Cibler HSP-90

An international consortium of scientists led by a group from the University of Leicester has announced a new advance in understanding the mechanisms of cancer and how to target it more effectively with new treatments.

Two papers published in the same issue of the Journal of Cell Biology have arisen from research work led by Professor Andrew Fry at the University of Leicester. Both papers suggest that new understanding of the mechanics of cell division can reveal new targets for cancer therapy.

Professor Fry, who is Director of Research in the College of Medicine, Biological Sciences and Psychology at Leicester, said: "Together, these two papers provide exciting new insights on how cells ensure that they faithfully pass on the right amount of genetic material to their offspring when they divide. They also highlight potential new targets for the development of novel cancer treatments.

"These papers identify a series of key steps that orchestrate the mechanics of cell division and highlight novel targets that could be inhibited to block cancer cell division. Through working with outstanding collaborators in Leicester and across the world, our future goal is to exploit this new understanding of the biology that underlies cell division to develop more effective medicines that will allow better treatments for patients with a wide range of cancers."

With funding from Worldwide Cancer Research, Cancer Research UK, The Wellcome Trust, BBSRC, Medical Research Council and Hope Against Cancer, a Leicestershire and Rutland-based charity, Professor Fry's group within the Department of Biochemistry at the University of Leicester has been studying the mechanics of cell division. Their aim is to gain new understanding on how this process is controlled in normal cells, how it goes wrong in cancer and how it might be targeted with drugs that can more effectively eradicate the tumour whilst causing less side-effects for cancer patients.

The first of these two papers, led by Dr Laura O'Regan, demonstrates that an enzyme called Nek6 controls the stability of the structural scaffold upon which the genetic material, encoded on chromosomes, is separated. They showed that Nek6 leads to recruitment onto this scaffold of a chaperone called Hsp70. Chaperones are proteins that act as cellular guardians folding proteins into their correct shape and assembling them into functional complexes. In the context of cancer, chaperones are particularly important as they protect cancer cells against the stressful environment of a tumour and keep them alive.

Not surprisingly then, there is growing interest from pharmaceutical companies in the development of chaperone inhibitors as novel anti-cancer therapies and the new findings provided in this paper will be key to identifying how best to use these new drugs to selectively kill cancer cells.

In the second paper, work led by Dr Suzanna Prosser demonstrated that an enzyme belonging to the same family as Nek6, in this case called Nek5, also provides a key function in enabling timely assembly of the structural scaffold required for chromosome division with loss of Nek5 leading to genetic damage.


Un consortium international de scientifiques dirigée par un groupe de l'Université de Leicester a annoncé une nouvelle avancée dans la compréhension des mécanismes du cancer et comment le cibler plus efficacement avec les nouveaux traitements.

Deux articles publiés dans le même numéro du Journal of Cell Biology ont surgi à partir de travaux de recherche dirigée par le professeur Andrew Fry à l'Université de Leicester. Les deux documents suggèrent qu'une nouvelle compréhension des mécanismes de la division cellulaire peut révéler de nouvelles cibles pour la thérapie du cancer.

Le professeur Fry, qui est directeur de recherche au Collège de Médecine a déclaré: «Ensemble, ces deux documents fournissent de nouveaux aperçus intéressants sur la façon dont les cellules veillent à passer fidèlement la bonne quantité de matériel génétique à leur progéniture quand elles se divisent. Ils mettent également en évidence de nouvelles cibles potentielles pour le développement de nouveaux traitements contre le cancer.

"Ces documents identifient une série d'étapes clés qui orchestrent les mécanismes de la division cellulaire et mettent en évidence de nouvelles cibles qui pourraient être inhibées pour bloquer la division cellulaire du cancer. En travaillant avec des collaborateurs exceptionnels à Leicester et dans le monde, notre objectif pour l'avenir est d'exploiter cette nouvelle compréhension de la biologie qui sous-tend la division cellulaire pour développer des médicaments plus efficaces qui permettront de meilleurs traitements pour les patients avec un large éventail de cancers ".

Le groupe du professeur Fry au sein du Département de biochimie de l'Université de Leicester a étudié la mécanique de la division cellulaire. Leur objectif est d'acquérir de nouvelles connaissances sur la manière avec laquelle ce processus est contrôlé dans les cellules normales, ce qui va de travers dans le cancer, et comment cela pourrait être ciblé avec des médicaments qui peuvent plus efficacement éradiquer la tumeur tout en causant moins d'effets secondaires pour les patients atteints de cancer.

Le premier de ces deux documents, dirigée par le Dr Laura O'Regan, démontre que une enzyme appelée Nek6 contrôle la stabilité de l'échafaudage structurel sur lequel le matériel génétique, codé sur les chromosomes, est séparé. Ils ont montré que Nek6 conduit au recrutement sur cet échafaudage d'un chaperon appelé Hsp70. Ces "chaperons" sont des protéines qui agissent comme des gardiens cellulaires pour le pliage des protéines dans leur forme correcte et pour les assembler dans des complexes fonctionnels. Dans le contexte du cancer, les chaperons sont particulièrement importants car ils protègent les cellules cancéreuses contre l'environnement stressant d'une tumeur et les gardent en vie.

Sans surprise donc, il y a un intérêt croissant de sociétés pharmaceutiques dans le développement d'inhibiteurs de chaperons comme nouvelles thérapies anticancéreuses et les nouvelles découvertes fournies dans le présent document sera essentiel pour identifier la meilleure façon d'utiliser ces nouveaux médicaments pour tuer sélectivement les cellules cancéreuses.

Dans le second article, le travail mené par le Dr Suzanna Prosser a démontré qu'une enzyme appartenant à la même famille que Nek6, dans ce cas appelé Nek5, fournit également une fonction clé en permettant l'assemblage en temps opportun de l'échafaudage structurel nécessaire pour la division chromosome avec perte de Nek5 conduisant à des dommages génétiques.

While developing a new cancer drug, researchers at The Wistar Institute discovered that mice lacking a specific protein live longer lives with fewer age-related illnesses. The mice, which lack the TRAP-1 protein, demonstrated less age-related tissue degeneration, obesity, and spontaneous tumor formation when compared to normal mice. Their findings could change how scientists view the metabolic networks within cells.

In healthy cells, TRAP-1 is an important regulator of metabolism and has been shown to regulate energy production in mitochondria, organelles that generate chemically useful energy for the cell. In the mitochondria of cancer cells, TRAP-1 is universally overproduced.

The Wistar team's report, which appears in the journal Cell Reports, shows how "knockout" mice bred to lack the TRAP-1 protein compensate for this loss by switching to alternative cellular mechanisms for making energy.

"We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers," said Dario C. Altieri. M.D., Robert and Penny Fox Distinguished Professor and director of The Wistar Institute's National Cancer Institute-designated Cancer Center. "Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells."

"We usually link the reprogramming of metabolic pathways with human diseases, such as cancer," Altieri said. "What we didn't expect to see were healthier mice with fewer tumors."

