen with some treatment-resistant neuroblastomas. Researchers also noted cells from the tumorspheres carried a gene (MYCN) that is found at amplified levels in aggressive forms of neuroblastoma.

Because neural stem cells and neuroblastoma cells both carry the protein nestin, Dr. Cripe and his colleagues tested the effect of an oncolytic herpes simplex virus called rQNestin34.5 on cells. Developed by cancer researchers Ohio State University, rQNestin34.5 carries a molecular promoter for nestin, which causes it to seek out the protein and cancerous, or precancerous, cells where nestin resides. The virus is genetically programmed to grow inside and be toxic to cancer cells, while leaving healthy tissues alone.

The tumorigenic cells were infected with rQNestin34.5 and then injected into mice to see if neuroblastoma tumors would form. Tumors did not form in any of the mice over a 60-day observation period, leading the researchers to report that rQNestin34.5 “abolished tumor growth” by attacking apparent tumor-initiating cells.

In comparison experiments for control, researchers also infected tumorigenic cells with another oncolytic herpes virus called rQLuc, which does not target cells that contain the nestin protein. Next to rQNestin34.5, rQLuc showed only moderate success, with all treated mice having tumor formation within 40 days. In mice where cells were treated only with saline, all animals had tumors form within 30 days.

Although a promising step forward, Dr. Cripe said the study’s main limitation is that precancerous cells were infected with the oncolytic virus in a laboratory culture before being injected into mice.

“Targeting and hitting the cells after they are already in the mice will be another matter,” he said.

The research team also nurtured the stem-cell like tumorigenic cultures over an extended period of time in the laboratory. In the next research phase, the team will try to verify results in the current study by seeing if they can detect the presence of cancer stem cells in primary neuroblastoma tumor cells from patients.

Dr. Cripe cautioned much more research is needed before determining whether rQNestin34.5 would be efficacious in treating neuroblastoma patients in a clinical setting.

Also participating in the study were: the divisions of Experimental Hematology / Cancer Biology and Pathology at Cincinnati Children’s; the Physician Scientist Training Program and the Graduate Program of Molecular and Developmental Biology, University of Cincinnati College of Medicine; and the Dardinger Laboratory for Neuro-Oncology and Neurosciences, the department of Neurological Surgery and the Comprehensive Cancer Center at Ohio State University. Other researchers include lead author, Yonatan Y. Mahller and Jon P. Williams, William H. Baird, Bryan Mitton, Jonathan Grossheim, Yoshinaga Sacki, Jose A. Cancelas and Nancy Ratner.

Funding support came from the division of Hematology / Oncology at Cincinnati Children’s,TeeOffAgainstCancer.org and the National Institutes of Health.

Cincinnati Children’s Hospital Medical Center is one of America’s top three children’s hospitals for general pediatrics and is highly ranked for its expertise in digestive diseases, respiratory diseases, cancer, neonatal care, heart care and neurosurgery, according to the annual ranking of best children’s hospitals by U.S. News & World Report. One of the three largest children’s hospitals in theU.S., Cincinnati Children’s is affiliated with the University of Cincinnati College of Medicine and is one of the top two recipients of pediatric research grants from the National Institutes of Health. For its achievements in transforming healthcare, Cincinnati Children’s is one of sixU.S. hospitals since 2002 to be awarded the American Hospital Association-McKesson Quest for Quality Prize ® for leadership and innovation in quality, safety and commitment to patient care. The hospital is a national and international referral center for complex cases, so that children with the most difficult-to-treat diseases and conditions receive the most advanced care leading to better outcomes.

Source: Cincinnati Children’s Hospital Medical Center

Cutting-Edge Procedure For Children’s Cancer Leaves Minimal Scars

The tumor in infant Joshua “Jak” Kaltenbach’s abdomen was nearly as big as his heart, about the size of a walnut. But instead of open, invasive surgery and a long, complicated healing process, Jak had to stay only one night in the hospital, took far less pain medication and has scars (if they can be called that) that are nearly invisible. These more patient-friendly circumstances are the direct result of a new, specialized procedure offered locally only at the MCG Children’s Medical Center.

For the Kaltenbachs, the worry began when ultrasound revealed a mass during mom Tanya’s pregnancy. A whirlwind of events followed, starting with Jak’s premature delivery, his hospitalization due to an unrelated case of necrotizing entercolitis (a bowel inflammation common in preemies) and finally, monthly ultrasound screenings of Jak’s belly to check on the tumor.

“A number of infants are born with tumors like Jak’s and amazingly, as the tumors mature, they often become benign,” said Dr. Walt Pipkin, head of the Center for Minimally Invasive Surgery for Children at the MCG Children’sMedicalCenter. “That’s something unique that often happens with these types of adrenal tumors. But in Jak’s case, that wasn’t to be.”

Just before Christmas, when Jak was four months old, the radiologist reported sobering news to the Kaltenbachs: The tumor had grown and it had grown a lot. Subsequent tests confirmed that the tumor was a neuroblastoma, a cancer of the body’s nerve network that manifests in solid tumors in the abdomen, chest, neck or head.

Jak had to have surgery. But not just any kind of surgery. Dr. Pipkin, who had been following Jak’s case since his hospitalization at the MCG Children’sMedicalCenter, removed the tumor using a new minimally invasive approach in the center’s high-tech endosuite. Jak’s case was the first ever to be performed at the children’s hospital, and only a few centers across the country offer this type of specialized approach.

During the procedure, Dr. Pipkin made several tiny incisions in Jak’s belly button and on his stomach. Ports were then inserted, which allowed him to use specialized tools, including a camera, to find the tumor. Watching his every move on a video screen, Dr. Pipkin pinpointed the mass, carefully disconnected it, placed it in a bag, and removed it through one of the small ports. A few small stitches and some Steristrips later, Jak was back in his hospital room and with his family.

The Kaltenbachs had a one-night stay at the MCG Children’sMedicalCenter, compared to four nights with conventional open surgery. To control pain, Jak had morphine the first night, but switched to Tylenol following that. A week and a half later, the Steristrips fell off, and his healing was well on its way. “He didn’t want to be on his tummy of course and there was a little swelling, but other than that, he did wonderfully,” said Mrs. Kaltenbach. “He never even got cranky. And his scars are so tiny, less than a quarter-inch across. If you didn’t know they were there, you wouldn’t even see them.”

“Because of our high-tech endosuite, we were able to offer Jak and his family a minimal access solution to a potentially large problem,” said Dr. Pipkin. “The tumor was completely removed, and we’re very glad that we could be here for this family when they needed us.”

MCG Health System is composed of three organizations – MCG Health Inc. and the clinical services offered by the faculty of the Medical College of Georgia and the members of the MCG Physicians Practice Group.  MCG Health, Inc. is a not-for-profit corporation operating theMCGMedicalCenter, MCG Children’sMedicalCenter, theMCGSportsMedicineCenter,MCGMCGHealthMedicalOfficeBuilding, theGeorgiaRadiationTherapyCenterand related clinical facilities and services.  MCG Health, Inc. was formed to support the research and education mission of the Medical College of Georgia, and to build the economic growth of the CSRA, the state of Georgia and the Southeast by providing an environment for delivering the highest level of primary and specialty health care.

For more information, please visit www.MCGHealth.org.

Donate By Phone
Call:
505-903-1406
Problems Donating?
Email Us:
donations@sierrarayn.org
Shopping Cart

Your shopping cart is empty
Visit the shop