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 Nouvelles avancées contre certaines leucémies.

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MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Mar 6 Nov 2012 - 13:39




"2012 has been a pivotal year of progress for Ambit, and this financing is a reflection of that progress and the momentum we have built as a team," said Michael Martino, Ambit's president and CEO, in a statement. "We've received the data from our large, 333 patient Phase 2 trial of quizartinib in patients with relapsed/refractory AML, and we are excited to present that data at ASH in Atlanta in December. We've refocused and prioritized our work on earlier stage pipeline assets, including our oral JAK2 and CSF1R inhibitor programs, and re-energized the team."

The fresh round of financing gives Ambit (a 2006 Fierce 15 company) some additional cash runway as it gears up for additional study of quizartinib with partner Astellas in 2013.

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"2012 est une année pivot pour le progrès de la société Ambit et son financement sera le reflet du momentum construit par l'équipe. nous avons reçu les résultats de notre large étude de phase II sur le quizartinib sur 333 patients avec la leucémie lymphoîde aigue et nous sommes excités de présenter ces données à Atlanta en Décembre."

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MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Lun 29 Oct 2012 - 14:16

A team of national and international researchers, led by Weill Cornell Medical College scientists, have decoded the key "software" instructions that drive three of the most virulent forms of acute lymphoblastic leukemia (ALL). They discovered ALL's "software" is encoded with epigenetic marks, chemical modifications of DNA and surrounding proteins, allowing the research team to identify new potential biomarkers and therapeutic targets.

une équipe de chercheurs ont décodé les instructions d'un "logiciel" important qui pilote 3 des plus virulentes formes de leucémie lymphoblastique aigue (LLA). Il sont découvert que le "logiciel" des LLAs est encodé avec dans des marques épigénétiques, des modifications chimiques de l'ADN dans les protéines voisines. CE qui a permis aux chercheurs d'identifier de nouveaux marqueurs potentiels ainsi que de nouveaux agents thérapeutiques.

The research, published in Cancer Discovery, is the first study to show how these three different forms of white blood cell cancer are epigenetically programmed by several different molecules controlling cascading biological networks that manipulate normal gene function, directing cancer development and growth.

Cette recherche est la permière à montrer comment ces 3 différentes formes de cancer de cellules blanches du sont programmées épigénétiquement par plusieurs molécules qui contrôlent une cascade de réseaux biologiques qui à leur tour manipulent différents fonctions de gènes pour diriger le développement et la croissance du cancer.

"Epigenetic programming is the software that is written on to human DNA, which can be viewed as its hard drive. This programming contains the instructions that determine how cells including leukemia cells function and cause disease," says the study's lead investigator, Dr. Ari Melnick, associate professor of medicine and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College.

La programmation épigénétique est le "logiciel" qui est écrit sur l'ADN, qui peut être vu à ce moment-là comme
le disque dur. Cette programmation contient les instruction qui détermine comment les cellules, incluant les fonctions des cellules leucémiques, cause la maladie.


"Finding the instructions that ultimately lead to cancer development, and to the especially bad outcome seen in patients with these different forms of ALL, is especially urgent. Epigenetic instructions are contained in many chemical layers. Our study is the first to integrate the decoding of many layers simultaneously, which has enabled us to unlock some of the mysteries explaining the malignant and aggressive behavior of these leukemias," says Dr. Melnick, who is also a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

«Trouver les instructions qui conduisent finalement au développement du cancer, et le résultat particulièrement mauvais chez les patients avec ces différentes formes de ALL, est particulièrement urgent. Les instructions épigénétiques sont contenues dans les nombreuses couches de produits chimiques. Notre étude est la première à intégrer le décodage de plusieurs couches simultanément, ce qui nous a permis de débloquer certains des mystères qui expliquent le comportement malin et agressif de ces leucémies », affirme le Dr Melnick.

Abnormal Epigenetic Programming Leads to Poor Outcomes

La programmation épigénétique anormale conduit à des résultats médiocres

The research team examined abnormalities in the "software" epigenetic programming that leads to the three forms of adult B-acute lymphoblastic leukemia (B-ALL), the most common form of ALL. These forms are BCR-ABL1-positive B-ALL, E2A-PBX1-positive B-ALL, and MLLr-B-ALL. These three B-ALL subtypes feature mutations of different master regulatory genes which force bone marrow cells to produce cancer-promoting proteins. Long-term survival is less than 40 percent among these patients.

"Similar to normal tissue, we believe that tumors may be dependent on specific patterns of epigenetic programming -- especially in B-ALL, where studies suggests epigenomic programming is globally disrupted," Dr. Melnick says. "Our goal was to identify epigenetically modified genes and the molecular machines that cause them to become abnormally programmed."

