Les cellules souches de la leucémie chronique.

ADAR1 is an enzyme that we may be able to specifically target with a small molecule inhibitor, an approach we have already used effectively with other inhibitors,” said Jamieson. “If we can block the capacity of leukemia stem cells to use ADAR1, if we can knock down that pathway, maybe we can put stem cells back on the right track and stop malignant cloning.”

ADAR1 est une enzyme que nous serions capable de cibler avec un petit inhibiteur de molecule, une approche que nous avons déjà utilisé. Si nous pouvions bloquer la capacité des cellules souches d'utiliser ADAR1, peut-être que nous remettrions les cellules souches dans le bon comportement et que nous arrêterions la reproduction par clonage des cellules malignes.

CML is a cancer initiated by a mutant gene called BCR-ABL in blood forming stem cells that leads to an expansion of white blood cells and their precursors. It is typically slow-growing and often not diagnosed until its later stages when there can be a sudden, dramatic increase in malignant cells, known as blast crisis. Median age of diagnosis is 66 years; incidence of the disease increases with age. Despite tremendous advances in BCR-ABL tyrosine kinase inhibitor therapies, the majority of patients relapse if therapy is discontinued, in part as a result of dormant cancer stem cell resistance. This work suggests a novel mechanism for overcoming cancer stem cell resistance to therapy that may prevent relapse and progression.

La leucémie lymphoîde chronique est un cancer initié par un gène mutant appelé le BCR-ABL dans les cellules souches qui forment le sang et leur précurseurs. C'est lent à se développer.

(Apr. 13, 2011) — A study from Tufts Medical Center researchers published today finds that a novel drug shows promise for treating leukemia patients who have few other options because their disease has developed resistance to standard treatment.

Une étude publiée aujourd'hui montre qu'un nouveau médicament est prometteur pour traiter la leucémie chez des patients qui ont peu d'options parce que leur maladie a développé de la résistance aux traitements standards.

Appearing in the journal Cancer Cell, the study is the first published report showing that the drug, DCC-2036, fights chronic myeloid leukemia (CML) in a mouse model of the disease and is effective against human leukemia cells.

Le DCC-2036 combat la leucémie myéloîde chronique dans un modèle de souris avec les cellules leucémiques humaines.

"These findings demonstrate that DCC-2036 is an excellent candidate for clinical development as a treatment for resistant CML. Not all drugs that work in a test tube will actually be effective in a living organism such as our mouse model," said Richard Van Etten, MD, PhD, Director of Tuft's Medical Center's Cancer Center and senior author of the study.

Ces découvertes démontrent que le DCC-2036 est un excellent candidat pour le développment clinique comme traitement pour la résistance dans le CML

Other authors of the study are scientists with Deciphera Pharmaceuticals LLC of Lawrence, Kansas, and Emerald Biostructures of Bainbridge Island, WA.

DCC-2036 is a tyrosine kinase inhibitor (TKI), a class of drugs that block the action of an abnormal enzyme, BCR-ABL1, that sends chemical messenges that tell CML cells to grow. The development of TKI drugs such as imatinib (Gleevec®) dramatically improved the prognosis for patients with CML, which strikes about 5,000 new patients each year in the United States. But about a third of patients will eventually relapse, principally because of mutations that render BCR-ABL1 resistant to the TKI. Such patients are left with few treatment options other than bone marrow transplantation.

Le DCC-2036 est une inhibiteur de tyrosine kinase, une sorte de médicaments qui bloque l'action d'une enzyme anormale, BCR-ABL1 qui dit aux cellules du cancers de la leucémie myéloide chronique de croitre. 1/3 des patients soigné au Gleevec vont rechuter éventuellement principalement à cause de mutations qui rendent BCR-ABL1 résistant au tk1. Ces patients n'ont plus que la transplantation de moelle pour traitement.

The study showed that in human cells taken from treatment-resistant patients who had received the new drug, DCC-2036 tamped down the mutant enzyme that led to their relapse. The study also found that the drug killed malignant cells and prolonged survival in a mouse model of CML developed by Van Etten's team.

Deciphera Pharmaceuticals, LLC used crystal structures of BCR-ABL1 to custom-design the novel drug to inhibit the mutant enzyme that leads to treatment resistance in CML patients. "The study illustrates the power of designing drugs based upon structures of the target and initial testing of these drugs in mouse models before proceeding to the clinic. This type of targeted design is a paradigm for how cancer treatments will be developed in the 21st century," Van Etten said.