Altieri and his colleagues created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, Gamitrinib, which targets the protein in the mitochondria of tumor cells. TRAP-1 is a member of the heat shock protein 90 (HSP90) family, which are "chaperone" proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria. Tumors use HSP90 proteins, like TRAP-1, to help survive therapeutic attack.

"In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in the death of the tumor cells," Altieri said. "Mice that lack TRAP-1 from the start, however, have three weeks in the womb to compensate for the loss of the protein."

The researchers found that in their knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which then triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This causes mitochondria in knockout mice to produce deregulated levels of ATP, the chemical used as an energy source to power all the everyday molecular reactions that allow a cell to function.

This increased mitochondrial activity actually creates a moderate boost in oxidative stress ("free radical damage") and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation -- slowing growth down to allow the cell's natural repair mechanisms to take effect.

According to Altieri, their observations provide a mechanistic foundation for the role of chaperone molecules, like HSP90, in the regulation of bioenergetics in mitochondria -- how cells produce and use the chemical energy they need to survive and grow. Their results explain some contradictory findings in the scientific literature regarding the regulation of bioenergetics and dramatically show how compensatory mechanisms can arise when these chaperone molecules are taken out of the equation.

"Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity," Altieri said. "I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions."

This work was supported by grants to Altieri from the National Institutes of Health (P01 CA140043, R01 CA78810) and the Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program (W81XWH-13-1-0193). Additional support was provided through the National Cancer Institute Cancer Center Support Grant (CA010815) to The Wistar Institute.

Co-authors from the Altieri lab include Sofia Lisanti, Michele Tavecchio, Ph.D., and Young Chan Chae, Ph.D., Wistar co-authors also include Qin Liu, M.D., Ph.D., an associate professor in Wistar Cancer Center's Molecular and Cellular Oncogenesis program. Co-authors from outside Wistar include Angela K. Brice, D.V.M., Ph.D., from the University of Pennsylvania School of Veterinary Medicine, and Madhukar L. Thakur, Ph.D., and Lucia R. Languino, Ph.D., from Thomas Jefferson University.

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Tout en développant un nouveau médicament contre le cancer, les chercheurs de l'institut Wistar ont découvert que les souris dépourvues d'une protéine spécifique vivre plus longtemps avec moins de maladies liées à l'âge. Les souris qui n'ont pas la protéine TRAP-1, ont montré moins de dégénérescence des tissus liée à l'âge, d'obésité, et de formation de tumeurs spontanées par rapport aux souris normales. Leurs résultats pourraient changer la façon dont les scientifiques considèrent les réseaux métaboliques dans les cellules.

Dans les cellules saines, TRAP-1 est un régulateur important du métabolisme et on a dit qu'il régulait la production d'énergie dans les mitochondries, les organites qui produisent de l'énergie chimique utile pour la cellule. Dans les mitochondries des cellules cancéreuses, TRAP-1 est universellement en surproduction.

Le rapport de l'équipe Wistar, qui apparaît dans les rapports revue Cell, montre comment des souris "knock-out" élevés pour manquer de protéine TRAP-1 compensent cette perte par le passage à des mécanismes cellulaires alternatives pour faire de l'énergie.

«Nous voyons ce changement étonnant dans les souris sans TRAP-1, où ils montrent moins de signes de vieillissement et sont moins susceptibles de développer des cancers», a déclaré Dario C. Altieri. MD, Robert et Penny Fox professeur émérite et directeur du Centre du cancer Institut national du cancer désigné de l'Institut Wistar. "Nos résultats fournissent une explication inattendue sur comment les protéines TRAP-1 et les protéines reliées régulent le métabolisme dans nos cellules."

"Nous relions généralement la reprogrammation des voies métaboliques avec des maladies humaines comme le cancer», a déclaré Altieri. "Ce que nous ne nous attendions pas à voir ce soint des souris plus saines avec moins de tumeurs."

Altieri et ses collègues ont créé des souris sans TRAP-1 dans le cadre de leur enquête en cours sur leur nouveau médicament, Gamitrinib, qui cible la protéine dans les mitochondries des cellules tumorales. TRAP-1 est un membre de la protéine de la famille de choc thermique 90 (HSP90), qui sont des protéines "chaperonnes" qui guident la formation physique des autres protéines et ont une fonction de régulation dans les mitochondries. Les tumeurs utilisent des protéines HSP90, comme TRAP-1, pour aider à survivre à une attaque thérapeutique.

"Dans les tumeurs, la perte de TRAP-1 est dévastatrice, déclenchant une série de défauts catastrophiques, y compris les problèmes métaboliques qui aboutissent à la mort des cellules tumorales», a déclaré Altieri. "Les souris qui n'ont pas TRAP-1 depuis le début, cependant, ont trois semaines dans l'utérus pour compenser la perte de la protéine."

Les chercheurs ont constaté que, dans leurs souris knock-out, la perte de TRAP-1 provoque des défauts dans les protéines mitochondriales, ce qui déclenche alors une réaction compensatoire qui provoque les cellules à consommer plus d'oxygène et à métaboliser plus de sucre. Cela provoque ;es mitochondries dans les souris knock-out pour produire des niveaux d'ATP non régulées, le produit chimique utilisé comme source d'énergie pour alimenter l'ensemble des réactions moléculaires de tous les jours qui permettent à une cellule de fonctionner.

Cette activité mitochondriale accrue crée en fait un coup de pouce modéré dans le stress oxydatif ("de dommages des radicaux libres") et l'altération de l'ADN associé. Bien que les dommages de l'ADN peut sembler contre-productif pour la longévité et la bonne santé, le faible niveau des lésions de l'ADN réduit effectivement la prolifération des cellules - ralentissement de la croissance pour permettre que les mécanismes naturels de réparation de la cellule prennent effet.

Selon Altieri, leurs observations fournissent une base mécaniste pour le rôle de molécules chaperonnes, comme HSP90, dans la régulation de la bioénergétique dans les mitochondries - comment les cellules produisent et utilisent l'énergie chimique dont ils ont besoin pour survivre et se développer. Leurs résultats expliquent certains résultats contradictoires dans la littérature scientifique concernant la réglementation de la bioénergétique et montrent clairement comment des mécanismes compensatoires peuvent survenir lorsque ces molécules chaperonnes sont prises hors de l'équation.

"Nos résultats plaident en faveur du ciblage HSP90 dans les cellules tumorales, mais ils ouvrent aussi un fascinant éventail de questions qui peuvent avoir une incidence sur le métabolisme et la longévité", a déclaré Altieri. "Je prédis que la souris sans TRAP-1 souris sera un outil précieux pour répondre à ces questions."

Ce travail a été financé par des subventions à Altieri des Instituts nationaux de la santé (P01 __gVirt_NP_NN_NNPS<__ CA140043, R01 CA78810) et le Bureau du Secrétaire adjoint à la Défense pour les affaires de santé à travers le Programme de recherche sur le cancer de la (W81XWH-13-1-0193). Un soutien supplémentaire a été fournie par le Centre de soutien de cancer Grant National Cancer Institute (CA010815) à l'institut Wistar.