To that end, the research team performed DNA methylation and gene expression profiling on 215 adult B-ALL patients enrolled in the ECOG E2993 clinical trial, a multi-center and multi-national study, testing different forms of treatment in patients with ALL.

Researchers identified core epigenetic gene signatures that were associated with abnormal fusion proteins. In the case of BCR-ABL1-positive B-ALL, they found that the most deregulated gene network centered around an extraordinarily epigenetically deregulated gene they identified as interleukin-2 receptor alpha, which encodes a protein called CD25.

"Among patients who had BCR-ABL1-positive B-ALL, it was those with aberrant epigenetic programming of CD25 that had significantly worse outcome," says Dr. Melnick. "It's the patients that have this programming glitch that do really poorly."

Although the researchers don't yet know what CD25 does, and why it is important, they say CD25 will be a useful biomarker to test for patients that are at highest risk for poorer outcome.

Dr. Melnick stresses that therapeutic antibodies to the CD25 protein already exist that can, theoretically, destroy leukemic cells expressing this protein. The research team showed that using the CD25 antibody successfully killed BCR-ABL1-positive B-ALL in laboratory experiments. "One could potentially conceive of a human clinical trial where those antibodies are used to attack these cancerous cells," he says.

Dr Melnick souligne que les anticorps thérapeutiques contre la protéine CD25 qui existent déjà peuvent, théoriquement, détruire les cellules leucémiques exprimant cette protéine. L'équipe de recherche a montré que l'utilisation de l'anticorps CD25 réussi à tuer BCR-ABL1 dans des expériences de laboratoire sur LLA-B. «On pourrait concevoir un essai clinique humain lorsque ces anticorps sont utilisés pour attaquer ces cellules cancéreuses», dit-il.

Researchers also discovered what is writing the bad software in the other two B-ALL subtypes. In both cases, the abnormal cancer proteins E2A-PBX1 and MLLr turn out to be directly involved in altering the epigenetic programming of leukemic cells. Remarkably, MLLr epigenetically turns on a powerful cancer protein called BCL6. In the study, drugs developed by Dr. Melnick that block BCL6 activity potently killed and suppressed the ALL cells in patients enrolled in this clinical trial, which warrants the testing of BCL6 inhibitors in this aggressive form of ALL.

Les chercheurs ont aussi découvert ce qui écrit le mauvais logiciel dans les deux autres LLA-B. Dans les deux cas, les protéines anormales E2A-PBX1 et MLLr sont impliqués directement dans la falsification de la programmation épigénétique des cellules leucémiques. Remarquablement, MLLr agit épigénétiquement sur une protéine puissante du cancer appelé BCL6. Dans l'étude, les médicaments mis au point par le Dr Melnick qui bloquent l'activité de BCL6 tuent et suppriment les cellules de LLA chez les malades inclus dans cet essai clinique, ce qui justifie l'essai d'inhibiteurs de Bcl6 pour cette forme agressive de LLA.

"This study links the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation that leads to abnormal production of cancer-driving genes," Dr. Melnick says. "It potentially provides us with a biomarker for cancer outcomes as well as potential treatments in these aggressive forms of leukemia."

«Cette étude relie les actions directes de protéines de fusion oncogénétique avec une perturbation de la régulation épigénétique qui conduit à une production anormale de gènes produisant le cancer», explique le Dr Melnick. "Il nous fournit potentiellement un biomarqueur sur l'issue du cancer ainsi que des traitements potentiels de ces formes agressives de leucémie."


This research study was supported by the Chemotherapy Foundation, Burroughs Wellcome Foundation, The Leukemia & Lymphoma Society and the Sackler Center for Biomedical and Physical Sciences at the Weill Cornell Medical College.

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MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Dim 15 Avr 2012 - 18:12

15 avril 2012

Published this week in the journal Nature, the work validates certain activating mutations in the FLT3 gene as targets for acute myeloid leukemia therapy -- a critically important finding for developing drugs.

Publié cette semaine dans le journal "Nature", ce travail valide certaines mutations dans le gène FLT3 comme étant des cibles pour une thérapie efficace de la leucémie myéloide aigue et représente une importante découverte pour développer des médicaments.

"These mutations are critically important for the survival of leukemia cells that harbor them," said Neil Shah, MD, PhD, who led the research, and is co-leader of the Hematopoietic Malignancies Program at the Helen Diller Family Comprehensive Cancer Center at UCSF and the Edward S. Ageno Distinguished Professor of Hematology/Oncology. "Our results also identify drug-resistant mutations in FLT3 that represent high-value targets for future drug development, and will hopefully rekindle interest in developing potent FLT3 inhibitors for the treatment of acute myeloid leukemia."

