C'est pratique un poisson tranparent

More than 4,000 children and teens are diagnosed with brain cancer each year and the disease kills more children than any other cancer. Writing this week in the journal Cell Reports, researchers at Huntsman Cancer Institute (HCI) at the University of Utah report they have identified an existing group of drugs that appear to reduce or eliminate a certain subgroup of childhood brain cancers while sparing normal brain tissue. The research was conducted using a new zebrafish animal model system developed by the researchers, which closely resembles an aggressive subtype of pediatric brain tumors.

"For many pediatric brain tumors no cell or animal model exist to test targeted, or personalized, medications that could significantly improve survival and alleviate the harmful side effects of conventional therapies," explains Rodney Stewart, PhD, an assistant professor in the Department of Oncological Sciences at the University of Utah and an HCI investigator. "Indeed, children with rare brain tumors have few options for life-saving treatment. Our hope is by creating this animal model we will be a step closer to finding effective therapies."

The researchers studied a particularly aggressive pediatric brain tumor, known as primitive neuroectodermal tumors of the central nervous system (CNS-PNET) for which few animal or cell line models exist. Without an animal model or cell lines, Stewart explained, treatments could not be tested. Over the course of seven years, Stewart and his team worked to develop a model which, at the genomic level, closely modeled the human condition they hoped to study.

"We spent a lot of time comparing brain tumors arising in fish with related human brain cancers at the molecular genetic level," Stewart says. "This is important because these childhood brain cancers are rare and as a result, there are few patient samples to study for comparisons."

Human tissue samples were necessary, however, in order to construct a reliable model. "We needed to reach out to several groups," he explains, including Primary Children's Hospital in Salt Lake City and The Hospital for Sick Children in Toronto.

Dr. Stewart credits discoveries announced by two other groups studying similar cancers that opened the way for his group to move forward. "They were able to re-classify CNS-PNET tumors into distinct subgroups at the molecular level. That opened up a new avenue for our team because that stratification made it possible for us to really nail down what the zebrafish brain tumor model represents."

Using the model, Stewart's lab was able to test already existing compounds to see if they could find a targeted therapy that would work on one of the newly identified subgroups: the oligoneural or NB_FOXR2 CNS-PNET subgroup. Through work they had done to create the tumor model, they knew that a particular drug already in human clinical trials might work.

"When we treated the fish with MEK inhibitors -- drugs that inhibit an enzyme -- they exhibited a remarkable response," says Stewart. "Not only was the tumor burden reduced, it completely eliminated the tumor in about 80% of the fish and those tumors have not come back. This is a durable response from a transient treatment. It's what we look for in cancer therapy, an effective drug that can be taken for a certain amount of time but, after the cancer is gone, patients can stop taking the drug and go on living their lives."

Stewart is careful to emphasize that while the brain tumor type between fish and humans is similar, more studies are needed to determine if the results can be translated into the clinic. He would like to see his discovery in the hands of physicians as soon as possible. "Currently, the outcome for children with these cancers is deplorable. We don't want to wait much longer," he says.

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Plus de 4 000 enfants et adolescents sont diagnostiqués avec un cancer du cerveau chaque année et la maladie tue plus d'enfants que tout autre cancer. Les chercheurs du Huntsman Cancer Institute (HCI) de l'Université d'Utah ont écrit qu'ils avaient identifié un groupe existant de médicaments qui semblent réduire ou éliminer un certain sous-groupe de cancers du cerveau chez l'enfant tout en épargnant le tissu cérébral normal. La recherche a été menée à l'aide d'un nouveau modèle de modèle animal zebrafish développé par les chercheurs, qui ressemble de près à un sous-type agressif de tumeurs cérébrales pédiatriques.

"Pour de nombreuses tumeurs cérébrales pédiatriques, il n'existe pas de modèle cellulaire ou animal pour tester des médicaments ciblés ou personnalisés qui pourraient améliorer considérablement la survie et atténuer les effets secondaires nocifs des thérapies conventionnelles", explique Rodney Stewart, PhD, professeur adjoint au Département d'Oncologie Sciences de l'Université de l'Utah et un chercheur HCI. "En effet, les enfants atteints de tumeurs cérébrales rares ont peu d'options de traitements qui leur sauveraient la vie. Notre espoir est en créant ce modèle animal, nous serons plus près de trouver des thérapies efficaces.

Les chercheurs ont étudié une tumeur cérébrale pédiatrique particulièrement agressive, connue sous le nom de tumeurs neuroectodermiques primitives du système nerveux central (CNS-PNET) pour lequel il existe peu de modèles de lignées cellulaires ou animales. Sans un modèle animal ou des lignées cellulaires, Stewart a expliqué, les traitements ne pouvaient pas être testés. Au cours de sept ans, Stewart et son équipe ont travaillé à l'élaboration d'un modèle qui, au niveau génomique, modélise étroitement la condition humaine qu'ils espèrent étudier.

