chloroquine

A new study shows that a 70-year-old malaria drug can block immune cells in the liver so nanoparticles can arrive at their intended tumor site, overcoming a significant hurdle of targeted drug delivery, according to a team of researchers led by Houston Methodist.

Many cancer patients do not respond to chemotherapies because the drugs never reach the cancer cells. Even in nanomedicine, which is one of the best new methods for delivering drugs to a tumor, only about one percent of a dose of nanoparticles will successfully arrive at the intended tumor site, while the rest are filtered out by the immune cells of the liver and spleen.

Using chloroquine, the researchers not only increased the circulation of nanoparticles in the body, but also reduced the body's filtration of nanoparticles, as well as improved drug delivery to breast tumors. The study was recently published in Scientific Reports, a research journal from the Nature Publishing Group.

Led by Mauro Ferrari, Ph.D., president and CEO of the Houston Methodist Research Institute, and Joy Wolfram, Ph.D. (now at Mayo Clinic's campus in Jacksonville, Florida), the research showed that chloroquine interfered with immune cells called macrophages, which are used by the body to identify microscopic foreign objects and destroy them.

In this study, mice models received injections of chloroquine, followed by an injection of nanoparticles. Chloroquine decreased the macrophages' ability to clean up the nanoparticles. The findings are significant, because the nanoparticles not only remained in circulation, but also accumulated in mouse tumors, as well as in the lungs of healthy mice, suggesting that the approach also may enhance treatment for lung diseases.

Chloroquine was invented in the 1940s for the prevention and treatment of malaria. Since it mildly suppresses the immune system, the drug also is used in some autoimmune disorders, such as rheumatoid arthritis and lupus. Apart from this research, the drug is also being studied in other cancers, such as triple-negative breast cancer and pancreatic cancer.

Ferrari, considered one of the founders of nanomedicine and transport oncophysics (the physics of mass transport within a cancer lesion), says researchers and clinicians need to understand the limitations of transport mechanisms to identify effective immunotherapy treatments for patients.

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Une nouvelle étude montre qu'un médicament contre le paludisme âgé de 70 ans peut bloquer les cellules immunitaires dans le foie afin que les nanoparticules puissent atteindre le site tumoral voulu, surmontant ainsi un obstacle important à l'administration ciblée de médicaments.

Beaucoup de patients atteints de cancer ne répondent pas aux chimiothérapies parce que les médicaments n'atteignent jamais les cellules cancéreuses. Même en nanomédecine, qui est l'une des meilleures nouvelles méthodes pour administrer des médicaments à une tumeur, seulement environ un pour cent d'une dose de nanoparticules parviendra au site de la tumeur, tandis que le reste est filtré par les cellules immunitaires du foie et de la rate.

En utilisant la chloroquine, les chercheurs ont non seulement augmenté la circulation des nanoparticules dans le corps, mais ont également réduit la filtration des nanoparticules dans le corps, ainsi que l'administration de médicaments aux tumeurs du sein. L'étude a récemment été publiée dans Scientific Reports, un journal de recherche du Nature Publishing Group.

Dirigé par Mauro Ferrari, Ph.D., la recherche a montré que la chloroquine interférait avec les cellules immunitaires appelées macrophages, qui sont utilisés par le corps pour identifier les objets étrangers microscopiques et les détruire.

Dans cette étude, des modèles de souris ont reçu des injections de chloroquine, suivies d'une injection de nanoparticules. La chloroquine diminue la capacité des macrophages à nettoyer les nanoparticules. Les résultats sont significatifs, car non seulement les nanoparticules sont restées en circulation, mais aussi accumulées dans les tumeurs de souris, ainsi que dans les poumons de souris en bonne santé, ce qui suggère que l'approche peut également améliorer le traitement des maladies pulmonaires.

La chloroquine a été inventée dans les années 1940 pour la prévention et le traitement du paludisme. Comme il supprime modérément le système immunitaire, le médicament est également utilisé dans certains troubles auto-immunes, tels que la polyarthrite rhumatoïde et le lupus. En dehors de cette recherche, le médicament est également étudié dans d'autres cancers, tels que le cancer du triple négatif et le cancer du .

Ferrari, considéré comme l'un des fondateurs de la nanomédecine et de l'oncophysique des transports (la physique du transport de masse dans une lésion cancéreuse), affirme que les chercheurs et les cliniciens doivent comprendre les limites des mécanismes de transport pour identifier les traitements immunothérapeutiques efficaces.

After her brain cancer became resistant to chemotherapy and then to targeted treatments, 26-year-old Lisa Rosendahl's doctors gave her only a few months to live. Now a paper published January 17 in the journal eLife describes a new drug combination that has stabilized Rosendahl's disease and increased both the quantity and quality of her life: Adding the anti-malaria drug chloroquine to her treatment stopped an essential process that Rosendahl's cancer cells had been using to resist therapy, re-sensitizing her cancer to the targeted treatment that had previously stopped working. Along with Rosendahl, two other brain cancer patients were treated with the combination and both showed similar, dramatic improvement.

"When I was 21 they found a large mass in my brain and I had it resected right away. They tested it for cancer and it came back positive," Lisa says.

"Lisa is a young adult with a very strong will to live. But it was a high-risk, aggressive glioblastoma and by the time we started this work, she had already tried everything. For that population, survival rates are dismal. Miraculously, she had a response to this combination. Four weeks later, she could stand and had improved use of her arms, legs and hands," says paper first author Jean Mulcahy-Levy, MD, investigator at the University of Colorado Cancer Center and pediatric oncologist at Children's Hospital Colorado.

The science behind the innovative, off-label use of this malaria drug, chloroquine, was in large part built in the lab of Andrew Thorburn, PhD, deputy director of the CU Cancer Center, where Mulcahy-Levy worked as a postdoctoral fellow, starting in 2009. Thorburn's lab studies a cellular process called autophagy. From the Greek "to eat oneself," autophagy is a process of cellular recycling in which cell organelles called autophagosomes encapsulate extra or dangerous material and transport it to the cell's lysosomes for disposal. In fact, the first description of autophagy earned the 2016 Nobel Prize in Medicine or Physiology for its discoverer, Yoshinori Ohsumi.

Like tearing apart a Lego kit, autophagy breaks down unneeded cellular components into building blocks of energy or proteins for use in surviving times of low energy or staying safe from poisons and pathogens (among other uses). Unfortunately, some cancers use autophagy to keep themselves safe from treatments.

"My initial lab studies were kind of disappointing. It didn't look like there was much effect of autophagy inhibition on pediatric brain tumors. But then we found that it wasn't no effect across the board -- there were subsets of tumors in which inhibition was highly effective," Mulcahy-Levy says.

Mulcahy-Levy's work with Thorburn (among others), showed that cancers with mutations in the gene BRAF, and specifically those with a mutation called BRAFV600E, were especially dependent on autophagy. In addition to melanoma, in which this mutation was first described, epithelioid glioblastomas are especially likely to carry BRAFV600E mutation.

With this new understanding, Mulcahy-Levy became an essential link between Thorburn's basic science laboratory and the clinical practice of oncologist, Nicholas Foreman, MD, CU Cancer Center investigator and creator of the pediatric neuro-oncology at Children's Hospital Colorado, who had been overseeing Lisa's care.