Ces mutations sont d'une grande importance pour la survie des cellules leucémiques qui les ont. Les résultats identifient aussi des mutations qui génèrent de la résistance aux médicaments dans le gène FLT3 qui représentent des cibles de choix pour le développement de médicaments et qui vont renouveler l'intérêt pour développer de puissant inhibiteur de FLT3 pour traiter la leuceumie aigue.

The new work also suggests why a handful of older drugs developed to treat acute myeloid leukemia by targeting FTL3 have previously failed in clinical trials. The problem with these drugs was not lack of precision but of power -- they were aimed at the right target needed to stop the cancer, but most likely did not hit this target hard enough.

Le nouveau travail suggère aussi qu'une poignée de vieux médicaments qui était supposé soigner cette leucémie ont raté leur but parce que trop faible.

Patients in the future may be better served by therapies that involve combinations of multiple, more potent drugs that can suppress all drug-resistant forms of FLT3, said Shah, whose lab is working to identify such compounds and bring them to the clinic as quickly as possible.

Les patients dans le futur seront mieux servis par des thérapies de combinaisons de médicaments plus puissants qui pourront suprimer toute résistance de la part de FLT3. Il travaille déja à ces médicaments pour les avoir en clinique le plus tôt possible.

Common and deadly form of cancer

Acute myeloid leukemia occurs when the precursors of our own blood cells become corrupted by mutations in their DNA. The mutant precursors then fail to produce several critical components of blood: white cells, which fight infections; red cells, which carry the blood's oxygen supply; and platelets, which clog vessels when they are cut and help minimize blood loss.

La leucémie aigue chronique se produit lorsque les précurseurs de nos cellules sanguines deviennent corrompues par des mutations dans leur ADN et faillissent à la tache de produire plusieurs composant du sang : les cellules blanches qui luttent contre les infections, les cellules rouges qui transporte l'oxygène et les plaquettes qui servent à cicatriser.

Instead, the mutant precursors give rise to leukemia cells, which accumulate in the bone marrow and bloodstream, crowding out the healthy blood components, and commonly lead to life-threatening infections, anemia, and bleeding.

Over the last several decades, the five-year survival for acute myeloid leukemia has not improved, even as better diagnostic tests, imaging techniques and treatments have driven down mortality for other forms of cancer. According to the National Cancer Institute, 1 in 256 Americans will be diagnosed with acute myeloid leukemia in their lifetime and today nearly four out of five people with the disease die within five years of their diagnosis.

The goal of therapy is to eliminate cancerous cells altogether from the bone marrow, and the discovery several years ago that many people with acute myeloid leukemia have activating mutations in the FTL3 gene, coupled with the relationship of these mutations to poor prognosis, led scientists to speculate that targeting this mutated gene might be an effective way to fight the cancer -- but only if the gene was critically important for the survival of leukemia cells.

Several drugs were tested in the clinic, but failed to put the disease into deep remission. The cause for these failures came down to one of two possible reasons: either the FTL3 gene mutations were not central "drivers" critical for cancer to develop and leukemia cells to survive, or the drugs themselves could not achieve the necessary degree of inhibition of FLT3.

The new work by Shah and his colleagues demonstrates the latter. They worked with eight leukemia patients who participated in a clinical trial involving a compound known as AC220, the first clinically-active FLT3 inhibitor. All eight relapsed after first achieving deep remissions with AC220.

In collaboration with Pacific Biosciences, a Menlo Park, Calif. company, a new sequencing technology was adapted to more sensitively and precisely detect drug-resistant mutations. The team showed that in all eight cases, one or more of these mutations evolved at the time AC220-resistant disease developed.

They are now searching for compounds that can specifically target these mutated, AC220-resistant forms of FTL3, and have identified several promising candidates, one of which is currently being evaluated in a clinical trial at UCSF by Catherine Smith MD, who works in Shah's laboratory and is the first author of the article.

Ils cherchent maintenant des molécules qui peuvent spécifiquement cibler ces mutations, les formes AC220 de résistance dans le gène FLT3. Ils ont identifiés plusieurs cancdidats prometteurs et un de ceux-là est en évalution dans un essai clinique.