Co-auteurs du laboratoire Altieri comprennent Sofia Lisanti, Michele Tavecchio, Ph.D., et Young Chae Chan, Ph.D., co-auteurs Wistar également Qin Liu, MD, Ph.D., professeur agrégé au Wistar le programme moléculaire et cellulaire de l'oncogenèse cancer Center. Co-auteurs de l'extérieur Wistar comprennent Angela K. Brice, DVM, Ph.D., de l'Université de Pennsylvania School of Veterinary Medicine, et Madhukar L. Thakur, Ph.D., et Lucie R. Languino, Ph.D. , de l'Université Thomas Jefferson.

(Dec. 1, 2011) — One major obstacle in the fight against cancer is that anticancer drugs often affect normal cells in addition to tumor cells, resulting in significant side effects. Yet research into development of less harmful treatments geared toward the targeting of specific cancer-causing mechanisms is hampered by lack of knowledge of the molecular pathways that drive cancers in individual patients.

Un obstacle majeur dans la bataille contre le cancer est que les médicaments employés affectent souvent les cellules saines en plus des cellules cancéreuses, ce qui résultent en des effets significatifs. Déjà le développement de traitements avec moins d'effets secondaires amène à cibler plus les causes et mécanismes spécifiques et à développer donc les connaissances des chemins cellulaires chez les patients individuels.

"A major goal of cancer research is to replace chemotherapy with drugs that correct specific molecular pathways disrupted by cancer," says Dr. Ari Melnick, one of the study's lead investigators and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences and associate professor of medicine at Weill Cornell Medical College. "But looking for mutations isn't always the way to find the most important factors that are keeping cancer cells alive."

Un des buts importants du cancer est de remplacer la chimiothérapie par des médicaments qui vont corriger des chemins cellulaires précis interrompus par le cancer. Mais chercher les mutations n'est pas le moyen le plus important pour trouver ce qui garde les cellules cancéreuses vivantes.

Through a collaboration among Weill Cornell Medical College, the Sloan-Kettering Institute at Memorial Sloan-Kettering Cancer Center and the National Cancer Institute (NCI), a team of scientists has now reported that a tumor-targeting compound called PU-H71 can reveal with great accuracy the set of altered pathways that contribute to malignancy. Because the drug specifically binds to abnormal protein complexes in cancer cells, it could lead to the development of more targeted and effective therapies that produce fewer side effects. These findings were recently published in the journal Nature Chemical Biology.

Une molécule qui cible les tumeurs et qui s'appelle PU-H71 peut révéler avec une très grande précision les chemins cellulaires altérés qui contribue au cancer. Parce que cette molécule se fixe aux protéines anormales dans les cellules cancéreuses. Cela pourrait conduire à développer des thérapies plus efficaces et plus ciblées avec moins d'effets secondaires. Ces découvertes récentes ont été publié dans le journal Nature chemical Biology.

"The holy grail in the field was to develop some way to figure out what factors keep cancer cells alive, regardless of whether they have mutations," says Dr. Melnick. "In this paper, we present a method to do just that."

Le saint Graal dans ce secteur était de développer un moyen de comprendre quels facteurs gardait les cellules vivantes sans regarder les mutations.

Through nearly a decade of research, PU-H71 was discovered and refined in the laboratory of Dr. Gabriela Chiosis, associate member of the Molecular Pharmacology and Chemistry Program at the Sloan-Kettering Institute and an associate attending chemist of Memorial Hospital, Memorial-Sloan Kettering Cancer Center. Dr. Chiosis, who is the senior investigator in this new study, reported initial findings about the drug five years ago. The compound was designed to inhibit heat shock protein 90 (Hsp90), which helps other proteins fold into the correct three-dimensional shape and function properly.

Après une décennie de recherches, on a découvert le PU-H71, le Docteur Chiosis a déja rapporté des découvertes initiales voici 5 ans environ (voir plus haut...), la molécule était pensée pour inhiber la protéine hsp90 qui aide les autres protéines à avoir la bonne forme et à fonctionner correctemnt.

Hsp90 plays an essential role in the ability of cells to tolerate stress. The altered growth and metabolism of tumors induce a high degree of stress in these cells. To cope with this stress, tumor cells produce a special form of Hsp90 that is tuned to specially protect those proteins required for their growth and survival. Because this tumor/stress form of Hsp90 regulates many pathways that go awry in cancer, it is a more promising drug target than current targets that play a role in only a single pathway, Dr. Chiosis says. Importantly, PU-H71 specifically suppresses the cancer form of Hsp90 but has little effect on Hsp90 in normal cells.

Hsp90 joue un rôle essentiel dans la capacité des cellules de tolérer le stress. La croissance altéré et le métabolisme des tumeurs induisent un haut degré de stress dans les cellules. Pour pallier à ce stress, les cellules cancéreuses produisent une forme spéciale de hsp90 qui est faite pour protéger ces protéines requises pour la survie et la croissance. PArce que cette forme de cellules cancéreuses et de stress régules plusieurs chemins cellulaires qui sont disfonctionels dans le cancer, c'est plus prometteur pour un médicamnet qui cible cela que de cibler seulement un chemin cellulaire incorrect. Le PU-H71 a peu d'effet sur les cellules avec le hsp90 normal mais élimine les cellules avec la forme anormal de hsp90.

Several years ago, Dr. Chiosis partnered with Dr. Melnick to examine the effectiveness of PU-H71 in treating breast cancer and lymphomas, and they have previously reported that the drug has dramatic antitumor effects without being toxic to animals. As a result of the drug's success in fighting these two aggressive types of cancer, the research team received approval from the National Cancer Institute to carry out clinical trials. Patients are currently being recruited for the first trial, which will test the drug's safety in treating a variety of tumor types, and subsequent clinical trials are being planned for patients with lymphomas, breast cancer, chemotherapy-resistant leukemia and other specific types of cancer.

Depuis plusieurs années le docteur Chiosis et le docteur Melnick examinent l'efficacité du Pu-H71 pour traiter le cancer du et le lymphome et ont précédemment vérifié sur des animaux pour de possibles effets toxiques. Le médicament a dusuccès à combattre ces deux formes de cancers agressifs, l'équipe a reçu l'approbation de la clinique pour poursuivre leurs essais en clinique. Le premier essais recrute des patients pour tester la sécurité du médicament dans une variété de tumeurs comme le cancer du le lymphome le cancer du et d'autres types de cancers.

In their new study Dr. Chiosis, Dr. Melnick, and collaborators demonstrated that because PU-H71 binds to tumor-Hsp90, and tumor-Hsp90 binds to proteins that are required for tumor survival, it is possible to use PU-H71 as a method to "fish out" entire networks of abnormal proteins in tumor cells in an unbiased fashion, which has not been possible up until now. Importantly, many or even most of the genes encoding proteins that maintain tumor cell survival are not mutated in tumors. Hence genetic screening would not be able to detect these networks, Dr. Melnick says. "The value of this method is that it's the first time you can go and probe the functional proteome, or the whole set of proteins that are important to maintaining the tumor." This strategy opens up new avenues for understanding in greater detail the molecular basis of cancer and identifying novel drug targets.