After many surgeries, radiation treatments and chemotherapy, Lisa had started the drug vermurafenib, which was originally developed to treat BRAF+ melanoma and is now being tested in pediatric brain tumors. Lisa's experience on the drug was typical of patients with BRAF+ cancers who are treated with BRAF inhibitors such as vemurafenib -- after a period of control, cancer develops additional genetic mechanisms to drive its growth and survival and is able to progress past the initial drug.

At that point, one promising strategy is to predict and/or test for new genetic dependencies and then treat any new dependency with another targeted therapy. For example, many BRAF+ cancers treated with BRAF inhibitors develop KRAS, NRAS, EGFR or PTEN changes that drive their resistance, and treatments exist targeting many of these "escape pathways." However, some cancers develop multiple resistance mechanisms and others evolve so quickly that it can be difficult to stay ahead of these changes with the correct, next targeted treatment.

"It's like that story of the boy who puts his finger in the dam," Mulcahy-Levy says. "Eventually you just can't plug all the holes."

Instead of this genetic whack-a-mole, the group chose to explore cellular mechanisms outside what can be a never-ending sequence of new mutations.

"Pre-clinical and clinical experience invariably shows that tumor cells rapidly evolve ways around inhibition of mutated kinase pathways like the BRAF pathway targeted here," the paper writes. "However, based on our results, we hypothesize that by targeting an entirely different cellular process, i.e. autophagy, upon which these same tumor cells rely, it may be feasible to overcome such resistance and thus re-establish effective tumor control."

In other words, knowing that Lisa Rosendahl's tumor was positive for BRAFV600E mutation, and that this marked the tumor as especially dependent on autophagy -- and also knowing that traditional options and even clinical trials were nonexistent -- the group worked with Rosendahl and her father, Greg, to add the autophagy-inhibiting drug chloroquine to her treatment.

"In September 2015, the previous targeted drugs weren't working anymore," says Greg Rosendahl. "Doctors gave Lisa less than 12 months to live. We took all our cousins up to Alaska for a final trip kind of thing. Then they came up with this new combination including chloroquine."

Vemurafenib had initially pushed Lisa's cancer past the tipping point of survival. Then the cancer had learned to use autophagy to pull itself back from the brink. Now with chloroquine nixing autophagy, vemurafenib started working again.

"My cancer got smaller, which is awesome for me," Lisa says.

"We have treated three patients with the combination and all three have had a clinical benefit. It's really exciting -- sometimes you don't see that kind of response with an experimental treatment. In addition to Lisa, another patient was on the combination two-and-a-half years. She's in college, excelling, and growing into a wonderful young adult, which wouldn't have happened if we hadn't put her on this combination," Mulcahy-Levy says.

Lisa recently bought a new wheelchair so that she could spend more time at the mall. She also applied for a handicap sticker to make it easier for her to visit a nearby park with food trucks. "She wants to get out and do more. She continues to have what she feels is a good quality of life," Mulcahy-Levy says.

Research accompanying these results in patients implies that the addition of autophagy inhibition to targeted treatments may have benefits beyond glioblastoma and beyond only BRAF+ cancers. Because chloroquine has already earned FDA approval as a safe and effective (and inexpensive) treatment for malaria, the paper points out that it should be possible to "quickly test" the effectiveness of adding autophagy inhibition to a larger sample of BRAF+ glioblastoma and other brain tumor patients, and also to possibly expand this treatment to other likely mutations and disease sites.

As Mulcahy-Levy's early studies show, many cancers do not depend on autophagy. But at the same time, many do. Because a safe and simple drug already exists to inhibit autophagy, the time between discovering an autophagy-dependent cancer and the ability to add autophagy-inhibiting chloroquine to a treatment regimen against this cancer may be short.

"I really like being able to really tailor therapy to the patient," Mulcahy-Levy says. "I like saying, 'I think this is going to be really important to you,' and not necessarily using the same treatment with another patient whose cancer is driven by different genetic alterations. This is the definition of patient-centered care -- designing therapy based on that individual patient's information. It's not just glioblastoma, but a certain mutation and not just the mutation but a certain pattern of previous treatments and resistance."

"It makes me feel really lucky to be a pioneer in this treatment," says Lisa Rosendahl. "I hope it helps and I hope it helps people down the road. I want it to help."

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Après que son cancer du cerveau soit devenu résistant à la chimiothérapie et puis à des traitements ciblés, les médecins Lisa Rosendahl, 26 ans, lui ont donné quelques mois à vivre. Un article publié le 17 janvier dans la revue eLife décrit une nouvelle combinaison de médicaments qui a stabilisé la maladie de Rosendahl et augmenté à la fois la quantité et la qualité de sa vie: l'ajout de la chloroquine à son traitement a arrêté un processus essentiel que les cellules cancéreuses de Rosendahl avaient utilisé pour résister à la thérapie, ré-sensibilisant son cancer au traitement ciblé qui avait auparavant arrêté de travailler. Avec Rosendahl, deux autres patients atteints de cancer du ont été traités avec la combinaison et les deux ont montré une amélioration similaire.

"Quand j'avais 21 ans, ils ont trouvé une grosse masse dans mon cerveau et je l'ai fait tester tout de suite. Ils ont testé pour le cancer et c'est revenu positif", dit Lisa.

«Lisa est une jeune adulte avec une très forte volonté de vivre, mais c'était un glioblastome agressif et à haut risque, et au moment où nous avons commencé ce travail, elle avait déjà tout essayé. Pour cette population, les taux de survie sont moroses. Miraculeusement, elle a eu une réponse à cette combinaison. Quatre semaines plus tard, elle pouvait se tenir debout et a amélioré l'utilisation de ses bras, de ses jambes et de ses mains », explique le premier auteur du papier Jean Mulcahy-Levy, MD, investigateur à l'Université du Colorado Cancer Center et oncologue pédiatrique À l'Hôpital des enfants du Colorado.

La science derrière l'utilisation hors étiquette de ce médicament de la malaria, la chloroquine, a été construite en grande partie dans le laboratoire de Andrew Thorburn, Ph.D., directeur adjoint du Centre de cancer de CU, où Mulcahy-Levy a travaillé comme étudiant postdoctoral, commençant en 2009. Le laboratoire de Thorburn étudie un processus cellulaire appelé autophagie. Du grec "se manger soi-même", l'autophagie est un processus de recyclage cellulaire dans lequel des organelles cellulaires appelées autophagosomes encapsulent des matériaux supplémentaires ou dangereux et le transportent aux lysosomes de la cellule pour l'élimination. En fait, la première description de l'autophagie a mérité le prix Nobel 2016 en médecine ou physiologie pour son découvreur, Yoshinori Ohsumi.

Comme déchirant un kit Lego, l'autophagie décompose les composants cellulaires inutiles en blocs d'énergie ou de protéines pour une utilisation dans des temps de survie de faible énergie ou de rester à l'abri des poisons et pathogènes (entre autres). Malheureusement, certains cancers utilisent l'autophagie pour se protéger contre les traitements.

«Mes premières études de laboratoire ont été assez décevantes, et il n'a pas semblé qu'il y ait eu beaucoup d'effet de l'inhibition de l'autophagie sur les tumeurs cérébrales pédiatriques, mais lorsque nous avons constaté qu'il n'y avait pas d'effet globale, il y avait des sous-unités dont l'inhibition était très efficace », explique Mulcahy-Levy.