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MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Ven 3 Fév 2012 - 13:02

Questions posés aux chercheurs français sur le cancer par le biais du site et de l'émission de télé du 4 février 2012 :

Alors c’est dans la génétique que la recherche doit se faire ?
Ces cinq dernières années, nous avons découvert beaucoup de gènes impliqués dans plusieurs types de cancers. Notamment, dans les cancers du sein, du poumon, de la prostate... Grâce à ces découvertes, nous avons mieux compris les prédispositions génétiques et les mécanismes biologiques à l'origine des tumeurs. Par contre, il y a encore beaucoup à faire ! Nous sommes très optimistes grâce aux développements technologiques. Dans les cinq prochaines années, on espère de vrais progrès.

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Atteint d'une leucémie LMMC, sans espoir de guérison semble-t-il, puisque qu'aucun traitement n'existe pour en éradiquer la racine du mal. j'aimerais avoir confiance en l'avenir; Pouvez-vous me dire où en est la recherche dans l'élaboration de nouvelles thérapies qui me permettraient à moi et à d'autres d'espérer. ?

Il s'agit de la Leucémie Myelo-Monocytaire Chronique, il s'agit d'une maladie chronique du sang entrainant des problèmes d'hémorragie, d'infection, etc. Il s'agit d'une maladie correspondant au syndrome myélodysplasique. Actuellement, sont en développement de nouveaux traitements agissant directement sur l'ADN. Ces traitements semblent prometteurs.

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MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Lun 30 Jan 2012 - 15:11

(Jan. 30, 2012) — Researchers at UC Santa Barbara have discovered a molecular pathway that may explain how a particularly deadly form of cancer develops. The discovery may lead to new cancer therapies that reprogram cells instead of killing them. The findings are published in a recent paper in the Journal of Biological Chemistry.

Les chercheurs ont trouvé un chemin moléculaire qui pourrait expliquer comment une forme particulièrement mortelle de cancer se développe. La découverte pourrait conduire à de nouvelles thérapies qui reprogrammeraient les cellules cancéreuses au lieu de le tuer.

The UCSB research team described how a certain mutation in DNA disrupts cellular function in patients with acute myeloid leukemia (AML). The researchers were prompted to study this process by another research team's discovery that AML patients have a mutation in a certain enzyme, which was reported in the New England Journal of Medicine. The enzyme is a protein called DNMT3A, which leads to changes in how the DNA of AML patients is methylated, or "tagged." Norbert Reich, professor in the Department of Chemistry and Biochemistry at UCSB, was already studying that particular enzyme with his research group, so they began to study the disease process of AML at the cellular level.

Les chercheurs ont découvert et décrit comment une certaine mutation dans l'adn empêche une certaine fonction cellulaire chez les parents avec la leucémie myéloîde aigue (AML). Les chercheurs ont été initié à étudier une découverte d'une autre équipe de chercheurs qui a été publié dans l'england journal of Medecine à propos d'une mutation dans une enzyme. Cette enzyme est une protéine appelée DNMT3A.


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MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Ven 23 Déc 2011 - 5:50

(Dec. 22, 2011) — A compound produced from fish oil that appears to target leukemia stem cells could lead to a cure for the disease, according to Penn State researchers.

Une molécule qui vient de l'huile de poisson qui cible les cellules souches de la leucémie pourrait guérir cette maladie.

The compound -- delta-12-protaglandin J3, or D12-PGJ3 -- targeted and killed the stem cells of chronic myelogenous leukemia, or CML, in mice, said Sandeep Prabhu, associate professor of immunology and molecular toxicology in the Department of Veterinary and Medical Sciences. The compound is produced from EPA -- Eicosapentaenoic Acid -- an Omega-3 fatty acid found in fish and in fish oil, he said.

La molécule Delta-12- protoglandin J3 (D12-PGJ3) a ciblé et détruit les cellules souches de la leucémie chronique, CML, chez les souris. La molécule est produite à partir de EPA, l'acide eicosapentaenoique (?) un acide oméga 3 trouvé dans l'huile de poisson.

"Research in the past on fatty acids has shown the health benefits of fatty acids on cardiovascular system and brain development, particularly in infants, but we have shown that some metabolites of Omega-3 have the ability to selectively kill the leukemia-causing stem cells in mice," said Prabhu. "The important thing is that the mice were completely cured of leukemia with no relapse."

La chose importante est que les souris furent complètement guéris sans rechutes

The researchers, who released their findings in the current issue of Blood, said the compound kills cancer-causing stem cells in the mice's spleen and bone marrow. Specifically, it activates a gene -- p53 -- in the leukemia stem cell that programs the cell's own death.

"p53 is a tumor suppressor gene that regulates the response to DNA damage and maintains genomic stability," Prabhu said.

Killing the stem cells in leukemia, a cancer of the white blood cells, is important because stem cells can divide and produce more cancer cells, as well as create more stem cells, Prabhu said.