Parce que le PU-H71 se lie au HSp90 et que le Hsp90 se lie aux protéines qui sont requises pour que la tumeur survive, C'est possible d'utiliser le PU-Hsp90 pour connaitre, d'une façon objective, le réseau entier de ces protéines anormales dans les cellules cancéreuses ce qui n'a pas été possible à venir jusqu'à maintenant. Beaucoup si ce n'est la majorité des gènes qui produisent ces protéines ne sont pas des gène mutés. La statègie offre de ouveaux moyens pour connaitre et comprendre plus en détails la base moléculaire des cancers et d'identifier de nouvelles cibles.

For example, in chronic myeloid leukemia cells, the PU-H71 drug preferentially binds to the Hsp90 complex containing Bcr-Abl, an abnormal protein that is overactive in these cells, rather than to Hsp90 associated with the normal protein Abl. Similar findings were observed in other tumor types, with PU-H71-Hsp90 complexes protecting only the tumor-associated proteins.

Par exemple, dans les cellules de la leucémie myéloîde, le PU-H71 se lie au complexe Hsp90 qui contient Bcr-Abl, une protéine anormale qui est hyperactive dans ces cellules au lieu de s'associerf avec la proétine normale Abl. Des découvertes semblables ont été observé dans d'autres formes de cancer.

The researchers then used PU-H71 and proteomic analyses to identify all of the abnormal proteins bound to Hsp90 in chronic myeloid leukemia cells and built networks of these proteins using bioinformatics analyses. They found that these proteins are part of signaling pathways involved in cell death, growth and division. Bcr-Abl is known to use many of these pathways to propagate abnormal signaling in this type of cancer cell. The researchers experimentally confirmed that proteins from these pathways are crucial for cancer cell growth, division and survival, suggesting that their approach can be used to accurately identify Bcr-Abl-related protein networks. Moreover, the same experiments identified many proteins not previously known to drive chronic myeloid leukemia cells. One example of such a protein was CARM1, a regulator of gene expression, which the investigators showed maintains survival of these tumor cells.

Les chercheurs ont confirmé que les protéines de ces chemins cellulaires sont très importantes pour la croissance de la cellule cancéreuse, sa division et sa survie, suggérant que que cette approche pourrait être utilisé pour identifier correctement le réseau de la protéine Bcr-Abl. De plus, les mêmes chercheurs avaient déja découvert plusieurs protéines inconnues jusqu'alors comme importante pour la leucémie myéloîde Un exemple de ces protéines est CARM1, un régulateur d'expression de gène qui maintient les celllules cancéreuses en vie.

Importantly, this PU-H71 cancer proteome method can also be used to identify networks of abnormal proteins in the cells from individual patients, paving the way to personalized therapies that target multiple pathways. "No two tumors are exactly alike, and we don't really know what is driving cancer in one patient versus the other," the researchers say. "If you can use this method to identify in a given individual the factors that are maintaining that patient's particular cancer, then you could develop targeted drugs that hit these specific factors -- in effect, designing personalized therapy for individual patients."

Tout ceci pave la voie à une médecine plus individualisée. aucune tumeur n'est exactement pareil comme celle d'un autre patient.

Based on these findings, Dr. Melnick and Dr. Chiosis recently received a multi-investigator collaborative grant from the National Cancer Institute to use this new PU-H71 proteome method to identify the proteins that maintain the survival of lymphoma cells. This funding is an example of how collaboration between investigators and institutions can synergistically accelerate the pace of biomedical research.

LEXINGTON, Mass., Jul 20, 2011 (BUSINESS WIRE) -- Synta Pharmaceuticals Corp. /quotes/zigman/104941/quotes/nls/snta SNTA -1.67% , a biopharmaceutical company focused on discovering, developing, and commercializing small molecule drugs to treat severe medical conditions, today announced that the first patient has been treated in a Phase 2b/3 clinical trial of ganetespib in combination with docetaxel in non-small cell lung cancer (NSCLC).

Une phase 2b d'essais clinique sur le médicament ganespib en combianison avec le docetaxel commence.

Ganetespib is a potent inhibitor of heat shock protein 90 (Hsp90) that is structurally unrelated to first-generation, ansamycin-family Hsp90 inhibitors such as 17-AAG or IPI-504, and has shown superior activity to these agents in preclinical studies. Ganetespib is currently being studied in broad range of Phase 2 trials, including NSCLC, with nearly 400 patients treated to date.

Ganetespib est un puissant inhibiteur de hsp-90 qui est différent de sa première version et qui a montré une activité supérieur en études précliniques. Ce médicamnet est dans plusieurs phase II d'essais cliniques incluant un essais sur des patients atteints du cancer du .Environ 400 patient ont été traité à date.

"Initiation of the Phase 2b/3 multinational randomized GALAXY trial of docetaxel in combination with ganetespib in NSCLC patients is a major step in exploring the therapeutic potential of Hsp90 inhibitors," said Vojo Vukovic, M.D., Ph.D., Senior Vice President and Chief Medical Officer, Synta Pharmaceuticals. "The combination of ganetespib and docetaxel has a strong scientific rationale as both drugs have single agent activity in NSCLC, their mechanisms of anticancer activity are complementary, and their toxicities are nonoverlapping. Results from the Phase 1 combination study with docetaxel and the combination cohort from the Phase 2 trial in NSCLC have been encouraging. We look forward to seeing interim results from the Phase 2b portion of the trial early in 2012."

Le commencement de cette phase 2b de l'essai à l'aveugle du docetaxel en combinaison avec le ganetespib pour le cancer du est un pas majeur dans l'exploration du potentiel de la thérapie des inhibiteurs de hsp90. La combianison de ces deux thérapies est tout à fait rationnelle parce que les deux médicaments ont chacun une activité singulière contre le cancer du poumon, leur mécanisme ne se superpose pas mais son complémentaire et leur toxicités non plus ne se superpose pas. Les résultats sont encourageants.

Results from a Phase 2 single agent NSCLC trial presented in June 2011 at the Annual Meeting of the American Society for Clinical Oncology (ASCO) showed that ganetespib had a 54% disease control rate in the broad population of patients in the trial with advanced relapsed/refractory NSCLC, all of whom had progressive disease upon study entry. In addition, six of eight patients (75%) with ALK rearrangement experienced tumor shrinkage, including four patients (50%) with durable, objective responses. Seven of eight of these patients (88%) received ganetespib for 16 weeks or more. Tumor shrinkage also occurred in 62% of patients whose tumors have a KRAS mutation, a particularly therapeutically challenging population. Ganetespib was well tolerated in this study and did not have the serious hepatic or common ocular toxicities reported with other Hsp90 inhibitors. The favorable safety profile seen in this trial is consistent with results seen in over 15 trials initiated to date with nearly 400 patients treated.