DCC-2036 is currently being tested in a phase 1 clinical trial in patients who have failed therapy with two other TKIs. The trial is actively enrolling patients at Tufts Medical Center, MD Anderson Cancer Center, and University of Michigan Cancer Center.

DCC-2036 est testé en phase 1 actuellement.

The BCR-ABL gene in chronic myeloid leukemia stem cells has a tendency to quickly mutate, and this may help explain why patients are predisposed to resistance to drugs like imatinib that target that gene, according to a study in the May 2 Journal of the National Cancer Institute.

Le gène BCR-ABL des cellules souches de la leucémie chronique myéloïde ont tendance à muter rapidement et ceci peut aider à expliquer pourquoi des patients sont prédisposés à résister aux médicaments comme le Glivec qui cible ce gène, selon une étude dans le Journal of the National Cancer Innstitute du 2 mai.

Treatment with imatinib causes clinical remissions in most patients with chronic myeloid leukemia, but relapses are common and the cancer can become resistant to the drug. The oncogene, BCR-ABL, is the cause of chronic myeloid leukemia. Researchers have hypothesized that the relapses are due to chronic myeloid leukemia stem cells with specific BCR-ABL gene mutations that make them resistant to the drug long before they are exposed to it.

Le traitement avec le Glivec produit une rémission dans la plupart des patients avec la leucémie chronique myéloïde mais les rechûtes sont fréquentes et le cancer devient résistant au médicament. L'oncogène BCR-ABL est la cause de la leucémie chronique myéloïde. Les chercheurs ont émis l'hypothèse que les rechûtes sont dues aux cellules souches de leucémie chroniques myéloïdes avec la mutation spécifique BCR-ABL qui les rends résistantes qu médicament longtemps avant qu'elles soient exposées à lui.

Xiaoyan Jiang, M.D, Ph.D., and Connie Eaves, Ph.D., of the British Columbia Cancer Agency in Vancouver, and colleagues isolated chronic myeloid leukemia stem cells from patients and analyzed them to identify mutations in the BCR-ABL gene.

The stem cells were found to be genetically unstable and had a high frequency of mutations, even in the absence of imatinib. The researchers identified more than 70 BCR-ABL mutations in the stem cells and their immediate progeny, many of which would be expected to alter the BCR-ABL protein--the target of imatinib. This could result in resistance to the drug.

On a trouvé que les cellules souches sont génétiquement instable et ont un haut taux de mutations même en l'abscence de Glivec. Les chercheurs ont trouvé 70 mutations de BCR-ABL dans les cellules souches et leurs progénitures immédiates, beaucoup d'entre elles peuvent a;térer la protéine BCR-ABL. Cela peut conduire à une résistance au médicament.

"Although this study was not designed to identify mutations that would contribute to disease progression, our results suggest that these would also be found. These considerations highlight the importance of gaining further understanding of the control of DNA replication and repair in the leukemic stem cells from patients with chronic phase [chronic myeloid leukemia] in future efforts to devise therapies with curative potential," the authors write.

In an accompanying editorial, Margret Rodrigues, Ph.D., and Martin Sattler, Ph.D., of the Dana Farber Cancer Institute in Boston, discuss the possible causes of genetic instability in the BCR-ABL gene and future approaches to developing successful therapies for chronic myeloid leukemia. "A future challenge will be to devise approaches that overcome drug resistance within these [chronic myeloid leukemia stem] cells without selecting for additional drug-resistant populations," the authors write.


The researchers hope to develop novel therapies by inhibiting endothelial heparan sulfate in the tumor environment. An example would be developing small-molecule inhibitors of Ndst1. By affecting a broad array of molecules -- such as VEGF, fibroblast growth factor, platelet-derived growth factor, or others that impact angiogenesis in a variety of carcinomas -- this therapy could be used to inhibit cancer growth and metastasis with fewer side effects.

These findings will be published in the May 7 online issue of Journal of Cell Biology. Additional contributors to the paper include Lianchun Wang, Janice Castagnola, Krisanavane Reddi, Manuela Shuksz and Joseph R. Bishop, of UCSD's Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center; Lyudmila Sikora and P. Sriaramarao from the Division of Vascular Biology at the La Jolla Institute for Molecular Medicine; Phillip H.A. Lee, Katherine Radek and Richard L. Gallo, M.D., Ph.D., of the Division of Dermatology, San Diego VA Medical Center and UCSD. The research was funded in part by grants from the National Institutes of Health and the U.S. Department of Veterans Affairs.