The current therapy for CML extends the patient's life by keeping the number of leukemia cells low, but the drugs fail to completely cure the disease because they do not target leukemia stem cells, said Robert Paulson, associate professor of veterinary and biomedical sciences, who co-directed this research with Prabhu.

"The patients must take the drugs continuously," said Paulson. "If they stop, the disease relapses because the leukemia stem cells are resistant to the drugs."

Current treatments are unable to kill the leukemia stem cells, Paulson said.

"These stem cells can hide from the treatment, and a small population of stem cells give rise to more leukemia cells," said Paulson. "So, targeting the stem cells is essential if you want to cure leukemia."

During the experiments, the researchers injected each mouse with about 600 nanograms of D12-PGJ3 each day for a week. Tests showed that the mice were completely cured of the disease. The blood count was normal, and the spleen returned to normal size. The disease did not relapse.

In previous experiments, the compound also killed the stem cells of Friend Virus-induced leukemia, an experimental model for human leukemia.

The researchers focused on D12-PGJ3 because it killed the leukemia stem cells, but had the least number of side effects. The researchers currently are working to determine whether the compound can be used to treat the terminal stage of CML, referred to as Blast Crisis. There are currently no drugs available that can treat the disease when it progresses to this stage.

The researchers, who applied for a patent, are also preparing to test the compound in human trials.

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MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Dim 11 Sep 2011 - 22:36

(Sep. 10, 2011) — Dana-Farber Cancer Institute scientists have successfully disrupted the function of a cancer gene involved in the formation of most human tumors by tampering with the gene's "on" switch and growth signals, rather than targeting the gene itself. The results, achieved in multiple myeloma cells, offer a promising strategy for treating not only myeloma but also many other cancer types driven by the gene MYC, the study authors say.

Les scientifiques ont interrompu la fonction d'un gène impliqué dans la formation de la plupart des tumeurs humaines en agissant sur les signes de mise en fonction et de croissance qui arrivent au gène plutot que sur le gène lui-même. Les résultats, obtenus dans les cellules du cancer du myélome multiple, ofrre une stratégie prometteuse pour traiter non seulement le myélome mais aussi d'autres types de cancers conduits par le gène MYC.

Their findings are being published by the journal Cell on its website Sept. 1 and in its Sept. 16 print edition.

"Cancer is a disease of disregulation of growth genes in a cell, and MYC is a master regulator of these genes," says James E. Bradner, MD, of Dana-Farber, one of the study's senior authors. Previous attempts to shut down MYC by inhibiting it directly with drug molecules have been notably unsuccessful. "In this study, our idea was to switch MYC off, interfering with its ability to activate the cell-growth program."

Le cancer est une maladie de la dérugalation des gènes de croissances et MYC est un régulateur important de ces gènes. Notre idée était de fermer le gène MYC interférant ainsi avec sa capacité d'activer la croissance du cancer.

They did so with a small molecule called JQ1, developed by Dana-Farber's Jun Qi, PhD, a co-author of the new study and namesake of JQ1. In multiple myeloma, MYC is hyperactive -- constantly ordering cells to grow and divide -- because it is in the wrong position in the cells' chromosomes. Instead of its normal, quiet neighborhood, MYC finds itself adjacent to a gene known as the immunoglobulin gene. This busy gene is switched on by bits of DNA known as immunoglobulin enhancers, which normally prompt the cell to begin producing disease-fighting antibodies. In myeloma, the immunoglobulin enhancers act on the out-of-place MYC gene like an impatient finger at a doorbell, repeatedly activating it.

Ils ont arrêté le gène MYC avec la pertite molécule JQ1 dans le myélome multiple.

Researchers found that the enhancers are loaded with a "bromodomain" protein called BRD4, which, they demonstrate, is used to switch on MYC. Conveniently, it is targeted by JQ1. When investigators added JQ1 to laboratory samples of myeloma cells, the bromodomain proteins fell off the enhancers and the enhancers abruptly stopped working. The result: a shutdown of MYC and a slowdown of cancer cell division.

"In a sense, the JQ1 molecule cuts the cable that activates MYC and also connects MYC to the cell-growth genes," Bradner says. "The signal is interrupted and growth abruptly stops."

Dans un sens, JQ1 coupe le cable qui active MYC et qui connecte MYC avec la croissance cellulaire.

When investigators administered JQ1 to laboratory mice harboring myeloma cells, the disease receded and the animals lived longer than those that had not been treated. The study authors emphasize that JQ1 is a protytpe drug and cannot be used immediately to treat myeloma or other cancers. Its success in the current study illuminates the promise of JQ1-based therapies that target bromodomain proteins in cancers dependent on MYC for their growth.

