Attacking the architecture of the cancer cell may help children with hard-to-treat neuroblastoma

Main Category: Neurology / Neuroscience
Also Included In: Cancer / Oncology;  Pediatrics / Children's Health;  Melanoma / Skin Cancer
Article Date: 19 Aug 2013 - 0:00 PDT Current ratings for:
Attacking the architecture of the cancer cell may help children with hard-to-treat neuroblastoma

Children with a particularly lethal cancer could benefit from potentially life-saving treatment, following breakthrough work led by researchers at the University of New South Wales (UNSW).

A whole new class of drugs has been developed that, for the first time, targets the structure of the cancer cell.

UNSW researchers have provided proof that the therapy is effective in two types of cancers in the animal model. They are neuroblastoma, a cancer that affects children, and melanoma. The resulting paper has been published in Cancer Research.

"It is much like what happens when you see a building collapse on the TV news," says the lead author, Professor Peter Gunning, from UNSW Medicine. "Our drug causes the structure of the cancer cell to collapse and it happens relatively quickly.

"We've been surprised and excited by the potential of this treatment," says Professor Gunning, the Head of the Oncology Research Unit, in the School of Medical Sciences.

The drug looks to be effective against every type of cancer cell.

The work could lead to an entirely new type of chemotherapy, which could have more positive outcomes for hard-to-treat cancers and have fewer long-term side-effects for survivors.

"Attacking the architecture of the cancer cell has long been an obvious target, but until now, attempts have failed because the building blocks of the structure of the cancer cell are also used to build the heart and muscle, so the toxicity was unacceptable," says the first author on the paper, Dr Justine Stehn, also from the Oncology Research Unit.

But the team recognised there was a second "building block", the protein tropomyosin, in the cancer cell structure that was sufficiently different from those in the heart and muscle, which could be safely targeted.

This latest work is vindication for Professor Gunning's team which was alone in its theory about the architecture of cells. The UNSW team is believed to be the only one working in this area internationally.

As toxicity had been a major stumbling block in earlier research, possible funders were scarce. Professor Gunning says the financial support of The Kids' Cancer Project is the only way this research has been possible.

"This research opens up a door on something the pharmaceutical industry and science gave up on 25 years ago," says the CEO of the Kids' Cancer Project, Peter Neilson.

"It shows that our founder's faith in this work was right," he says. "We will continue to invest in this and we are determined to see it going into clinical trials in children with hard-to-treat neuroblastoma.

"Normally it would go into adults and it would take 7 to 8 years to be trialled in kids," says Mr Neilson.

The first clinical trials are expected in 2015.

"Cancer in children is not the result of lifestyle issues, so you're relying on medical research to see any improvement in survival rates," says the Dean of UNSW Medicine, Professor Peter Smith, who is also the Chair of the Research Advisory Committee of The Kids' Cancer Project.

Childhood cancer is the single greatest cause of death from disease in Australian children, with three children a week dying from the condition.

"In the 1960s, less than 10 per cent of children survived cancer and now it's 80 per cent," says Professor Smith, who campaigned to have chemotherapy used in children in the 1970s, dramatically improving survival rates. "That improvement is all down to research. So it shows how important these partnerships are."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells, doi: 10.1158/0008-5472.CAN-12-4501

This work is also supported by the National Health and Medical Research Council, the Cancer Council NSW, the Cancer Institute NSW and the Office for Health and Medical Research, NSW Ministry of Health.

University of New South Wales

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Children with high-risk neuroblastoma benefit from new, precise proton therapy cancer treatment

Main Category: Cancer / Oncology
Also Included In: Neurology / Neuroscience;  Pediatrics / Children's Health
Article Date: 15 Aug 2013 - 1:00 PDT Current ratings for:
Children with high-risk neuroblastoma benefit from new, precise proton therapy cancer treatment

Proton therapy, using high-energy subatomic particles, may offer a precise, organ-sparing treatment option for children with high-risk forms of neuroblastoma. For patients in a new study of advanced radiation treatment, proton therapy spared the liver and kidneys from unwanted radiation, while zeroing in on its target.