«Nous avons passé beaucoup de temps à comparer les tumeurs cérébrales survenant chez les poissons avec des cancers du cerveau humains liés au niveau de la génétique moléculaire», dit Stewart. «C'est important parce que ces cancers du cerveau chez l'enfant sont rares et, par conséquent, il ya peu d'échantillons de patients à étudier pour les comparaisons.

Des échantillons de tissus humains ont cependant été nécessaires pour construire un modèle fiable. «Nous avions besoin de toucher plusieurs groupes», explique-t-il, y compris l'Hôpital pour enfants de Salt Lake City et l'Hôpital pour enfants malades de Toronto.

Le dr Stewart attribue des découvertes annoncées par deux autres groupes étudiant des cancers semblables qui ont ouvert la voie à son groupe pour aller de l'avant. «Ils ont pu ré-classifier les tumeurs du SNC-PNET en différents sous-groupes au niveau moléculaire. Cela a ouvert une nouvelle avenue pour notre équipe parce que cette stratification nous a permis de vraiment attaquer ce modèle de tumeur cérébrale du poisson zèbre.

En utilisant le modèle, le laboratoire de Stewart a pu tester des composés déjà existants pour voir s'ils pouvaient trouver une thérapie ciblée qui fonctionnerait sur l'un des sous-groupes nouvellement identifiés: Pour sous-groupe oligonucléaire ou NB_FOXR2 CNS-PNET. Grâce au travail qu'ils avaient fait pour créer le modèle de tumeur, ils savaient qu'un médicament particulier, déjà dans les essais cliniques humains, pourrait fonctionner.

«Lorsque nous avons traité le poisson avec des inhibiteurs de MEK - médicaments qui inhibent une enzyme - ils ont présenté une réponse remarquable», explique Stewart. "Non seulement la charge tumorale a-t-elle été réduite, mais elle a complètement éliminé la tumeur dans environ 80% des poissons et ces tumeurs ne sont pas revenues. C'est une réponse durable d'un traitement transitoire. Le médicament peut être pris pendant un certain laps de temps, mais, après que le cancer soit parti, les patients peuvent cesser de prendre le médicament et continuer à vivre leur vie.

Stewart fait attention de souligner que si le type de tumeur cérébrale entre le poisson et les humains est semblable, il faut faire plus d'études pour déterminer si les résultats peuvent être traduits dans la clinique. Il voudrait voir sa découverte dans les mains des médecins dès que possible. "Actuellement, le résultat pour les enfants atteints de ces cancers est déplorable. Nous ne voulons pas attendre plus longtemps", dit-il.

Primitive neuroectodermal tumors (PNETs) are the largest group of malignant brain tumors in children. They can arise from the brain's cerebellum or, more rarely, from tissue located throughout the central nervous system (CNS). Little is known about how CNS-PNETs develop, although these tumors are more aggressive than other PNETs and have an overall survival rate of only about 20 percent. In a new study, researchers for the first time have identified a possible target for a new CNS-PNET therapy.

The study was carried out by researchers from the University of Utah Huntsman Cancer Institute in Salt Lake City and the University of Toronto Hospital for Sick Children in Ontario, Canada. Using zebrafish, they developed the first animal model for the oligoneural subtype of CNS-PNET. A novel drug screening platform for zebrafish brain tumors was then designed to identify drugs that could eliminate brain tumors without affecting development of the normal brain. These studies showed that inhibiting the activity of the signaling protein MEK was essential for these tumors to grow. As these compounds are already approved for clinical trails in pediatric brain tumors, these findings suggest that drugs inhibiting MEK activity could offer a new therapy option for children with these devastating tumors.

Rodney Stewart will present this research on Saturday, July 16 from 3:15 -- 3:30 p.m. during the Cancer symposium in Grand Ballroom 7B as part of The Allied Genetics Conference, Orlando World Center Marriott, Orlando, Florida

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Les tumeurs neuroectodermiques primitives (d'origine neuroectodermique) sont le plus grand groupe de tumeurs malignes du chez les enfants. Elles peuvent provenir du cervelet du cerveau ou, plus rarement, de tissus situés dans le système nerveux central (SNC). On sait peu sur la façon dont les SNC-PNETs développent, bien que ces tumeurs soient plus agressifs que d'autres PNETs et ont un taux de survie globale de seulement environ 20 pour cent. Dans une nouvelle étude, les chercheurs ont pour la première fois ont identifié une cible possible pour une nouvelle thérapie CNS-TNEP.