Le travail de Mulcahy-Levy avec Thorburn (entre autres), a montré que les cancers avec des mutations dans le gène BRAF, et spécifiquement ceux avec une mutation appelée BRAFV600E, étaient particulièrement dépendants de l'autophagie. En plus du mélanome, dans lequel cette mutation a été décrite pour la première fois, les glioblastomes épithélioïdes sont particulièrement susceptibles de porter la mutation BRAFV600E.

Avec cette nouvelle compréhension, Mulcahy-Levy est devenu un lien essentiel entre le laboratoire scientifique de base de Thorburn et la pratique clinique de l'oncologue, Nicholas Foreman, MD, investigateur du Centre de cancérologie de la CU et créateur de neuro-oncologie pédiatrique au Children's Hospital Colorado,
Les soins de Lisa.

Après de nombreuses chirurgies, des traitements de radiothérapie et la chimiothérapie, Lisa avait commencé le médicament vermurafenib, qui a été initialement développé pour traiter le mélanome BRAF + et est maintenant testé dans les tumeurs cérébrales pédiatriques. L'expérience de Lisa sur le médicament était typique des patients atteints de cancer BRAF + qui sont traités par des inhibiteurs de BRAF tels que le vemurafenib - après une période de contrôle, le cancer développe des mécanismes génétiques supplémentaires pour stimuler sa croissance et sa survie et est capable de progresser au-delà du médicament initial.

À ce stade, une stratégie prometteuse consiste à prédire et / ou à tester de nouvelles dépendances génétiques, puis à traiter toute nouvelle dépendance par rapport à une autre thérapie ciblée. Par exemple, de nombreux cancers BRAF + traités avec des inhibiteurs de BRAF développent des changements de KRAS, NRAS, EGFR ou PTEN qui entraînent leur résistance, et des traitements existent ciblant bon nombre de ces "voies d'échappement". Cependant, certains cancers développent des mécanismes de résistance multiples et d'autres évoluent si rapidement qu'il peut être difficile de rester en avance sur ces changements avec le prochain traitement correct et ciblé.

«C'est comme cette histoire du garçon qui met son doigt dans le barrage,» dit Mulcahy-Levy. "Finalement, vous ne pouvez tout simplement pas boucher tous les trous."

Au lieu de cette génétique, le groupe a choisi d'explorer les mécanismes cellulaires en dehors de ce qui peut être une séquence sans fin de nouvelles mutations.

«L'expérience clinique et pré-clinique montre invariablement que les cellules tumorales évoluent rapidement autour de l'inhibition des voies de la kinase mutée comme la voie BRAF ciblée ici», écrit le journal.

Cependant, d'après nos résultats, nous supposons qu'en ciblant un processus cellulaire entièrement différents, c'est-à-dire l'autophagie, sur laquelle reposent ces mêmes cellules tumorales, il peut être possible de surmonter une telle résistance et de rétablir ainsi une lutte tumorale efficace.

En d'autres termes, sachant que la tumeur de Lisa Rosendahl était positive pour la mutation BRAFV600E, et que cela marquait la tumeur comme particulièrement dépendante de l'autophagie - et sachant aussi que les options traditionnelles et même les essais cliniques étaient inexistants - le groupe a travaillé avec Rosendahl et son père , Greg, d'ajouter le médicament inhibiteur de l'autophagie chloroquine à son traitement.

«En septembre 2015, les médicaments ciblés précédents ne fonctionnaient plus», explique Greg Rosendahl. «Les médecins ont donné à Lisa moins de 12 mois à vivre. Nous avons emmené tous nos cousins ​​en Alaska pour un dernier voyage, puis ils ont trouvé cette nouvelle combinaison, y compris la chloroquine.

Le Vemurafenib avait initialement poussé le cancer de Lisa au-delà du point de basculement de la survie. Puis le cancer avait appris à utiliser l'autophagie pour se retirer du bord. Maintenant avec la chloroquine et l'inhibition de l'autophagie, vemurafenib a commencé à travailler à nouveau.

"Mon cancer est devenu plus petit, ce qui est génial pour moi", dit Lisa.

«Nous avons traité trois patients avec la combinaison et les trois ont eu un avantage clinique. C'est vraiment excitant - parfois, vous ne voyez pas ce genre de réponse avec un traitement expérimental.En plus de Lisa, un autre patient a été sur la combinaison des deux. Elle est au collège, elle est excellente et grandit comme une merveilleuse jeune adulte, ce qui n'aurait pas eu lieu si nous ne l'avions pas mis sur cette combinaison », dit Mulcahy-Levy.

Lisa a récemment acheté un nouveau fauteuil roulant afin qu'elle puisse passer plus de temps au centre commercial. Elle a également demandé un autocollant handicap pour rendre plus facile pour elle de visiter un parc à proximité avec des camions alimentaires. «Elle veut sortir et faire plus. Elle continue d'avoir ce qu'elle estime être une bonne qualité de vie», dit Mulcahy-Levy.

La recherche accompagnant ces résultats chez les patients implique que l'addition de l'inhibition de l'autophagie aux traitements ciblés peut avoir des avantages au-delà du glioblastome et au-delà uniquement des cancers BRAF +. Parce que la chloroquine a déjà obtenu l'approbation de la FDA comme un traitement sûr et efficace (et peu coûteux) pour le paludisme, le papier souligne qu'il devrait être possible de "tester rapidement" l'efficacité de l'ajout d'inhibition autophagie à un plus grand échantillon de BRAF + glioblastome et d'autres cerveaux Et éventuellement d'étendre ce traitement à d'autres mutations et sites de maladies probables.

Comme le montrent les premières études de Mulcahy-Levy, de nombreux cancers ne dépendent pas de l'autophagie. Mais en même temps, beaucoup en dépendent. Parce qu'un médicament sûr et simple existe déjà pour inhiber l'autophagie, le temps entre la découverte d'un cancer dépendant de l'autophagie et la capacité d'ajouter la chloroquine inhibant l'autophagie à un régime de traitement contre ce cancer peut être court.

«J'aime vraiment pouvoir adapter vraiment la thérapie au patient», dit Mulcahy-Levy. «Je pense que cela va être vraiment important pour vous», et pas nécessairement en utilisant le même traitement avec un autre patient dont le cancer est entraîné par des altérations génétiques différentes.C'est la définition de la conception de soins centrée sur le patient Thérapeutique basée sur l'information de ce patient individuel. Ce n'est pas seulement le glioblastome, mais une certaine mutation et pas seulement la mutation mais un certain modèle de traitements et de résistance antérieurs.

«Je me sens vraiment chanceuse d'être une pionnière dans ce traitement», explique Lisa Rosendahl. "J'espère que cela aidera et j'espère que ça aidera les gens. Je veux que cela aide."

A new study by University of Kentucky Markey Cancer Center researchers shows that chloroquine -- a drug currently used to treat malaria -- may be useful in treating patients with metastatic cancers.

Published in Cell Reports, the study showed that chloroquine induced the secretion of the tumor suppressor protein Par-4 in both mouse models and in cancer patients in a clinical trial. Secreted Par-4 is essential for tumor cell death and the inhibition of tumor metastasis.

Chloroquine induces Par-4 secretion via the classical secretory pathway that requires activation of p53 (a mutation of the p53 protein, or disturbances in the pathways that signal to p53, is common in many cancers). Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion. The study's findings indicate that chloroquine induces p53- and Rab8b-dependent Par-4 secretion from normal cells for Par-4-dependent inhibition of metastatic tumor growth.

