Un virus détruit les cellules souches cancéreuses.

Mise à jour, l'article date de février 2016

For searching efficient drugs in targeting CSCs, researchers used unidentified drug pool or FDA
approved drugs to treat CSCs. The effect of the small molecules on the cell viability or stemness
on CSCs will be evaluated. One or several putative efficient drugs will be selected for further
confirmation. In 2012, Sachlos, E, et al. used compound libraries to screen drugs on the neoplastic
and normal human Pluripotent Stem Cells (hPSC). The cell viability and differentiation were both
considered for drug selection. The authors found an interesting drug, thoridazine, an antipsychotic
drug. It was also demonstrated with inhbitory effect on leukemia and breast CSCs in this paper.
Thoridazine is an inhibitor of dopamine receptor D2 family proteins [13]. It has already been
approved by FDA and classically used to treat patients with psychotic problems. The novel function
of the old drug
The novel function of the old drug attracted lots of attentions. People found inhibitory ability
of thioridazine on cancer cells or CSCs in various types of cancers, gastric cancer, cervical cancer,
liver cancer, glioblastoma, endometrial cancer and ovarian cancer. Thioridazine could induce CSCs
apoptosis and inhibit cell viability in vitro. It also prevented tumor growth in vivo. Thioridazine
regulates the key pathways, FAK-mTOR [14], PI3K/Akt/mTOR, to alter cells viability in vitro
and in vivo [15]. Thioridazine was also wrapped into nanomaterial to target CSCs [16]. Besides
the effect of thoridazine, the expression of dopamine receptors and
their correlation with cancer prognosis were analyzed. These further
support the function of thoridazine in targeting CSCs.
In the Cell paper, Sachlos, E. et al. found the novel anti-CSCs
function of an old antipsychotic drug thioridazine. Its effect was
further confirmed by other researchers in the various kinds of
cancers. As thioridazine is a FDA approved drug, it will easily be
used for clinical research on cancer by targeting CSCs. This is a big
advantage in comparison with new developed drugs. Its application
in cancer therapy will be largely shortened.

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Pour la recherche de médicaments efficaces dans le ciblage CSCs, les chercheurs ont utilisé une liste de médicaments non identifiés ou des médicaments approuvés FDA pour traiter CSCs. L'effet des petites molécules sur la viabilité cellulaire sur les cellules souches CSCs seront évaluées. Un ou plusieurs médicaments efficaces potentiellement seront sélectionnés pour plus amples confirmation.
En 2012, Sachlos, E, et al. ont utilisé des bibliothèques de molécules  pour cribler des médicaments sur les cellules néoplasiques et les cellules normales souches pluripotentes humaines (HPSC). La viabilité cellulaire et la différenciation étaient à la fois pris en considération pour la sélection de médicaments. Les auteurs ont trouvé un médicament intéressant, le thoridazine, un médicament antipsychotique. Il a également été démontré ayant un effet inhbiteur sur les  CSCs de la leucémie et du cancer du dans le présent document. La Thoridazine est un inhibiteur du récepteur de la dopamine D2 de la famille des protéines. Il a déjà été approuvé par la FDA et classiquement utilisé pour traiter les patients atteints de troubles psychotiques.

La nouvelle fonction de l'ancien médicament a attiré beaucoup d'attentions. Les gens ont trouvé la capacité inhibitrice de la thioridazine sur les cellules cancéreuses ou des cellules souches cancéreuses dans divers types de cancers, le cancer gastrique, le cancer du col utérin, cancer du , le glioblastome, le cancer de l'endomètre et le cancer de l'ovaire  . La Thioridazine pourrait induire  l'apoptose des CSCs et inhiber la viabilité des cellules in vitro. Elle a également empêché la croissance tumorale in vivo. La thioridazine régule les principales voies, FAK-mTOR [14], PI3K / Akt / mTOR, pour modifier la viabilité des cellules in vitro
et in vivo [15]. La Thioridazine a également été enveloppé dans des nanomatériaux pour cibler les CSCs. Outre l'effet de la thoridazine, l'expression des récepteurs de la dopamine et leur corrélation avec le pronostic du cancer ont été analysés. ces autres soutenir la fonction de thoridazine dans le ciblage CSCs.

Dans le document de Cell, Sachlos, E. et al. a trouvé la nouvelle fonction anti-CSCs d'un vieux médicament antipsychotique appelé thioridazine. Son effet a été en outre confirmée par d'autres chercheurs dans les différents types de cancers. Comme thioridazine est un médicament approuvé par la FDA, il sera facilement être utilisé pour la recherche clinique sur le cancer en ciblant les cellules souches cancéreuses. Ceci est un grand avantage par rapport à de nouveaux médicaments développés. Son application dans le traitement du cancer sera largement raccourcie.

Le Dr Mick Bhatia, un expert des cellules souches cancéreuses de renommée mondiale, a découvert qu’un médicament actuellement utilisé comme antipsychotique, la thioridazine, détruit avec succès les cellules souches à l’origine des leucémies tout en épargnant les cellules souches normales. Les cellules souches cancéreuses favorisent le développement du cancer et elles joueraient un rôle dans la récidive du cancer après le traitement. Les chercheurs souhaitent mener des essais cliniques pour évaluer le médicament notamment chez des patients atteints d’une leucémie aiguë myéloblastique qui a récidivé après un traitement de chimiothérapie.

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A tailored virus destroys brain tumor stem cells that resist other therapies and cause lethal re-growth of cancer after surgery, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in the Sept. 18 edition of the Journal of the National Cancer Institute.