L'étude a été réalisée par des chercheurs de l'Université de l'Utah Huntsman Cancer Institute à Salt Lake City et l'Université de Toronto Hospital for Sick Children en Ontario, Canada. En utilisant le zebrafish, ils ont développé le premier modèle animal pour le sous-type oligoneural du CNS-TNEP. Une plate-forme de criblage de médicaments nouveaux pour les tumeurs cérébrales de poisson zèbre a ensuite été conçu pour identifier les médicaments qui pourraient éliminer les tumeurs cérébrales, sans affecter le développement du cerveau normal. Ces études ont montré que inhiber l'activité de la protéine MEK était essentielle dans le cas de ces tumeurs. Comme ces composés sont déjà approuvés pour les essais cliniques dans les tumeurs cérébrales pédiatriques, ces résultats suggèrent que médicaments inhibant l'activité MEK pourraient offrir une nouvelle option thérapeutique pour les enfants avec ces tumeurs dévastatrices.

Rodney Stewart présentera cette recherche, le samedi 16 Juillet à partir de 3 heures 15-15:30 au cours du symposium sur le cancer au Grand Ballroom 7B dans le cadre de la Conférence de génétique alliée, Orlando World Center Marriott, Orlando, Floride

Un poisson transparent peut-être une bonne idée pour avoir des processus qui se font en dedans du corps.

(Feb. 6, 2008) — Zebrafish are genetically similar to humans and are good models for human biology and disease. Now, researchers at Children's Hospital Boston have created a zebrafish that is transparent throughout its life. The new fish allows scientists to directly view its internal organs, and observe processes like tumor metastasis and blood production after bone-marrow transplant in a living organism.

...permets aux scientifiques d'observer des processus comme la métastatisation des tumeurs et la production de sang après la transplantation de la moelle.

The fish, described in the February 7 issue of Cell Stem Cell, was created by Richard White, MD, PhD, a clinical fellow in the Stem Cell Program at Children's, with others in the laboratory of Leonard Zon, PhD.

The classic method for studying human diseases in animals is to allow the animal to get the disease, kill and dissect the animal, then ask, "what happened?" But in cancer and other fast-changing processes that traverse the body, this method is bound to miss something. "It's like taking a photograph when you need a video," says White, also an instructor of medicine at the Dana-Farber Cancer Institute.

Zebrafish embryos have enabled researchers to study disease in live organisms, since they are transparent. But zebrafish adults are opaque. "Everything after four weeks has been invisible to us," says White.

White's first experiment on the zebrafish examined how a cancer spreads. "The process by which a tumor goes from being localized to widespread and ultimately fatal is the most vexing problem that oncologists face," says White. "We don't know why cancer cells decide to move away from their primary site to other parts in the body."

White created a fluorescent melanoma tumor in the transparent fish's abdominal cavity. Viewing the fish under a microscope, White saw the cancer cells begin to spread within five days. He even saw individual cells metastasize, something that has not been observed, so readily and in real-time, in a living organism.

The spreading melanoma cells appeared to "home" to the skin after leaving the abdominal cavity. "This told us that when tumor cells spread to other parts in the body, they don't do it randomly," says White. "They know where to go."
White plans to study tumor cell homing, then look for ways to modify the tumor cells or cells of the host so that the spreading cells never find their new location.


Quand les tumeurs se répandent à travers le corps, elles ne le font pas au hasard.

The fish may also answer questions about stem cell transplants. While transplants of blood-forming stem cells help cancer patients rebuild healthy blood, some transplants don't "take," for reasons that are unknown. Scientists have lacked a full understanding what steps blood stem cells must take to do their job, says White.

White showed the process is observable in the fish. He first irradiated a transparent fish's bone marrow, then transplanted fluorescent blood-forming stem cells from another zebrafish. By four weeks, the fluorescent stem cells had visibly migrated and grown in the fish's bone marrow, which is in the kidney. Even individual stem cells were visible, something researchers haven't easily observed in a living organism, White says.

By studying how the stem cells embed and build blood in the fish, scientists can look for ways to help patients rebuild their blood faster. Drugs and genes could be tested in the living fish, with direct observation of results, White says.
White created the transparent fish simply by mating two existing zebrafish breeds. Zebrafish have three pigments in their skin--reflective, black, and yellow. White mated a breed that lacks reflective pigment, called "roy orbison," with one that lacks black pigment, called "nacre." The offspring had only yellow pigment in their skin, essentially looking clear. White named the new breed "casper."

The fish's brain, heart, and digestive tract are also visible, allowing researchers to study genetic defects of these organs from early embryonic development through adulthood. White hopes this tool will provide insight into how mutated genes cause diseases ranging from Alzheimer's disease to inflammatory bowel disease.
"What happens in a living organism is different than what happens in a dish," White says.