The study was led by the lab of Vivek M. Rangnekar, the Alfred Cohen endowed chair in oncology research at the UK Markey Cancer Center and a professor in the UK Department of Radiation Medicine. UK Researchers Ravshan Burikhanov and Nikhil Hebbar in Rangnekar's group were co-first authors in the study.

"Because p53 is often mutated in tumors, it makes the tumors resistant to treatment," said Rangnekar, also the co-leader of the Cancer Cell Biology and Signaling research program and associate director at Markey. "However, this study shows that the relatively safe, FDA-approved drug chloroquine empowered normal cells -- which express wild type p53 -- to secrete Par-4 and stop metastasis in p53-deficient tumors."

At the UK Markey Cancer Center, one clinical trial using chloroquine for Par-4 induction in a variety of cancer patients is ongoing. Researchers are now planning a second clinical trial that would involve giving a maintenance dose of chloroquine to patients who are in remission, with the hopes of preventing cancer relapse.

This research was funded with grants from the National Institutes of Health and the UK Markey Cancer Center/Center for Clinical and Translational Science. Researchers from the University of Pittsburgh, Kansas University Cancer Center, and Osaka University in Japan collaborated with UK scientists in this study.

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Une nouvelle étude menée par l'Université du Kentucky Markey Cancer Center chercheurs montre que la chloroquine - un médicament actuellement utilisé pour traiter le paludisme - peut être utile dans le traitement des patients atteints de cancers métastatiques.

Publié dans Cell Reports, l'étude a montré que la chloroquine induit la sécrétion de la protéine Par-4 dans la tumeur des modèles de souris et chez les patients cancéreux dans un essai clinique. Le Par-4 sécrété est essentiel à la mort des cellules tumorales et à l'inhibition des métastases tumorales.

La chloroquine induit la sécrétion de Par-4 via la voie sécrétoire classique qui nécessite l'activation de p53 (une mutation de la protéine p53, ou des perturbations dans les voies signalant la p53, est fréquente dans de nombreux cancers). Mécaniquement, p53 induit directement Rab8b, une GTPase essentielle pour le transport des vésicules de Par-4 vers la membrane plasmique avant la sécrétion. Les résultats de l'étude indiquent que la chloroquine induit la sécrétion de Par-4 dépendante de p53 et de Rab8b à partir de cellules normales pour l'inhibition de la croissance de la tumeur métastatique dépendante de Par-4.

L'étude a été menée par le laboratoire de Vivek M. Rangnekar, Alfred Cohen doué chaire en recherche en oncologie au Royaume-Uni Markey Cancer Center et professeur au Département britannique de radiothérapie. UK Les chercheurs Ravshan Burikhanov et Nikhil Hebbar dans le groupe de Rangnekar ont été co-premiers auteurs dans l'étude.

«Parce que p53 est souvent muté dans les tumeurs, il rend les tumeurs résistantes au traitement», a déclaré Rangnekar, également le co-leader du Cancer Cell Biology and Signaling programme de recherche et directeur associé à Markey. "Cependant, cette étude montre que le médicament relativement sûr approuvé par la FDA chloroquine a habilité les cellules normales - qui expriment p53 de type sauvage - à sécréter Par-4 et arrêter la métastase dans les tumeurs p53-déficientes.

Au Royaume-Uni Markey Cancer Center, un essai clinique utilisant la chloroquine pour l'induction Par-4 chez une variété de patients atteints de cancer est en cours. Les chercheurs planifient maintenant un deuxième essai clinique qui impliquerait de donner une dose d'entretien de la chloroquine aux patients qui sont en rémission, dans l'espoir de prévenir la rechute du cancer.

Cette recherche a été financée par des subventions des National Institutes of Health et le Royaume-Uni Markey Cancer Centre / Center for Clinical and Translational Science. Des chercheurs de l'Université de Pittsburgh, du Kansas Cancer Center Université et l'Université d'Osaka au Japon a collaboré avec des scientifiques britanniques dans cette étude.

The anti-cancer effect of the antimalarial agent chloroquine when combined with conventional chemotherapy has been well documented in experimental animal models. To date, it was assumed that chloroquine increases the sensitivity of cancer cells to chemotherapy by means of a direct effect on the cancer cells. However, a recent study by investigators at VIB and KU Leuven has demonstrated that chloroquine also normalizes the abnormal blood vessels in tumors. This blood vessel normalization results in an increased barrier function on the one hand -- thereby blocking cancer cell dissemination and metastasis- and in enhanced tumor perfusion on the other hand, which increases the response of the tumor to chemotherapy.

Chloroquine is a well-known medicine with a good safety profile that has been in use since World War 2 for the treatment of malaria and certain auto-immune diseases, including rheumatoid arthritis. More recently, chloroquine has also been used in anti-cancer treatment. Chloroquine blocks autophagy, a process that cancer cells use to survive to anti-cancer treatments. Therefore, blocking autophagy would reduce the resistance of the cancer cells to chemotherapy.

Normalization of abnormal tumor blood vessels

Hannelore Maes from the team of Patrizia Agostinis (KU Leuven), together with Anna Kuchnio from the team of Peter Carmeliet (VIB-KU Leuven) have started a study to explain how chloroquine can strengthen the effect of anti-cancer treatments.

"Although it is assumed that chloroquine strengthens anti-cancer treatment by blocking autophagy, there is little in vivo evidence that this is the only way in which chloroquine works. In this study, we found that chloroquine not only has an effect on the growth of the cancer cells, but also makes the tumor environment less aggressive by normalizing the abnormal blood vessels in the tumor," says Patrizia Agostinis.

Peter Carmeliet: "Blood vessel normalization results in improved tumor perfusion. This reduces the aggressive nature of the cancer cells and means that the anti-cancer medicines are better able to reach the cancer cells, which makes chemotherapy more effective. In addition, tumor blood vessel normalization also increases the barrier function of the blood vessels, which reduces the access of cancer cells to the circulation -- the most important transport system for the spreading of cancer cells to other tissues. Therefore, chloroquine can nip the metastatic spreading of cancer cells in the bud, which is the most important therapeutic goal in any tumor treatment."

Disadvantages do not outweigh the benefits -- the impact of this study on the use of chloroquine in anti-cancer treatment

This study forms a new rationale for the use of chloroquine in anti-cancer treatment. With a view to clinical studies (tests on humans) it is important to note that the effects on the tumor vasculature were even observed at chloroquine concentrations that had little effect on autophagy in the cancer cells. This sheds new light on the therapeutic schedule for combination therapy with chloroquine, which could result in decreased toxicity. In other words, the same "old" medicine simultaneously targets the cancer cells themselves and the blood vessels with great efficiency.

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L'effet anti-cancer de la chloroquine en combinaison avec la chimiothérapie conventionnelle a été bien documentée dans des modèles animaux expérimentaux. A ce jour, il a été supposé que la chloroquine augmente la sensibilité des cellules cancéreuses à la chimiothérapie par l'intermédiaire d'un effet direct sur les cellules cancéreuses. Toutefois, une étude récente menée par des chercheurs a démontré que la chloroquine normalise également les vaisseaux sanguins anormaux dans les tumeurs. La normalisation de ces vaisseaux sanguins résulte en une fonction de bloquage accru, d'une part - cela diminue la diffusion de cellules de cancer et la métastasisation - et en perfusion tumorale accrue, d'autre part, ce qui augmente la réponse de la tumeur à la chimiothérapie.