Un virus modifié détruit les cellules souches du cancer du cerveau qui résistent aux autre thérapies et qui causent la resurgence du cancer après la chirurgie, selon une étude conduite par les sicentifiques de l'université du Texas.

"We have shown first in lab experiments and then in stem cell-derived human brain cancer in mice, that we have a tool that can target and eliminate the cells that drive brain tumors," says co-senior author Juan Fueyo, M.D., associate professor in M. D. Anderson's Department of Neuro-Oncology. A request to launch a clinical trial of the virus, called Delta-24-RGD, is expected to go to federal regulators this month.

"Nous l'avons démontré en premier dans les expériences de laboratoire et puis après sur les souris avec implantation de cancers humains, nous pouvons cibler et éliminer les cellulles qui font le cancer du ." dit Juan Fueyo. une demande d'essai clinique sur le virus appelé Delta-24-RGD devrait être acheminé au fédéral ce mois-ci.

The virus was tested against the most aggressive brain tumor - glioblastoma multiforme, which originates in the glial cells that surround and support neurons. It is highly resistant to radiation and chemotherapy and so invasive that surgery almost never eliminates it. Patients suffering from this malignant glioma live on average for about 14 months with treatment.

Fueyo and colleagues developed Delta-24-RGD to prey on a molecular weakness in tumors and altered the virus so it could not replicate in normal tissue. They showed in a JNCI paper in 2003 that the virus eliminated brain tumors in 60 percent of mice who received injections directly into their tumors. The virus spreads in a wave through the tumors until there are no cancer cells left, then it dies.

Since 2004 scientists have found that brain tumors are driven by haywire stem cells that replicate themselves, differentiate into other types of cells, and bear protein markers like normal stem cells.

"Research has shown that these cancer stem cells are the origin of the tumor, that they resist the chemotherapy and radiation that we give to our patients, and that they drive the renewed growth of the tumor after surgery," Fueyo said. "So we decided to test Delta-24-RGD against glioma stem cells and tumors grown from them."

The research team led by Fueyo, co-senior author Frederick Lang, M.D., professor in M. D. Anderson's Department of Neurosurgery, and first author Hong Jiang, Ph.D., instructor in neuro-oncology, derived four brain tumor stem cell lines from four specimens of glioblastoma multiforme. All four lines exhibited the characteristics and protein signatures of stem cells. Delta-24 succeeded in killing all four types in the lab.

Next, the researchers grafted the stem cell lines into the brains of mice and treated the resultant tumors with injections of Delta-24-RGD. Untreated mice had a mean survival time of 38.5 days, while treated mice had a mean survival of 66 days. Two of the eight treated mice survived for 92 days, until the end of the experiment, with no neurological symptoms.

Les souris non-traitées ont une survivance de 38.5 jours tandis que celles traitées ont une survivance de 66 jours. 2 des 8 traitées ont survécu 92 jours soit jusqu'à la fin de l'expérience sans symptômes de la maladie.

"It's important in animal models to see improvement in survival in the majority of animals, but to have some be cured and survive a long time without neurological symptoms is very rare," Fueyo said. "We have to be cautious, because an animal model doesn't fully represent humans, but the tumors grown by these stem cells closely resemble the tumors we see in our patients, which is an exciting finding in itself."

Tumors in other mouse models tend to be round and self-contained, explains co-senior author and Frederick Lang, M.D., professor in M. D. Anderson's Department of Neurosurgery. Malignant tumors in patients are never round, they invade other tissues and delve deeply into the brain. The cancer stem cell-derived tumors in these experiments have the irregular shape and invasive characteristics of their human counterparts.

"That similarity to the human tumor is encouraging," Lang said. "And it's also encouraging that we got basically the same results with Delta-24-RGD in this experiment that we got in our earlier experiment using other tumor models."

A clinical quality version of Delta-24-RGD has been manufactured by the National Cancer Institute and an independent consultant has completed a toxicology assessment. An Investigational New Drug Application to proceed with a phase I clinical trial is expected to be filed with the U.S. Food and Drug Administration in September. A clinical trial could began as early as this fall.

Delta-24-RGD exploits the fact that a protein called retinoblastoma (Rb) is either missing or defective in brain tumors. Rb normally guards against both the proliferation of cancerous cells and against viral infection. So the virus has an easier time invading tumors and replicating in its cells. Adenoviruses attacking normal cells employ their own protein, E1A, to counteract retinoblastoma's defensive measures. To keep Delta-24-RGD out of normal cells, Fueyo and colleagues deleted a small part of the gene that produces E1A.

The JNCI paper shows that Delta-24-RGD forces tumor cells to devour themselves until they die. This self-cannibalization, called autophagy, occurs when a cell forms a membrane around part of its cytoplasm or an organelle and then digests the contents, leaving a cavity. A cell that dies from autophagy is riddled with cavities.

Cells normally employ autophagy temporarily to survive when nutrients are short, to recycle components to form new organelles, or to fend off viral or bacterial infection. In cancer research, there is evidence both that autophagy is a form of programmed cell death triggered to prevent the replication of damaged cells and that cancer cells in some instances employ it to survive attack.

"Our next experiments will address whether the cell kills itself or dies defending itself against the virus," Fueyo says. Sure, the cell dies either way, but the distinction is important, Fueyo says, because the virus could be redesigned to either fuel or block autophagy to make it more effective. The autophagic protein Atg5 is heavily expressed in the dead tumor cells, making it a potential biomarker of the virus' effectiveness.