6 de 8 patients avec des réarrangements de ALK ont eu des rétrécissements des tumeurs incluant 50% (4 patients) avec des réponses objectives durables. Le rétrécissement de tumeurs s'est produit aussi pour les patients avec une mutation du KRAS. Le médicament a été bien toléré également.

About the Phase 2b/3 GALAXY Trial(TM) in NSCLC

The Phase 2b/3 trial will evaluate treatment with ganetespib and docetaxel vs. docetaxel alone, with 1:1 randomization, in patients with Stage IIIB or IV NSCLC who have completed one prior systemic therapy for advanced disease. The first stage, Phase 2b portion, will assess efficacy as measured by progression-free survival in approximately 240 patients. Results from this stage will also be used to inform the choice of patient subpopulation, by histology or biomarker, for the second stage, Phase 3 portion. The second stage will assess efficacy as measured by overall survival, and will enroll between 400 and 600 patients. Interim results from the first-stage portion of the trial are expected in early 2012. More information on the trial can be found at www.clinicaltrials.gov .

About Ganetespib

Ganetespib (formerly STA-9090) is a potent, synthetic, small-molecule inhibitor of heat shock protein 90 (Hsp90). Hsp90 is a molecular chaperone required for the proper folding and activation of many cancer-promoting proteins, and is recognized as a key facilitator of cancer cell growth and survival. In preclinical experiments, ganetespib has shown activity in multiple tumor models both as a single agent and in combination with certain widely used cancer agents. Ganetespib is currently being evaluated in a broad range of cancer clinical trials. In these trials, ganetespib has shown clinical activity in heavily pretreated patients and has been well tolerated to date with no evidence of severe liver or common ocular toxicities seen with other Hsp90 inhibitors. The most common adverse event seen to date has been diarrhea, which has been manageable with standard supportive care. Information on clinical trials with ganetespib can be found at www.clinicaltrials.gov .

(Apr. 19, 2011) — Researchers at The Wistar Institute have found a new way to force cancer cells to self-destruct. Low doses of one anti-cancer drug currently in development, called Gamitrinib, sensitize tumor cells to a second drug, called TRAIL, also currently in clinical development as part of an anticancer regimen.

Les chercheurs ont trouvé un nouveau moyen de forcer les cellules cancéreuses à s'auto-détruire. De petites doses d'un médicament en développement appelé Gamitrinib sensibilise les celllules cancéreuses à un second médicament appelé TRAIL également en développement clinique comme partie d'un régime anticancer.

Their findings, published in the April issue of the Journal for Clinical Investigation, show how this combination approach kills tumor cells in both mouse models of glioblastoma and human glioblastoma cells. Glioblastomas are the most common and aggressive form of malignant brain cancer, affecting roughly 6 out of every 100,000 people. There is currently no effective treatment for glioblastoma, and patients rarely survive more than a year after diagnosis.

Leurs découvertes publiées dans le numéro d'Avril du Journal CLinical Investigation montre comment cette combinaison tue les cellules cancéreuses dans le modèle du glioblastome. Les glioblastomes sont la forme la plus agressives et communes du cancer du

"We found that a low dose of Gamitrinib makes cancer cells susceptible to TRAIL, bypassing many of the mechanisms tumors use to survive," said senior author Dario Altieri, M.D., the Robert and Penny Fox Distinguished Professor at Wistar and director of The Wistar Institute Cancer Center. "Here we have found a new way to combine cancer therapies, one that could be applied to treating many types of cancer because both of these drugs target different mechanisms of tumor cell survival that revolve around mitochondria."

Nous avons trouvé qu'une petite dose de Gamitrinib rend le cancer plus sensible au TRAIL en bypassant plusieurs mécanismes que les cellules cancéreuses utilisent pour survivre. Nous avon strouvé une nouvell ecombinaison de thérapies qui pourraient être appliquées à plusieurs cancers parce que ces deux médicaments ciblent différents mécanismes que les cellules cancéreuses utilisent pour survivre surtout par leurs mitochondries.

As commonly depicted in high school biology texts, mitochondria are the "powerhouses" of the cells, organelles whose main function is to turn sugar into useable energy. What is less commonly known is the role of mitochondria in programmed cell death, or apoptosis, the self-destruct system hardwired into every cell. Apoptosis evolved, in part, as a way for the body to react to extreme stress, a means to sacrifice damaged cells for the greater good of the organism. Cancer cells rely on the mitochondria to provide the energy rapidly-growing tumors need to survive, but find ways to block the signaling pathways that trigger apoptosis. Many researchers, including Altieri, have looked for ways to force tumor cells to hit this self-destruct switch.

Les mitochondries sont les parties qui forunissent de l'énergie à la cellule en transformant le sucre en énergie utilisable. CE quyi est moins connu c'est le rôle des mitochondries dans l'apoptose, le processus de mort cellulaireprogrammé. L'apoptose a évolué dans le corps comme un moyen de réagir à des stress extrêmes, un moyen pour les cellules endommagées de se sacrifier pour le bien de tout l'organisme. Les cellules du cancer se fie sur les mitochondries pour fournir l'énergie dont les tumeurs en rapide croissance on besoin et trouve des moyens de bloquer les chemins vers l'apoptose. Plusieurs chercheurs dont Altieri ont cherché des moyens de remettre en marche le processus d'apoptose.

Gamitrinib is a chemical inhibitor first developed by Altieri and his colleagues in 2009 at the University of Massachusetts. The drug binds to and inhibits Hsp90 -- Heat Shock Protein-90 -- a so-called chaperone protein that is highly active in mitochondria and other cellular organelles where it helps regulate and "rescue" other proteins, particularly in times of stress. Their previous studies have shown that Gamitrinib is effective in damaging tumor cell mitochondria, which can lead to cell death.

Le Gamitrinib est une inhibiteur developpé au Massachusset pour se lier et inhiber Hsp90, une protéine chaperon qui est très active dans les mitochondries et dans d'autres organelles ou elle aide à réguler et sauver d'autres protéines en particuleir en période de stress. Les études préliminaires ont montré que le Gamitrinib endommage le smitochondries ce qui peut conduire à la mort des cellules cancéreuses.

"When tumor cells are confronted with lower concentrations of Gamitrinib, they mount a stress-related defensive system, essentially eating damaged mitochondria and altering how genes are turned on and off to compensate for induced defects in the mitochondria," Altieri said. "This process naturally suppresses Nuclear Factor-kappa Beta, a protein that prevents apoptosis from happening. Ironically, it's this very defensive measure that we can exploit in killing tumor cells."

Quand les cellules cancéreuses sont confrontés avec de petites concentration de Gamitrinib, elles montent un système de défense essentiellement en mangeant les mitochondries endommagées et en changeant la façon dont les gènes sont activés et désactivés pour compenser pour les défauts des mitochondries. cE processus supprime le Facteur-Kappa nucléaire, une protéine qui empêche l'apoptose de survenir. Ironiquement nous pouvons utiliser à notre avantage les moyens de défense de la cellule cancéreuse.