"Together, our findings show that BRD4 has an important role in maintaining MYC activity in myeloma and other blood-related malignancies," says the study's senior author, Constantine Mitsiades, MD, of Dana-Farber. "They also point to the potential usefulness of drug-like bromodomain inhibitors as novel therapies against these diseases."

Nos études montre que BRD4 a un important rôle dans le maintien de l'activité de MYC dans le myélome et autres cancers du Elles montrent aussi l'utilité de médicaments ocmme les inhibiteurs de bromodomain comme nouvelle thérapie.

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MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Mer 3 Aoû 2011 - 16:41

(Aug. 3, 2011) — Scientists at Cold Spring Harbor Laboratory (CSHL) and five other institutions have used an unconventional approach to cancer drug discovery to identify a new potential treatment for acute myeloid leukemia (AML). As reported in Nature online on August 3, the scientists have pinpointed a protein called Brd4 as a novel drug target for AML, an aggressive blood cancer that is currently incurable in 70% of patients. Using a drug compound that inhibits the activity of Brd4, the scientists were able to suppress the disease in experimental models.

Des scientifiques de Cold Spring Harbor Laboratory (CSHL) et cinq autres institutions ont utilisé une approche non conventionnelle à la découverte de médicaments contre le cancer afin d'identifier un nouveau traitement potentiel pour la leucémie myéloïde aiguë (LMA). Comme rapporté dans Nature en ligne le 3 août, les scientifiques ont identifié une protéine appelée Brd4 comme une nouvelle cible de médicament pour la leucémie myéloide aigue, un cancer du sang agressif qui est actuellement incurable, dans 70% des patients. En utilisant un composé médicament qui inhibe l'activité de Brd4, les scientifiques ont réussi à supprimer la maladie dans des modèles expérimentaux.

"The drug candidate not only displays remarkable anti-leukemia activity in aggressive disease models and against cells derived from patients with diverse, genetic subtypes of AML, but is also minimally toxic to non-cancerous cells," says CSHL scientist Chris Vakoc, M.D., Ph.D., who led the team. "The drug is currently being developed for therapeutic use for cancer patients by Tensha Therapeutics and is expected to enter clinical trials within two years."

«Le candidat-médicament affiche non seulement une activité anti-leucémique remarquable dans des modèles de maladie agressive et contre les cellules dérivées de patients atteints de divers, sous-types génétiques de la LMA, mais il est aussi très peu toxique pour les cellules non-cancéreuses», explique Chris Vakoc CSHL chercheur, MD, Ph.D., qui a dirigé l'équipe. «Le médicament est actuellement développé pour un usage thérapeutique pour les patients atteints de cancer par la Therapeutics Tensha et devrait entrer en essai clinique dans les deux ans."

The protein target identified in the RNAi screen described in the current study, Brd4 -- which contains a distinct domain or region known as a bromodomain -- is a member of the BET family of proteins, which help regulate gene expression. By "reading" certain epigenetic marks or chemical tags attached to chromatin -- the combined package of DNA and proteins around which it is coiled within the cell's nucleus -- Brd4 helps control the pattern of which genes are switched on and how they work.

La protéine cible identifiée dans le "screening" ARNi ( interférent ARN) décrit dans l'étude actuelle est Brd4 - qui contient un domaine distinct ou d'une région connue comme une bromodomain et qui est une protéine de la famille des protéines BET, qui aident à réguler l'expression des gènes.

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MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Mer 8 Déc 2010 - 15:09

(Dec. 7, 2010)


Phase 2 Study of MLN8237: Investigational Aurora A Kinase (Aak) Inhibitor in Patients With Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndromes (MDS)

Dr. Stuart Goldberg, Chief, Leukemia, John Theurer Cancer Center led this open-label, multicenter, phase 2 trial of MLN8237 in patients with advanced AML or intermediate/high-risk MDS. AAK is essential for cell division (mitotic progression) and is amplified or overexpressed in AML and other blood cancers. An investigational drug, MLN8237 is an orally available, potent, and selective AAK inhibitor. It has shown preclinical activity against leukemia, lymphoma, and myeloma, and clinical activity against treatment-resistant cancers in early-stage human trials.

La phase 2 d'étude sur MLN8237, inhibiteur de aurora a kinase chez les patients avec la leucémie myélogénique auge ou le syndrome myélodisplasique.