La chloroquine est un médicament bien connu avec un bon profil de sécurité qui a été en usage depuis la Seconde Guerre mondiale pour le traitement du paludisme et certaines maladies auto-immunes, comme la polyarthrite rhumatoïde. Plus récemment, la chloroquine a également été utilisé dans le traitement anti-cancer. La chloroquine bloque l'autophagie, un processus que les cellules cancéreuses utilisent pour survivre aux traitements anti-cancéreux. Par conséquent, le blocage de l'autophagy permettrait de réduire la résistance des cellules cancéreuses à la chimiothérapie.

La normalisation des vaisseaux sanguins de la tumeur.

Des chercheurs ont entrepris une étude pour expliquer comment la chloroquine peut renforcer l'effet des traitements anti-cancéreux.

"Bien que l'on suppose que la chloroquine renforce le traitement anti-cancer par inhibition de l'autophagie, il y a peu de preuve in vivo que c'est la seule façon dont fonctionne la chloroquine. Dans cette étude, nous avons constaté que la chloroquine n'a pas seulement un effet sur la croissance de les cellules cancéreuses, mais fait aussi rend l'environnement de la tumeur moins agressive en normalisant les vaisseaux sanguins anormaux dans la tumeur », explique Patrizia Agostinis.

"La normalisation des vaisseaux sanguins dans l'amélioration de la perfusion réduit l'agressivité des cellules cancéreuses et signifie que les médicaments anti-cancer sont mieux en mesure d'atteindre les cellules cancéreuses, ce qui rend la chimiothérapie plus efficace En outre, la normalisation de l'arrivée de sang dans la tumeur augmente également la fonction de barrière des vaisseaux sanguins, ce qui réduit l'accès des cellules de cancer de la circulation -. système de transport le plus important pour la propagation des cellules cancéreuses à d'autres tissus, la chloroquine peut tuer la dissémination métastatique des cellules cancéreuses dans l'oeuf, ce qui est l'objectif thérapeutique la plus importante dans un traitement de la tumeur ".

Les inconvénients ne l'emportent pas sur les avantages selon cette étude sur l'utilisation de la chloroquine dans le traitement anti-cancer

Cette étude constitue une nouvelle justification de l'utilisation de la chloroquine à un traitement anti-cancer. En vue d'études cliniques (essais sur les humains), il est important de noter que les effets sur le système vasculaire de la tumeur ont même été observés à des concentrations de chloroquine qui avaient peu d'effet sur l'autophagie dans les cellules cancéreuses. Cela jette une lumière nouvelle sur le calendrier thérapeutique pour la thérapie de combinaison avec la chloroquine, ce qui pourrait entraîner une toxicité réduite. En d'autres termes, le même vieux médicament vise à la fois les cellules cancéreuses elles-mêmes et les vaisseaux sanguins avec une grande efficacité.

A malarial drug is showing promise in stopping breast cancer before it starts, Mason researchers are discovering during a clinical trial.

Un médiament contre la malaria montre des promesses d'arrêter le cancer du avant qu'il ne commence.

"The bold long-term goal is a short-term oral treatment that prevents breast cancer by killing the precursor cells that initiate breast cancer," says Lance Liotta, co-director of Mason's Center for Applied Proteomics and Molecular Medicine (CAPMM). "And it's looking hopeful."

The PINC trial (Preventing Invasive Neoplasia with Chloroquine) targets ductal carcinoma in situ, or DCIS, the most common type of pre-invasive breast cancer. Chloroquine is a drug given to prevent or treat malaria; it's showing promise in the early phase of the PINC trial.

CAPMM has three ongoing breast cancer research projects, including the PINC trial, which span the full scope of breast cancer's impact on patients.

In the PINC trial, DCIS is the focus. DCIS shows up as white spots in the MRI of a breast. Those white spots are calcifications that may mark the milk ducts where DCIS cells are growing, says Virginia Espina, assistant research professor at CAPMM. Not all DCIS becomes cancer, but all breast cancer goes through the DCIS stage, she says.

If the patient is diagnosed with DCIS after a biopsy, then she can enter the trial, says Espina, adding that the study doesn't interfere with standard medical treatment. Mason researchers are working with Kirsten Edmiston, a breast surgeon at Inova Fairfax Hospital who recruits the patients and clinically directs the trial.

Chloroquine for Every Woman?

De la chloroquine pour chaque femme ?

While patients are waiting between their diagnosis and the surgery, they take chloroquine once a week for four weeks, Espina says.

Pendant que les patientes attendent leur diagnostic et la chirurgie, elle prennent de la chloroquine une fois par semaine pour 4 semaine.

A significant reduction in the lesion's size is the sought-after outcome, says Espina, who can be seen in this video describing individual differences in cancer. The widely prescribed malaria drug chloroquine has few side effects -- a rare rash is one, Espina says. There could come a day when chloroquine is taken by women worldwide to prevent breast cancer.

Une baisse significative de la grosseur des lésions est le résultat tangible. Le médicament contre la malaria, chloroquine, a peu d'effets secondaire. Peut-être qu'un jour toutes les femmes prendront de la chloroquine pour prévenir le cancer du

"We can imagine that in the future every woman will take chloroquine once a year," Espina says. "Chloroquine kills off the pre-malignant cells that are starting to accumulate. You'd do this periodically as a new type of chemo prevention."

La choloroquine tue les cellules pré-cancéreuses qui commencent à s'accumuler. On pourrait prendre la chloroquine une fois/an comme un nouveau type de prévention.

Chloroquine works by stopping autophagy, which is used by cells to survive under stress. "When your cells realize they don't have enough nutrients, they eat themselves," Espina says. "It's a way to make energy when you don't have enough food."

La chloroquine fonctionne en arrêtant l'autophagie qui est utilisée par les cellules pour survivre au stress.

And that's the spot the DCIS cells are in as they pile up in the milk duct. They're not getting enough oxygen and food and are squashed together.

Les cellules pré-cancéreuses s'accumulent dans les conduits pour le lait maternel.

"It's like being in an elevator," Espina says. "You're next to people but not necessarily next to people you know or like. It's the same way for these tumor cells or pre-malignant cells. They're next to a cell, but they're not anchored anywhere, and cells like to be anchored and have a home.

"For all these reasons, they're under stress. When a cell is under stress, it's a life-and-death struggle. They're not just going to die. They're going to do what they can to survive. That's when they use autophagy to stay alive."

Chemotherapy, a common treatment for cancer, can rev up autophagy, Espina says. "A doctor selects a treatment to try to kill the cell, but the cell is trying to survive; it's trying to do what it's programmed to do. We have to find a way to defeat this cellular process."

Chloroquine works like Pepto-Bismol; it alters the cell's digestive process and therefore autophagy. "But the chloroquine doesn't kill the normal cells because the normal cells aren't dependent on autophagy to survive," Espina says.

Individualized Treatment for Metastatic Breast Cancer

The second CAPMM study on breast cancer is funded by the Side-Out Foundation. Researchers are developing individualized treatment for women with metastatic breast cancer. These advanced tumors have spread to other organs, such as the liver, brain and bone, and have limited response to conventional therapies. Standard chemotherapy failed the 25 women Mason has worked with to pinpoint more effective treatments, says Mariaelena Pierobon, CAPMM assistant research professor.

Pierobon is using technology created by Liotta and Emanuel "Chip" Petricoin III to identify which drug targets are activated within each patient tumor. Pierobon's team is building on the promise of personalized medicine by focusing on the molecular profile of the metastatic lesions.