"As survival rates improve for children with neuroblastoma, we need to reduce treatment-related long-term toxicities," said study leader Christine Hill-Kayser, MD, a radiation oncologist in The Children's Hospital of Philadelphia's (CHOP) Cancer Center. "Proton beam therapy offers precise targeting with less radiation exposure to healthy tissue."

Hill-Kayser and colleagues published their study online recently in Pediatric Blood & Cancer.

Owing to collaboration between Children's Hospital and radiation oncologists at Penn Medicine, the Roberts Proton Therapy Center, where the study was conducted, is the first proton therapy facility in the U.S. conceived with pediatric patients in mind from the earliest planning stages.

Proton therapy for high-risk neuroblastoma

Protons, the positively charged particles in an atom's nucleus, are used in therapy to destroy DNA in tumors and prevent cancer cells from multiplying. In children, this therapy is often used against spinal tumors. CHOP has recently been directing protons at neuroblastoma, long a special focus of the Hospital's clinical and research programs.

Neuroblastoma, the most common solid tumor of early childhood, strikes the peripheral nervous system, usually appearing as a solid tumor in a young child's chest or abdomen.

Pediatric oncologists have an arsenal of weapons against neuroblastoma, but high-risk forms of this cancer present a particular challenge, often frustrating conventional treatment from the start or recurring in a resistant form.

The current study, said Hill-Kayser, included 13 children with a median age of 3 years who responded well to initial chemotherapy, followed by surgery, more chemotherapy, bone marrow transplant, and in some cases, immunotherapy. The advanced radiation treatment aimed to destroy remaining microscopic areas of cancer cells while minimizing toxicity to healthy tissue. Importance of tailoring treatment for each child

In planning radiation treatment for each child, the study team determined that 11 patients should receive proton therapy, and that two other patients, because of their specific anatomy and the location of their tumors, should receive intensity-modulated X-ray therapy (IMXT). In IMXT, radiologists sculpt the radiation emitted from 7 different angles to modify radiation dosages in and around the targeted area.

None of the 13 patients had local disease recurrence or acute organ toxicity. For 11 of them, proton therapy provided the best combination of target coverage and organ sparing. "Protons are heavier than the particles in X-rays and have more stopping power," said Hill-Kayser. "They deposit 90 percent of their energy precisely at the tumor site, with nearly zero radiation away from the tumor. That protects healthy organs - which, as growing tissues, are especially vulnerable to radiation damage in young children."

The fact that individual characteristics made IMXT preferable to proton therapy in two children, said Hill-Kayser, underscores the need to meticulously customize radiation treatment to each patient. Overall, the current study shows that proton therapy should be considered for children with high-risk neuroblastoma. She added, "To better assess the use of proton therapy against high-risk neuroblastoma, we'll need to study larger numbers of patients and do long-term follow-up. However, this represents a great start."

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Co-authors of this study were Robert Lustig, MD, Zelig Tochner, MD, and Stefan Both, PhD; like Hill-Kayser, all are from the Department of Radiation Oncology of the Perelman School of Medicine at the University of Pennsylvania. Co-authors Anne Reilly, MD, Naomi Balamuth, MD, Richard Womer, MD, John Maris, MD, Stephan Grupp, MD, PhD, and Rochelle Bagatell, MD, are from the Cancer Center for Children at CHOP.