Nuclear Factor-kappa Beta (NF-κΒ) broadly promotes survival in tumors by halting the processes that lead to apoptosis. Altieri and his colleagues wanted to see if the suppression of NF-κΒ would provide an opportunity for TRAIL, a small engineered molecule that mimics the signals used to induce apoptosis.

NF-KB en gros promeut la survie des cellules cancéreuses en arrêtant le processus qui conduit à l'apoptose. Altieri voulait voir si la suppression de NF-KB fournirait une opportunité à TRAIL, une petite molécule faite pour imiter le signal utiliser pour induire l'apoptose.

In their experiments, researchers confirmed previous studies that showed how TRAIL alone did not affect glioblastoma in cell and animal models of the disease. TRAIL plus Gamitrinib, however, stimulated damage to mitochondria in tumor cells, which started a cascading series of reactions, culminating in cell death. Preclinical experiments conducted in mouse models of glioblastoma demonstrated that the combination did not cause any detectable toxic side effects.

TRAIL plus Gamitrinib encouragent les dommages dans les mitochondries des cellules cancéreuses ce qui initie une série d'évênements qui cumulent en la mort de la cellule. Des expériences pré-cliniques ont montré que dans des modèles de souris avec le glioblastome le médicament n'a pas eu d'effet toxique.

According to Altieri, the fact that Gamitrinib and TRAIL are in clinical development already may help speed the process that could see eventual clinical trials of the two drugs together. "There is much preclinical work to be done, of course, but we are very interested in laying the groundwork now toward initial clinical trials," said Altieri.

Selon Altieri, le fait que Gamitrinib et TRAIL sont déjà en développement clinique peut aider à accélérer le processus qui pourrait voir à terme les essais cliniques de ces deux médicaments ensemble. "Il ya beaucoup de travail préclinique à faire, bien sûr, mais nous sommes très intéressés à jeter les bases maintenant vers les premiers essais cliniques", a déclaré Altieri.

Going forward, the researchers also plan to delve deeper into the cellular processes at work.

"I find the basic biology of this system fascinating, since here we show how mitochondria, which are the only organelles that have their own DNA, must communicate with the DNA in the cell's nucleus," Altieri said. "It is not a well-understood process by any means."

«Je trouve la biologie de base de ce système passionnante, car ici nous montrons comment les mitochondries, les organites qui sont seuls à avoir leur propre ADN, doivent communiquer avec l'ADN dans le noyau de la cellule», a déclaré Altieri. "Ce n'est pas un processus bien compris par n'importe quel moyen"

(May 27, 2010) — A Florida State University College of Medicine researcher has discovered a new interaction between a cell signaling system and a specific gene that may be the cause of B-cell lymphoma. The finding suggests a similar interaction could be occurring during the development of other types of cancer, leading to further understanding of how cancer works -- and how it might be stopped.
Yoichi Kato, an assistant professor in the Department of Biomedical Sciences, and his lab team found that the gene -- known in scientific shorthand as BCL6 -- can inhibit one of the pathways cells use to transmit signals to other cells. Called the Notch signaling pathway, it's an important mechanism for cells to control gene regulation.

Des chercheurs ont découvert une nouvelle interaction entre un système dans une cellule et un gène spécific qui pourrit être en cause du lymphome B cellule. La découverte suggère une interaction similaire dans d'autres cancers, et pourrait conduire à une meilleure compréhension de comment le cancer marche et comment il pourrait être arrêter. Un gène, le BCL6 peut inhiber un des chemins cellulaires pour transmettre les signaux aux autres cellules. Le chemin cellulaire appelé Notch, c'est un mécanisme important pour les cellules pour contrôler la régulation des gènes.

"There are very few molecules that we know directly inhibit Notch signaling," Kato said. "So that is why the interaction, and our finding, is very interesting to people in many areas -- cancer specialists, neuroscientists, and many others."

Il y a très peu de molécules que nous connaissons et qui inhibe directement Notch. C,est pourquoi c'est intéressant pour des spécialistes de différents secteurs, des spécialistes du cancer, des neuroscientifiques et plusieurs autres.

Kato's team produced a paper outlining the findings that was published in the journal Developmental Cell, and Kato recently presented the paper at an international conference in Cold Spring Harbor, N.Y., for scientists studying early development of vertebrates.

Kato and his researchers have focused on the Notch signaling pathway's role in vertebrate early development. In their study, they found that when BCL6 inhibits the Notch signaling pathway during the early stages of embryo development, the alignment of the embryo's internal organs is affected, which can lead to a congenital disorder.

However, the Notch signaling pathway, which creates the equivalent of a molecular highway across a cell's membrane, is involved in many types of cell-to-cell interaction, including neuron development, stem cell differentiation and apoptosis (programmed cell death).

The fact that BCL6 regulates the Notch signaling pathway could be important for any cellular process where Notch plays a role, including the formation of many cancers. BCL6 is a gene that, when mutated in certain ways, can lead to several types of B-cell lymphoma. B-cell lymphomas, including both Hodgkin's and non-Hodgkin's lymphomas, occur when B-cells, which produce antibodies to fight infections, mutate and become cancerous.

Le fait que BCL6 régule le chemin cellulaire Notch pourrait être important pour le processus cellulaire ou Notch joue un rôle incluant la formation de plusieurs cancer. BCL6 est un gène qui lorsqu'il est muté d'une certaine manière peut conduire à plusieurs types ce lymphome B.

With more study of the interaction between the Notch signaling pathway and the BCL6 gene, scientists may be able to better understand how these cancers form. Kato and his lab plan to further investigate the interaction's role in neural development, as well as how the interaction could affect stem cell formation.
Kato's research is supported by grants from the National Institute of Child Health and Human Development and the Bankhead-Coley Cancer Research Program.

(Nov. 22, 2009) — Physician-scientists from Weill Cornell Medical College have discovered a molecular mechanism that may prove to be a powerful target for the treatment of non-Hodgkin's lymphoma, a type of cancer that affects lymphocytes, or white blood cells. By exploiting this mechanism, researchers have been able to powerfully suppress tumor formation in lab testing and in animal models.

Des médecins-chercheurs ont découvert un mécanisme moléculaire qui pourrait s'avérer être une cible importante pour le traitement du lymphome non-hodgkinien, un type de cancer qui affecte les lymphocytes, ou globules blancs. en exploitatant ce mécanisme, les chercheurs ont pu réprimer fortement la formation de tumeurs dans les essais en laboratoire et sur des modèles animaux.
Promising results have led to the design of a clinical trial that will soon be under way to test a compound -- called PU-H71 -- in human patients. This compound is in a new class of drugs, called heat shock protein inhibitors.

Des résultats prometteurs ont conduit à la conception d'un essai clinique qui sera bientôt réalisé pour tester un composé appelé PU-H71 sur des patients humains. Cette molécule fait partie de la classe d'inhibiteurs de la protéine de choc thermique.