"We hope that by providing physicians with detailed information on the mechanisms that are driving our patients' tumors, we can facilitate the selection of the most appropriate treatment," Pierobon says. "We are trying to guide that decision by using the cutting-edge molecular technologies that were created in our laboratory to select among the FDA-approved drugs that might be the most promising for each patient."

In this approach, patients don't have to wait for new drugs to be developed. "By using drugs that are already approved, you don't have to study toxicity. That's a huge advantage," Pierobon says.

The third study is the I-SPY 2 TRIAL in which CAPMM researcher Julia Wulfkuhle is leading molecular profiling efforts developed uniquely in the Mason laboratory for women with stage II/III breast cancer. The FDA singled out I-SPY 2 as a leading trial design for accelerated drug approval.

Researchers at the University of Pennsylvania School of Medicine may have found a way to turn an adaptive cellular response into a liability for cancer cells. When normal cells are starved for food, they chew up existing proteins and membranes to stay alive. Cancer cells have corrupted that process, called autophagy, using it to survive when they run out of nutrients and to evade death after damage from chemotherapy and other sources. When the Penn investigators treated a group of patients with several different types of advanced cancers with temsirolimus, a molecularly targeted cancer drug that blocks nutrient uptake, plus hydroxychloroquine, an anti-malarial drug that inhibits autophagy, they saw that tumors stopped growing in two-thirds of the patients.

Les chercheurs de l'université de Pensylvanie pourraient bien avoir trouvé un moyen de changer un processus d'adaptation cellulaire en contrainte pour les cellules cancéreuses. Quand les cellules normales manquent de nourriture, elles mâchent les protéines existantes et des bouts de membranes pour rester en vie. Les cellules cancéreuses ont corrompu ce processus, appelé autophagie, en utlisant pour survivre quand elles sont en manque de nutriments pour échapper à la mort après avoir été endommagées par la chimiothérapie et les autres sources. Quand les chercheurs ont traité un groupe de patients aux prises avec différents cancers avec du temsirolimus, un médicament ciblé qui bloque la prise de nutriment par les cellules, et du hydroxychloroquine, un médicament anti-malaria qui inhibe l'autophagie. Ils ont vu ces tumeurs arrêtées pour deux patients sur trois

Amaravadi's team is presenting the data at the American Association for Cancer Research 102nd Annual Meeting 2011 in Orlando on Tuesday, April 5.

"The results are very encouraging -- striking, even" says senior author Ravi Amaravadi, MD, an assistant professor of Medicine at Penn's Abramson Cancer Center. "Temsirolimus by itself has little effect in this patient population. Tumors laugh at it, with response percentages of just zero to 5 percent. But by combining it with hydroxychloroquine, we found that 14 out of 21 patients had stable disease after treatment, including five out of six melanoma patients."

Les résultats sont très encourageants, frappants même, Le temsirolimus par lui-même a peu d'effets pour les patients, les tumeurs se rient de lui, avec une érponse de 0 à 5 % Mais en le combinant avec l'hydroxychloroquine, nous avons trouvé que 14 patients de 21 ont stabilisé leur maladie après le traitement, incluant 5 patients avec un mélanome sur 6

In addition to melanoma, patients involved in the study also had colorectal, head and neck, breast, gastro-esophageal, prostate, pancreatic, lung and adrenal cancers. Not only did patients show substantial rates of disease stabilization with the treatment combination, but the researchers report that side effects observed were relatively limited; most commonly mouth sores, weight loss, nausea, and fatigue. Two patients developed infections when the large tumors they had at the start of the trial caved in on themselves as treatment killed off the internal cancer cells, but both patients responded to antibiotics and were able to remain on the study regimen.

non seulement des patients avec ces etc. ont eu des taux de stabilisation subtanciels mais les chercheurs rapportent peu d'effets secondaires.

Amaravadi's group was able to see evidence of autophagy inhibition in peripheral blood cells in patients treated with the combination. And the inhibition increased with increasing doses of hydroxychloroquine, suggesting that the drug is working as they hypothesized it would.

More serious side effects, including low blood cell counts, in a previous phase I trial that combined hydroxychloroquine with chemotherapy and radiation. "That was unexpected and shows that hydroxychloroquine is an experimental drug, even though it has been approved for other treatments for many years," he says. "We didn't see that problem in this trial, so our findings show that what you combine it with is critical -- and some combinations will be less tolerable."

The researchers note that the relatively limited side effect profile of the novel temsirolimus-hydroxychloroquine combination suggests researchers may be able to layer other therapies on top of it, making the combination an even more powerful treatment.

Given the large proportion of melanoma patients who benefited from this combination in the initial cohort of patients, the investigators are currently enrolling an additional 12 patients in an expansion cohort at the 1200 mg dose of hydroxychloroquine. They are also hopeful that the drug combination will also be useful in patients with head and neck and breast cancers.

Étant donné la grand proportion de patients avec un mélanome qui bénéficie de cette combinaison de médicament dans la cohorte initiale, les chercheurs enrolent 12 patients additionnels. Ils espèrent aussi que la combinaison de médicaments sera utile pour le cancer du cou et de la tête et celui du

(Mar. 16, 2011) — Dana-Farber Cancer Institute scientists report they have shrunk or slowed the growth of notoriously resistant pancreatic tumors in mice, using a drug routinely prescribed for malaria and rheumatoid arthritis.

Des scientifiques rapportent avoir rétréci ou ralenti la croissance de tumeurs du pancréas notoirement résistantes chez des souris en utlisant un médicamnet prescrit pour la malaria et les rhumaitistes.

The pre-clinical results, which will appear in the April issue of the journal Genes & Development and is currently published on its web site, have already prompted the opening of a small clinical trial in patients with advanced pancreatic cancer, one of the deadliest and hardest-to-treat forms of cancer, said the investigators, led by Alec Kimmelman, MD, PhD, a radiation oncologist at Dana-Farber.

Ces résultats pré-clinique vont être publiés sous peu en avril dans le Journal "Genes et developpement" etmais déja il y a un petit essai clinique sur quelques patients avec le cancer du

"We are seeing robust and impressive responses in pancreatic cancer mouse models," said Kimmelman, whose laboratory specializes in studies of pancreatic cancer, the fourth-leading cause of cancer death in the United States. The oral drug, hydroxychloroquine, is inexpensive, widely available, and causes relatively mild side effects, he said. A second, planned clinical trial will combine the drug with radiation.

Nous avons vu des réponses robustes et impressionnantes sur des modèles de souris a dit Kimmelman. Le médicament oral, hydroxychloroquine est peu cher largement disponible et cause peu d'effets secondaires. Un autres essai clinique sera fait pour combiner le médicament avec de la radiation.

"While these findings are indeed exciting and a cause for optimism, one needs to be mindful that so far the effects, while impressive, have only been shown in mice," said Ronald DePinho, MD, director of the Belfer Institute for Applied Cancer Science at Dana-Farber. "I eagerly await to see how the human studies will progress."

Bien que ces découvertes soient excitantes et fournissent une raison d'être optimiste il faut se rappeler que les résultats ont été vu sur des souris seulement. J'ai hâte de voir comment les études sur les humains progressent.

A new treatment avenue would be extremely welcome in pancreatic cancer. The National Cancer Institute estimates that 43,140 people were diagnosed in 2010 and 36,800 died. Despite some recent gains with targeted molecular agents and combination regimens, only about 6 percent of patients live five years, and the median survival is less than six months.