Hill-Kayser et al, “Proton versus photon radiation therapy for patients with high-risk neuroblastoma: The need for a customized approach,” Pediatric Blood & Cancer, published online, June 4, 2013. DOI: 10.1002/pbc.24606

Children's Hospital of Philadelphia

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Tumor suppressor may provide clues for improved treatment for neuroblastoma

Main Category: Neurology / Neuroscience
Also Included In: Cancer / Oncology;  Stem Cell Research
Article Date: 14 Aug 2013 - 0:00 PDT Current ratings for:
Tumor suppressor may provide clues for improved treatment for neuroblastoma

Loss of a gene required for stem cells in the brain to turn into neurons may underlie the most severe forms of neuroblastoma, a deadly childhood cancer of the nervous system, according to a Ludwig Cancer Research study. Published in Developmental Cell, the findings also provide clues about how to improve the treatment of this often-incurable tumor.

Neuroblastoma can appear in nervous tissue in the abdomen, chest and spine, among other regions of the body, and can spawn body-wracking metastasis. The most severe tumors respond poorly to treatment, and the disease accounts for 15 percent of cancer deaths in children.

Johan Holmberg, PhD, at the Ludwig Institute for Cancer Research Stockholm took a close look at the role of the CHD5 tumor suppressor during normal nervous system development. Previous studies had shown that the gene CHD5 is often inactivated in the most severe forms of neuroblastoma, but little was known about its function in healthy tissue or how it operates. The study, which was conducted in close collaboration with colleagues at Trinity College, Dublin, Ireland, addressed these two key issues.

The researchers found that CHD5 is required for the cellular transition from a stem cell to a mature neuron. In one experiment, the researchers knocked down the CHD5 gene by injecting a small RNA into the brains of fetal mice while in the womb.

"The result was a complete absence of neurons," says Ludwig researcher Holmberg who is based at the Karolinska Institutet. "Instead of becoming neurons, the cells with CHD5 knocked down stayed in a limbo-like state between an actively-dividing stem cell and a mature nerve cell. It was a very robust effect," added Holmberg.

The researchers also dissected how CHD5 operates, showing that it sticks to certain modifications of histone proteins. These modifications help control how genes are turned on and off. In the absence of CHD5, key stem cell genes are not turned off, and genes required for neuronal maturation are not turned on. The findings highlight how the failure of a cell to properly mature into its terminal state can underlie cancer, a relatively understudied area of research.

"It is necessary for cells in the healthy nervous tissue to be able to go from stem cells to neurons," explains Holmberg. "If you lose this capacity, these cells become locked in an immature state, which might yield quite dangerous tumor cells, especially in combination with additional cancer-promoting cellular events."

The research could also lead to new ways to treat neuroblastoma, perhaps using currently approved drugs. One component of neuroblastoma treatment is retinoic acid, a drug that can drive neuronal maturation. Holmberg and his colleagues found that knocking down the expression of CHD5 in more benign neuroblastoma cells blocked their capacity to mature in response to retinoic acid treatment. "These cells were completely insensitive to treatment, no matter how much we gave them, mirroring the same unresponsiveness to retinoic acid in the more malignant CHD5-negative neuroblastoma cells," says Holmberg.

The results of these cell-based experiments are consistent with clinical findings that retinoic acid is often unsuccessful in patients with severe forms of the disease. Holmberg reasons that if CHD5 could be re-activated in such hard-to-treat patients, it might increase responsiveness to retinoic acid. The findings may also have relevance for other types of tumors. For instance, CHD5 is often inactivated in glioblastoma multiforme, the most common and most aggressive form of brain cancer in adults.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Funding for this research came in part from Science Foundation Ireland; the Health Research Board; the Swedish Cancer Society, the Swedish Research Council, the Lilian Sagen and Curt Eriksson Research Foundation; DBRM; the Swedish Childhood Cancer Foundation; the Danish National Research Foundation; the Lundbeck Foundation; and the Novo Nordisk Foundation.

CHD5 Is Required for Neurogenesis and Has a Dual Role in Facilitating Gene Expression and Polycomb Gene Repression

Developmental Cell, Volume 26, Issue 3, 223-236, 12 August 2013. 10.1016/j.devcel.2013.07.008

Ludwig Institute for Cancer Research

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