Standard treatment for non-Hodgkin's lymphoma includes radiation therapy, chemotherapy and monoclonal antibodies. Approximately 66,000 people are diagnosed in the United States each year and approximately 50 percent of patients will not be cured by current treatments.
The author's results are published online November 22 in the journal Nature Medicine.
"We observed almost complete tumor regression after treating the animals with PU-H71," says Dr. Ari Melnick, associate professor of medicine from the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College. "I hope that clinical testing will have similar results for human participants."

"Nous avons observé des régressions presque complètes après avoir traiter des animaux avec le PU-H71" a dit le docteur Melnick "J'espère que les tests sur des patients humains auront des résultats similaires."

The research team discovered that a molecule called heat shock protein 90 (Hsp90) is necessary for the functioning of a protein called BCL-6, which is known to drive the activity of lymphoma tumor cells.

L'équipe de recherche a découvert que la molécule appelé protéine de choc de chaleur 90 est nécessaire pour le fonctionnement d'une protéine appelé BCL-6 qui est connue pour diriger les activités dans les cellules cancéreuses du lymphome.

BCL-6 is the most commonly involved protein in diffuse large B-cell lymphomas, which is the most common form of non-Hodgkin's lymphoma. Approximately 70 percent of these tumors test positive for BCL-6, making it a primary target for therapies.

70% des tumeurs dans le lymphome à larges cellules B test positif pour le BCL-6.

Dr. Melnick and his team found that Hsp90 and BCL-6 joined together within cancer cells to form a complex. They also learned that Hsp90 binds directly to the gene responsible for producing the BCL-6 protein, which led them to believe that blocking Hsp90 would have a powerful effect on BCL-6 production within the cell and, therefore, tumor formation.

To prevent the two molecules from joining, the scientists tested the experimental drug, PU-H71, which was designed to block the activity of Hsp90. PU-H71 was developed by Dr. Gabriela Chiosis, a principal author of the study, from the Memorial Sloan-Kettering Cancer Center, in New York City. The scientific team discovered that exposing lymphoma cells to PU-H71 in laboratory experiments prevented the combination of the two molecules -- killing lymphoma cells and inhibiting new cell reproduction.

Pour empêcher les 2 molécules de s'unir, les scientifiques ont testé le PU-H71 pour bloquer l'activité de HSP-90, ce qui tue les cellules du lymphome cancéreus et empçeche la production de nouvelles cellules cancéreuses.

"The next step was to test the findings in an animal model to see what kind of effect PU-H71 had," explains Dr. Melnick. "We were excited to find that the treated animals' tumors decreased in both size and weight, and that the animals had a significantly prolonged survival compared with controls."

"La prochaine étape fut de tester les découvertes sur un modèle animal pour voir quelle sorte d'effet le PU-H71 aurait. Nous sommes très excités de trouver que les animaux traités avaient moins de tumeurs et que celles-ci étaient plus petites. de plus. l'animal traité avait une vie significativement plus longue comparé à ceux qui servaient de contrôle".

The researchers also found that PU-H71 had a very low toxicity in the animal models. Dr. Melnick believes that this may indicate that when tested in human patients, the drug will be well tolerated, with few side effects, such as damage to the bone marrow and immune system, which are common in cancer therapies.

(Nov. 17, 2008) — A very difficult-to-treat child leukemia may benefit from the discovery of a small but potent epigenetic change that launches the cancer – but could potentially be reversed relatively easily, preventing cancer-promoting genes from being turned on. The study, led by researchers at Children's Hospital Boston and the Dana-Farber Cancer Institute, is the cover article in the November 4 issue of Cancer Cell.

Une leucémie très difficille à traiter pourrait bénéficier d'une découverte d'un petit mais puissant changement épigénétique qui produit ce cancer. Ce changement pourrait être relativement facile à défaire ce qui empêcherait des gènes d'être activés. Les études conduites par par l'hopital pour enfant de Boston et centre Dana-Faber font l'objet du numéro du 4 novembre de Cancer Cell.

While cure rates for the major types of childhood leukemia are now about 80 percent, they are much lower for patients with a subtype of acute lymphoblastic leukemia (ALL) known as MLL-AF4, which accounts for 5 percent of all ALLs but 70 percent of ALLs striking infants. Children with this form of leukemia suffer rapid relapses and have a cure rate of just under 50 percent with chemotherapy.

Même si le taux de guérison pour la plus grande partie des leucémie d'enfants est autour de 80%, il est plus bas pour une catégorie de cancer lymphoblastique (ALL) connu comme MLL-AF4 qui conte pour 5 % de tous les cancers. Les enfants avec cette forme de leucémie ont des rechûtes rapides et ont un taux de guérison plus bas.

"MLL-AF4 leukemias are very difficult to treat and in desperate need of new therapeutic approaches," says senior investigator Scott Armstrong, MD, PhD, of Children's and Dana-Farber. Like other other leukemias, the disease leads to abnormally high numbers of immature, dysfunctional white blood cells that crowd out the bone marrow, interfering with its ability to produce healthy blood cells.

"Le MLL-AF4 est difficille à traiter et a besoin de nouvelles approches" dit Scott Armstrong. Comme les autres leucémies, la maladie conduit a un grand nombre de cellules immatures qui empêhce la capacité de la moelle épinière de former des cellules en bonne santé.

The researchers, led by Armstrong, Andrei Krivtsov, PhD and Zhaohui Feng, also of Children's and Dana-Farber, first developed a mouse model of MLL-AF4, which had eluded scientists in the past. They then showed that the abnormal "fusion" protein that characterizes the disease, also known as MLL-AF4, goes to the cell's DNA and causes abnormal modification of one of the histones, "scaffolding" proteins that give chromosomes their shape and help control gene activation. As a result of this epigenetic change, chromosome structure is altered. This jump-starts activity of a diverse group of genes, including some known to be critical in initiating leukemia.

Le MLL-AF4 cause des une modification anormale d'un des histones

Studying samples from children with MLL-AF4 leukemias, the team made the same observations. "The fusion protein modifies histones and turns on genes that are not supposed to be turned on, and that initiate the development of the cancer," says Armstrong. "If you could inhibit that abnormal histone modification, you might be able to reverse the tumorigenic properties of the fusion protein."

"Si vous pouvez inhiber le histone anormal, vous pourriez être capable de renverser les propriétés de fusion de la protéine."

It appears this inhibition may be relatively simply to accomplish. The researchers went on to demonstrate that MLL-AF4 does its evil work by recruiting an enzyme called DOT1L, which modifies the histone H3 by attaching a methyl group to a particular amino acid. While MLL-AF4 itself would be difficult to target chemically, enzymes are generally fairly easy to target with small-molecule drugs. Simply by inhibiting DOT1L, a variety of critical genes that contribute to the malignancy could potentially be inhibited.

Cette inhibition est relativement simple à faire.

A pharmaceutical DOT1L inhibitor hasn't yet been found, but when the researchers suppressed DOT1L indirectly through RNA interference techniques, the abnormally activated genes were turned off.