Un nouveau traitement serait extrêmement bienvenue pour le cancer du

Hydroxychloroquine is a form of the drug chloroquine, which is used to prevent and treat malaria and also prescribed for autoimmune diseases, including lupus and rheumatoid arthritis. These compounds have recently stirred much interest in cancer research, because they inhibit a process called autophagy (from the Greek for "self-eating") that is elevated in cancer cells.

L'hydroxychloroquine est une forme du médicament chloroquine qui est utilisé pour prévenir la malaria (...) Ces molécules ont attiré récemment l'attention pour la recherche dcontre le cancer parce qu'elles inhibent un processu appelés autophagie qui est élevé parmi les cellules cancéreuses.

Autophagy is present in normal cells as well, but at a much lower level. The process enables cells to break down and eliminate proteins, such as damaged cell membranes and worn-out organelles like mitochondria. But it is also a survival strategy. When nutrients are scarce, cells can digest and feed on their own non-critical proteins to avoid starvation.

L'autophagie est présente normalement dans les cellules mais à un niveau moindre. Le processu permet aux cellules de briser et d'éliminer certaine protéines comme des enveloppes de cellules endommagées ou des organelle déchirées comme des mithochondries. Mais c'est aussi une startégie de survie. Quand les nutriments sont moulus, les cellules peuvent les digérer et nourrir leurs propres protéines pourne pas mourir de faim.

Cancer cells also use autophagy to outwit chemotherapy treatment. Research has shown that cancer cells can activate this process in response to a variety of cancer treatments, allowing them to survive during the stress of therapy. But, as Kimmelman noted, autophagy can also be a cell-death mechanism. Cancer researchers are intensely studying -- and debating -- how to manipulate autophagy as a potential method to slow tumors' growth or make them more sensitive to other therapies.

Les cellules cancéreuses peuvent aussi utiliser l'autophagie pour survivre aux traitements chimiothérapiques. La recherche a démontré que les cellules cancéreuses peuvent activés ce mécanisme en réponse à une variété de traitement contre le cancer. Les chercheurs débattent comment manipuler l'autophagie pour ralentir la croissance du cancer ou le rendre plus sensible aux thérapies.

In their research reported in Genes & Development, Kimmelman and colleagues were stunned to find that autophagy was turned on at all times in pancreatic cancer cell lines -- not just under conditions of stress, treatment or starvation. "This was a big surprise," he said. "These cells weren't deprived of nutrients; they were swimming in all the nutrients they could ever want." This suggested that for some unknown reason, pancreas tumors are highly dependent on autophagy, and therefore potentially uniquely good candidates for autophagy-inhibiting treatment.

In their next experiments, the team administered chloroquine to several different pancreatic cancer cell cultures, and also tested its effects in three types of mouse models. In the laboratory cultures, they reported, the drug "markedly decreased" the growth of the tumor cells, showing that the cells were heavily dependent on autophagy to for continued growth.

Dans leur expériences, ils ont administré de la chloroquine à différentes cellules cancéreuses pancréatiques et testé ses effets sur trois sortes de souris modèles. En laboratoire, ils rapportent que le médicament décroit beaucoup la croissance des cellules cancéreuses et cela montre que ces cellules dépendent beaucoup de l'autpphagie pour survivre et continuer à croitre.

In vivo testing involved three types of mouse models -- human pancreatic cancer cells placed under the rodents' skin (xenografts); human cells injected into the animals' pancreases (orthotopic transplants); and a genetic model (mice bioengineered to develop native pancreatic tumors).

The response to chloroquine was "profound" in the xenograft models, Kimmelman said: All eight untreated mice died of their cancer within 140 days, while only one of eight treated mice had died by 180 days.

The drug's effects were less dramatic but still impressive in the orthotopic and genetic mouse models, the researchers said. The tumors that developed in the genetically pancreatic cancer-prone mice were, like their equivalent in human patients, extremely resistant to all treatments. Among other properties, these tumors were embedded in tough, fibrous tissue that is difficult for drugs to penetrate.

Nevertheless, the scientists reported that chloroquine treatment as a single agent increased the rodents' survival by 27 days compared with untreated control mice. This is encouraging, Kimmelman commented, because even the newest targeted drugs aimed at pancreatic cancer "don't have much effect in this genetic mouse model."

The Dana-Farber trial of hydroxychloroquine, led by Kimmelman and oncologist Brian Wolpin, MD, is designed to enroll 36 pancreatic cancer patients in whom first- or second-line treatments have failed. The drug is taken in pill form twice a day. Results won't become available for at least a year, said Kimmelman.

Kimmelman said the next step will be to investigate the combination of hydroxychloroquine with radiation in patients with operable pancreatic cancer.

"This is a very interesting and promising approach, attacking the Achilles' heel in pancreatic cancer's defenses," commented Robert Mayer, MD, of Dana-Farber's Center for Gastrointestinal Oncology. "But it's too early to say whether hydroxychloroquine should be added to chemotherapy, and what the risks and benefits might be, so we want to examine it in a clinical trial."

Kimmelman's lab is also investigating other forms of cancer that might be good candidates for inhibition of autophagy by the drug. He said that their work, as well as recent findings from other labs, suggests that those cancers may be ones that are primarily driven by the KRAS oncogene -- as nearly all pancreatic tumors are.

Nov. 16, 2009— A powerful new breast cancer treatment could result from packaging one of the newer drugs that inhibits cancer's hallmark wild growth with another that blocks a primordial survival technique in which the cancer cell eats part of itself, researchers say.
Un puissant nouveau traitement pourrait résulter du fait d'envelopper un des plus récents médicaments qui inhibe la croissance sauvage du cancer avec un autre médicament qui bloque un de ses moyens de survie dans lequel les cellules cancéreuses mangent une partie d'elles-mêmes.
While they are powerful killers of some breast cancer cells, new drugs called histone deacetylase inhibitors, or HDAC inhibitors, also increase self-digestion, or autophagy, in surviving, mega-stressed cells, Medical College of Georgia Cancer Center researchers reported during the Molecular Targets and Cancer Therapeutics International Conference in Boston. The conference is sponsored by the American Association for Cancer Research, the National Cancer Institute and the European Organisation for Research and Treatment of Cancer.
Même si elles sont de puissants tueurs de cellules cancéreuses su , les nouveaux médicaments appelés inhibiteurs d'histone deacetyle, ou inhibiteurs HDAC, augmentent l'autophagie en laissant survivre ainsi les cellules très stressées.
"To meet the energy demands of growth and survival, cancer cells start eating up their own organelles, so that surviving cells become dependent on this autophagy," says Dr. Kapil Bhalla, director of the MCG Cancer Center.
"Pour rencontrer les demandes d'énergie de croissance et de survie, les cellules cancéreuses commencent à manger leur propres organelles ainsi les cellules survivantes deviennent dépendantes de leur autophagie" dit le docteur Bhalla.
"By also using autophagy inhibitors, we pull the rug out from under them. The only way out is death," he says.
"En utilisant également des inhibiteurs d'autophagie,nous leurs tirons le tapis sous les pieds. Le seul chemin qui leur restent est de mourir."
Researchers showed the potent HDAC inhibitor panobinostat's impact on autophagy in human breast cancer cells in culture as well as those growing in the mammary fat pads of mice. When they added the anti-malaria drug chloroquine, which inhibits autophagy, breast cancer kill rates increased dramatically.
Les chercheurs ont démontré que le puissant inhibiteur HDAC panobinostat a un impact sur l'autophagie dans les cellules du cancer du humain en culture aussi bien que sur les souris. Quand les chercheurs ajoutent de la chloroquine, un médicament anti-malaria qui inhibe l'autophagie, le taux de mort des cellules cancéreuses augmente de beaucoup.