Le médicament a montré des effets contre la leucémie, le lymphome et le myélome
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Nombre de messages : 16595
Date d'inscription : 23/02/2005

MessageSujet: Re: Nouvelles avancées contre certaines leucémies.   Lun 21 Déc 2009 - 16:14

(Dec. 21, 2009) — A targeted drug that is active against acute myeloid leukemia (AML) is particularly effective when teamed with chemotherapy in patients whose cancer cells harbor a key genetic mutation, researchers at Dana-Farber Cancer Institute and their colleagues will report at the American Society of Hematology's (ASH) annual meeting on Dec. 7.

Un médicament ciblé qui est actif contre la leucémie aigue myéloïde est particulièrement efficace quand adminstré aux patients qui ont une certaine mutation génétique.

The Phase I study focused on the potential of administering the drug midostaurin (PK412) with high doses of the chemotherapy drug cytarabine in AML patients whose disease has been driven into remission by cytarabine and another chemotherapy agent, daunorubicin. Midostaurin is a kinase inhibitor, blocking a key class of enzymes -- kinases -- that often spur cancer cell growth. It works by targeting the FLT3 cell receptor, which is overactive in the white blood cells of many AML patients as a result of genetic mutation.
On its own, midostaurin reduces the number of circulating leukemia cells in AML patients, but rarely produces complete remissions. Preclinical studies have shown that FLT3 inhibitors like midostaurin work synergistically with chemotherapy agents, reinforcing each other's effect against cancer.

Dans la phase 1 de l'étude, on a administré du midostaurin (PK412) avec de hautes doses de cytarabine à des patients avec la leucémie aigue myloïde en rémission à cause de médicaments comme cytarabine et daunorubicin.

Midostaurin est un inhibiteur de kinases qui travaille en inhibant le récepteur FLT3 qui est suractivé dans les cellules blanches de beaucoup de patients AML à cause d'une mutation génétique. Le midostaurin par lui-même réduit le nombre de cellules leucémiques en circulation mais produit rarement des rémissions complètes. Des études précliniques ont démontré que les inhibiteurs de FLT3 comme le midostaurin travaille en synergie avec les autres agents chimiothérapeuthiques se renforcant l'un et l'autre contre le cancer.

In the new study, researchers led by Richard Stone, MD, of Dana-Farber treated 40 newly diagnosed AML patients under age 61 with daunorubicin and cytarabine to induce remission, followed by high-dose cytarabine and oral midostaurin in twice-daily doses of either 100 mg or 50 mg. The higher dose level often produced nausea and vomiting, but patients at the lower dosage tolerated the therapy well.


Dans cette nouvelle étude, les chercheurs ont traité 40 patients nouvellement diagnostiqués et sous l'âge de 61 ans avec daunorubicin et cytarabine pour induire la rémission et ils ont fait suivre^par de hautes doses de cytarabine et de midostaurin administré oralement dans des doses de 100 ou 50 mg 2 fois par jour. Les hautes doses ont produit des vomissements et de la nausée souvent mais les patients avec des doses moins élevé ont bien tolérés.

Of the 40 patients who completed the therapy, 32 (or 80 percent of the group) had a complete response, in which circulating AML cells were reduced to undetectable levels. Complete responses occurred in 74 percent of the patients whose cells had normal FLT3, and in 92 percent of those with mutated FLT3 -- significantly better than had been achieved with midostaurin alone. Eighty-five percent of the group with mutated FLT3 were alive one year after treatment, and 62 percent were alive two years after. These results were comparable to those of the normal FLT3 group (81 percent one-year survival, and 62 percent two-year survival).

Des 40 patients qui ont complété la thérapie, 32 (80%) ont eu une réponse coomplète (les cellules circulantes d'AML ont été réduites à un taux non perceptible) Des réponses complètes sont arrivés à 74% des patients avec le FLT3 normal et 92% dans les patients avec le FLT3 muté. 85% des patients avec le FLT3 muté étaient encore en vie 1 an après le traitement et 62 % 2 ans après (comparé à 81% après 1 an et 62 après 2 ans chez les patients avec le FLT3 normal.

Although the study involved a relatively small number of patients, "the results suggest that a combination of an FLT3 inhibitor and chemotherapy might be effective enough to reduce the need for donor stem cell transplantation in AML patients with mutated FLT3 who have entered first remission," Stone says. "These findings also support the value of ongoing phase 3 studies of the potential benefits of midostaurin during various phases of AML treatment."