Un inhibiteur de DOT1L n'a pas encore été trouvé mais quand les chercheurs supprime DOT1L par un iARN, les activités anormales des gènes s'arrêtent.

"Based on these data, we are searching for small molecules or drugs that inhibit DOT1L," says Armstrong. "Reversal of histone modifications could be an important therapeutic approach for this and potentially other cancers."

"Basé là-dessus, nous cherchons des petites molécules ou des médicaments pour inhiber DOT1L" dit Armstrong "renverser les modifications d'histones pourraient bien être une thérapie importante pour ce cancer et pour d'autres cancers."

Armstrong notes that there are already drugs in clinic that target enzymes that modify histones, namely histone deacetylase (HDAC) inhibitors, which are used to treat a kind of lymphoma and are being tested in other cancers.

Armstrong note qu'il y a déja des médicaments en clinique qui ciblent les enzymes qui modifie les histones, notamment les inhibiteurs d'HDAC qui sont utiliser pour traiter une sorte de lymphome et qui sont en essaie pour d'autres cancers.

The study was funded by the National Cancer Institute, the Leukemia & Lymphoma Society, and the Damon Runyon Cancer Research Foundation.

A novel strategy to hopefully beat into oblivion one of the most aggressive forms of acute myelogenous leukemia combines the strengths of some of the newest leukemia agents, researchers say.

Une nouvelle stratégie pour vaincre une des formes la plus agressive du cancer du sang combine les forces de quelques agents contre la leucémie disent les chercheurs.

“These are not traditional chemotherapy regimens. These are targeted therapies that our earlier laboratory studies have shown have a synergistic effect,” says Dr. Kapil N. Bhalla, director of the Medical College of Georgia Cancer Center.

"Ce ne sont pas des chimios habituelles, ce sont des thérapies ciblées et qui ont démontré un effet synergétique" dit le docteur Bhalla.

The strategy takes on the mutated protein receptor that enables the deadly proliferation of leukemic cells by degrading it with histone deacetylase and heat shock protein 90 inhibitors. It uses protein kinase inhibitors to reduce the function of any remaining protein and kills off leukemic cells with a natural cell death mechanism called TRAIL.

La stratégie agit sur le récepteur de protéine mutée qui rend possible la prolifération des cellules leucémiques en le dégradant avec des inhibiteurs de histone deacetylase et de protéines de choc thermique 90. Cela utilise les inhibiteur de protéine kinases pour réduire la fonction des protéines restantes et tuer les cellules leucémiques avec un processus de mort naturel appelé TRAIL.


Dr. Bhalla recently received a five-year, $1.3 million grant from the National Cancer Institute that will enable his research team to do more preclinical testing of the strategy in human leukemic cells and an AML animal model.

About six years ago, researchers found the mutation in the FLT-3 gene that results in the mutated protein receptor on the cell surface. This receptor usually responds to a growth factor that gives rise to normal bone marrow cell proliferation. “But in this case, this mutated protein receptor is constantly triggered, is constantly on and it drives proliferation, promotes survival and shuts down differentiation,” Dr. Bhalla says.

Within weeks, leukemic cells take over the bone marrow, then spread throughout the body. “Patients typically develop abnormalities of white blood cell count and platelet count, anemia or weakness and present with either an infection because they don’t have enough white blood cells or bleeding,” he says.

“We don’t know what causes these mutations, but if you have FLT-3 mutation – about 30 percent of AML patients do – then the leukemia is generally more aggressive,” says Dr. Bhalla. For whatever reason, this aggressive leukemia occurs most commonly in the elderly which means, with the aging population, it’s likely to become even more common.

“If you just target FLT-3 with an inhibitor of its activity, that would not be enough,” says Dr. Bhalla. “If you combine it with something that also depletes its levels, that would be better. But if you deplete its levels, inhibit its activity and combine it with another leukemia cell death-inducing agent, it would be even better,” says Dr. Bhalla, who believes the laboratory work will evolve into a strategy that can be used effectively in the clinics, maybe even before the laboratory work is done.

"Si vous cibler seulement FLT-3 avec un inhibiteur, cela ne sera pas suffisant" dit le docteur Bhalla "Si vous combinez l'inhibiteur avec quielque chose qui fait décroitre le niveau de FLT-3 cela sera meilleur. Mais si vous faites décroitre son activité et combiner cela avec un autre agent qui induit la mort des cellules leucémiques, ce sera encore mieux" dit Bhalla qui croit que le travail du laboratoire évoluera dans une stratégie qui va pouvoir être utilisée dans les cliniques peut-être même avant que le travail soit fini.

A big plus is that several drugs that do each of these things already are being studied in patients. However, combined effects of these drugs have not been fully studied against leukemia cells, and the drugs just haven’t been used together in patients with leukemia.

For example, one of the histone deacetylase inhibitors Dr. Bhalla will study in the lab, LBH589, developed by Novartis Corp., he’s also studying in an early clinical trial for patients with leukemia and lymphoma for whom standard therapies have failed. Several FLT-3 kinase inhibitors are under study for a variety of cancers and MCG will soon join one of those studies for leukemia. Apo2L/TRAIL, developed by Genetech, is under study in a variety of solid tumors and leukemia. TRAIL activates on leukemic cells the same death-inducing stimulus immune cells use to kill cancer cells. “It’s a normal mechanism of killing offending cells,” says Dr. Bhalla.

“We have designed combinations of agents that we will be studying in mouse models and against patient-derived leukemia cells. This grant doesn’t fund a clinical trial, but it allows us to take patient samples and study them in vitro to further define why this gene confers poor survival and what combinations can work against it,” says Dr. Bhalla. He notes that since the drugs are new and have not previously been used together, issues such as unforeseen toxicity will need to be explored.

“We are studying the combination and how it kills, so when the combination goes into the patient, we will be able to get samples from patients, pre- and post-treatment, to see whether what we are observing in the lab works and, if there are patients who still don’t respond, why don’t they?” says Dr. Bhalla.

Histone deacetylase and heat shock protein 90 inhibitors take direct hits at the mutant protein by targeting HSP 90, a molecular chaperone, which, in this case, improperly folds the protein, leaving it active and producing leukemic cells rather than healthy bone marrow cells as needed. Dr. Bhalla’s lab was the first to show the mutant protein kinase is particularly susceptible to depletion by targeting it with HSP 90 or histone deacetylase inhibitors. He also uncovered the synergy of kinase inhibitors.

“We are targeting HSP 90, which folds and keeps this abnormal protein in its active form,” he says. “By using this agent that targets HSP 90, you also take away many other mechanisms that drive cell proliferation and survival. Once you lower the threshold for cell death by depleting this protein, you use additional strategies to kill leukemic cells. It makes it more effective.”

Nous ciblons HSP 90 qui multiplie et garde cette protéine anormale dans sa forme active. En utilisant cet agent qui cible HSP 90, nous enlevons du même coup plusieurs mécanismes qui conduisent à la prolifération cellulaire et à la survie des cellules anormales. Si en même temps vous employez une stratégie pour tuer les cellules de la leucémie c'est encore mieux