"As breast cancer is growing, it's developing these mechanisms of resistance to death," says Dr. Bhalla, Cecil F. Whitaker, Jr., M.D./Georgia Research Alliance Eminent Scholar in Cancer and Georgia Cancer Coalition Distinguished Cancer Scholar. "What we are saying is there is a new way to affect a resistant population."
Fundamentals of survival and growth put a lot of stress on cancer cells. Their drive for both comes from the activation of oncogenes and loss of tumor suppressor genes that leaves cells looking desperately for ways to support their marching orders. Much like the extreme measures plane crash victims may take while stranded on a frozen mountaintop, autophagy becomes a survival strategy for the most stressed out cancer cells.

Stress kicks in as cancer cells quickly outgrow available blood supplies and nutrients, which stimulates new blood vessel formation and consumption of unprecedented amounts of fuel. Alterations in gene copy numbers create an imbalance in gene products or proteins adding to the stress of cancer cells, which are starting to make improperly folded -- and functioning -- proteins.

Protein degradation gets revved up and cells also start making more heat shock proteins which are supposed to help properly fold proteins and protect against cell death, a stress cause and effect Dr. Bhalla showed nearly a decade ago. He suspected then the connection he just found: promoting autophagy is one way heat shock proteins carry out their protective mission.
This is where HDAC inhibitors come into play: they promote acetylation or a modification in the key heat shock protein, hsp70, which further promotes autophagy. "Basically HDAC inhibitors promote acetylated hsp70 which promotes autophagy on which a stressed-out cancer cell depends," Dr. Bhalla says.

He notes that chloroquine, a known anti-malarial and inhibitor of autophagy, already is being paired with chemotherapy and radiation is some cancer clinical trials. But because of its significant side effects, new, more tolerable autophagy inhibitors need to be developed which can be combined with currently available anticancer agents, such as panobinostat, to attain superior therapeutic effect against breast cancer, Dr. Bhalla says.

(Jan. 5, 2009) — A single tumor-suppressing gene is a key to understanding, and perhaps killing, dormant ovarian cancer cells that persist after initial treatment only to reawaken years later, researchers at The University of Texas M. D. Anderson Cancer Center report in the December Journal of Clinical Investigation.

Un simple gène est une clé pour comprendre, et peut-être tuer, les cellules cancéreuses et dormantes de l'ovaire qui persistent après le traitement initial pour se réveiller des années plus tard

The team found that expression of a gene called ARHI acts as a switch for autophagy, or self-cannibalization, in ovarian cancer cells. Often a mechanism for cancer cell death, in this case "self-eating" acts as a survival mechanism for dormant cancer cells.

L'équipe a trouvé que l'expression d'un gène appelé ARHI agit comme une switch pour l'autophagie chez les cellules cancéreuses de l'ovaire. Souvent un mécanisme pour la mort des cellules cancéreuses, dans ce cas-ci l'autaphagie, agit comme un mécanisme de survie pour les cellules dormantes du cancer.

"Prolonged autophagy is lethal to cancer cells, but a little autophagy can help dormant cancer cells survive, possibly by avoiding starvation," said senior author Robert Bast, M.D., vice president for translational research

Une autophagie prolongée est mortelle pour les cellules cancéreuses, mais un peu d'autophagie peut aider les cellules cancéreuses à survivre et possiblement éviter de mourir de faim"

"Dormant cells are a major problem in ovarian cancer, breast cancer and other malignancies," Bast said. "We often see ovarian cancer removed, leaving no remaining sign of disease. After two or three years, the cancer grows back. If any remaining cancer cells had continued to grow normally, the disease should have returned in weeks or months.

"Les cellules dormantes sont un problème majeur dans le cancer de l'ovaire, le cancer du sein et d'autres cancers" dit Bast "Nous voyons souvent des cancers qui sont enlevés et dont ils ne restent aucun signes visible revenir après 2 ou 3 ans. Si une cellule restante avait continué à croitre normalement, la maladie serait revenue dans les semaines ou les mois suivant l'opération."

"So the assumption is that some cells remain dormant without dividing and without developing a blood supply, but the mechanism for this has not been well understood," Bast said.

Bast and colleagues focused on ARHI, short for aplasia Ras homolog member I, a gene found in normal cells, but that is underexpressed in 60-70 percent of ovarian cancers.

When normal levels of ARHI were restored to ovarian cancer cells in the laboratory, autophagy was induced and cancer cells died within a few days.

Quand le niveau normal de ARHI a été restauré dans le cancer ovarien en laboratoire, l'autophagie a été induite et les cellules cancéreuses sont mortes en dedans de quelques jours.

When the experiments moved to human ovarian cancer grafts in mice, a different effect was noted. ARHI stopped tumor growth and induced autophagy, but did not kill the cancer cells. When ARHI was turned off at 4 to 6 weeks, the ovarian cancer cells grew rapidly.

Quand les expérimentateurs ont essayés sur des cancers greffés sur des souris, un effet différent a été noté. L'ARHI a arrêté la croissance de la tumeur et a induit l'autpphagie, mais cela n'a pas tué les cellules cancéreuses. Quand l'ARHI a été neutralisé à 4 ou 6 semaines, les cellules de cancer ovarien ont repris leur croissance rapidement.

"Cancer cells had remained viable during ARHI-induced growth arrest and autophagy, which is consistent with a dormant state," Bast said. "When we blocked autophagy with chloroquine, a drug also used to treat malaria, regrowth of the cancers was inhibited, suggesting that autophagy had helped the cancer cells to survive in the absence of a blood supply."

Les cellules cancéreuses ont demeuré viable durant l'arrêt induit et l'autpphagie, ce qui est consistant avec un état dormant" dit Bast " Quand nous avons bloqué l'autpphagie avec le choroquine, un médicament utilisé aussi pour traité la malaria, la croissance du cancer a été inhibé, suggérant que l'autophagie a aidé les cellules cancéreuses a survivre en l'absence de sang."

Autophagy is a cellular survival mechanism that protects cells in a variety of ways. In the case of stress caused by lack of nutrients, autophagy is roughly comparable to a person burning body fat to survive the absence of food.

Several protein survival factors were detected within the microenvironment of the ovarian cancer grafts that could prevent autophagy-induced death of ovarian cancer cells in the laboratory. Blocking these survival factors could provide a novel strategy for eliminating dormant ovarian cancer cells and curing more patients.

Whether cancer cells die an autophagic death, remain dormant or exit dormancy to grow again depends on the balance between ARHI's tumor-suppressing activity and the anti-autophagic and proliferative activity of these environmental survival factors, the authors note.

The ARHI-autophagy pathway also provides an inducible model for tumor dormancy. Lack of a model has hindered understanding of dormant cells and the development of treatments to eliminate them, Bast noted.

Le chemin cellulaire de l'autophagie de l'ARHI fournit un modèle pour la dormance de la tumeur. Le manque de modèle a empêché la compréhension des cellules dormantes et donc le développement de traitement poure les éliminer a noté Bast.

The research was funded by grants from the National Cancer Institute, the National Foundation for Cancer Research and the Blanton-Davis Ovarian Cancer Research Fund.