Même si ces résultats impliquent peu de gens, ils suggèrent qu'un inhibiteur de FLT3 avec une chimio pourrait être suffisamment efficace pour réduire le besoin de donneur de cellules souches et de transplantation pour es patients d'AML avec la mutatioin FLT3 qui ont eu une premi;re rémission. Les résultats suportent aussi une étude de phase 3.
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MessageSujet: Nouvelles avancées contre certaines leucémies.   Jeu 21 Déc 2006 - 12:28

Francis J. Giles, M.D., professor in the Department of Leukemia at M. D. Anderson Cancer Center, presented the Phase I / II trial data at the annual meeting of the American Society of Hematology.

Le docteur Francis J. GIles, professeur au départemetn de leucémie au centre du cancer Anderson, a présenté la phase I et II d'une étude au meeting annuel de la société américaine d'hématologie.

According to Giles, the study of 44 patients, conducted at M. D. Anderson Cancer Center and Duke University Medical Center, showed the first clinical activity of a kinase inhibitor against the T315I BCR-ABL mutation found in chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL). In addition, the trial showed the first activity against the JAK-2 mutation found in myeloproliferative disorders (MPD), a group of blood diseases that can evolve into leukemia. MK-0457 has also been found in previous studies to inhibit Aurora kinases A, B, C and FLT3 in leukemias.

Selon Giles, l'étude de 44 patients, conduite à l'université de Duke montre la première réaction clinique d'un inhibiteur de kinases contre la mutation de t3151 bcr-abl troouvé dans la leucémie myélo¸ide chronique (CML) et la leucémie lymphoïde aigue (ALL). En plus l'essai montre que la première activité clinique contre la mutation JAK-2 trouvé dans les désodres myéloproliférants (MPD). Le MK-0457 a aussi été reconnu pour inhiber les kinases aurora A,B,C et leFLT3 présent dans les leucémies.
Giles reported that patients on the study experienced minimal side effects, such that no maximum tolerated dose was defined. Mild side effects included lowering of white blood cells, hair loss, nausea and inflammation of the mouth.

"MK-0457 is a drug that produces clinical and biologic activity where we have not seen it before - in T315I-positive CML and ALL and JAK-2-positive MPD. This is a very active biologic agent for patients with advanced leukemia, and has very few side effects, all of which are quite manageable," Giles said. "With the data from this trial, we have a strong rationale to take this agent forward to more definitive and larger studies."

Though CML, ALL and MPD are relatively rare cancers, they are very aggressive and often fatal after failing standard therapy, said Giles. For the subset of leukemia patients who have the T315I mutation or for MPD patients with the JAK-2 mutation - about 10 percent of patients with the respective diagnoses - there are no therapies available to specifically attack these key mutations.

"This is a relatively small population that can potentially benefit from the drug, but for those who have these mutations, this research opens the door to a tremendous option for them," said Giles. "At present, there is nothing to offer them."

According to the American Cancer Society, there are about 4,000 new cases of ALL, about 4,500 new cases of CML and about 10,000 new cases of MPD diagnosed each year.

The T315I mutation is known to be responsible for the aggressive biological growth cycle and resistance to imatinib (Gleevec), nilotinib (Tasigna) and dasatinib(Sprycel) in CML and ALL. These kinase inhibitors have been found to be effective treating patients with leukemias who carry different mutations.

According to the study, the 35 leukemia patients on the study had at least four prior types of therapy, many of who received at least one of the three standard chemotherapies. The nine MPD patients' treatments ranged from one to seven prior lines of therapy.

But because of the mutations associated with resistance to these treatments, the patients did not respond until they were given the intravenous MK-0457 for five consecutive days. Of the patients with the T315I mutation, eight of nine patients with CML responded as did both of the T315I-positive ALL patients who had a partial response after the second cycle and complete response after the third cycle of treatment respectively.

"While we went into this trial to determine the safety and dosage of the drug, it became apparent quite quickly that the drug was very well tolerated and showing clinical response not only in patients but in terms of pharmacodynamics," said Giles. "As a result, we ended the Phase I aspect of the trial earlier than anticipated and moved into Phase II with a range of different doses to safely prescribe, depending on the patient's condition and outlook. We are quite hopeful that this drug will be beneficial for this segment of patients, but additional research will be needed."

Giles and his team are planning to begin later this month an international Phase II study of MK-0457 in patients with the T315I mutation.

Merck and Co. is currently conducting clinical trials of MK-0457 in various cancer types as part of a collaboration with Vertex Pharmaceuticals Incorporated. Merck and Co. holds worldwide and commercialization rights to MK-0457. MK-0457 (VX-680) was discovered by Vertex Pharmaceuticals.

Note: This story has been adapted from a news release issued by University of Texas M. D. Anderson Cancer Center.


Dernière édition par Denis le Jeu 26 Oct 2017 - 19:06, édité 19 fois
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