Researchers at the University of California, San Diego (UCSD) and the Moores UCSD Cancer Center have discovered what could be a novel drug target for an often difficult-to-treat form of leukemia. The investigators have identified a unique "signature" or pattern of a specific family of enzymes in patients with chronic lymphocytic leukemia (CLL), the most common form of adult leukemia.

Les chercheurs ont identifié une signature unique, une famille spécifique d'enzymes chez les patients aux prises avec la leucémie chronique (CLL) la forme la plus commune de la leucémie adulte.

Paul Insel, M.D., professor of pharmacology and medicine at the UC San Diego School of Medicine and his co-workers compared white blood cells in patients with CLL to those of healthy adults. They found that one form of the group of enzymes, collectively known as cyclic nucleotide phosphodiesterases, was 10 times higher in CLL patients than in normal individuals. The specific type of enzyme, phosphodiesterase 7B (PDE7B), controls the levels of cyclic AMP (cAMP), a molecule that can promote programmed cell death, a process that is defective in CLL. The team reports its findings this week in the Proceedings of the National Academy of Sciences.

Les chercheurs ont comparé les cellules blanches de patients leucémiques chroniques avec les cellules blanches de personnes en santé. Ils ont trouvé un groupe d'enzyme (PDE7B) qui est 10 fois plus élevé chez les patients avec le CLL que chez les individus normaux.

Whereas most cancers have out-of-control cell growth, CLL is characterized by an overabundance of white blood cells that do not die when they should, Insel explained.

Comme les autres cancers, le CLL est caractérisé par une surabondance de cellules blanches qui devraient mourir mais ne le font pas.

The scientists subsequently tested the effects of drugs that blocked PDE7B in CLL cells, and found that this raised cAMP levels and caused CLL cells to undergo cell death. He explained that since PDE7B degrades cAMP, blocking PDE7B in essence takes the clamp off of programmed cell death, enabling CLL cells to die.

Les scientifiques ont testés des médicaments pour bloquer PDE7B dans les cellules CLL et ont découverts que cela augmente le niveau de cAMP et fait que les cellules CLL suivent le processus de mort cellulaire. Puisque PDE7B dégrade cAMP,bloquer le PDE7B enlève le frein sur le processus de mort cellulaire des cellules leucémiques.

"PDE7B is thus a new drug target for CLL," he said. "We have preliminary data from patient samples studied in the laboratory showing that we can increase the killing of CLL cells even more if we block PDE7B and also add other drugs used to treat CLL."
He noted that a test for PDE7B might also potentially be used as a way to detect CLL, though this has yet to be proven. CLL, which usually strikes adults over age 35, has two major forms. One form progresses slowly, with few symptoms for years, and can be difficult to detect. The other form is more aggressive and dangerous. No one knows what makes one form different from the other. Current therapies have limited effectiveness, especially once the disease is in its aggressive phase.
The researchers are planning to screen potential drugs to treat CLL based on the PDE7B-cAMP connection. They are also exploring other potential treatment strategies to increase cAMP or disrupt its breakdown.

"We think that CLL cells may have found ways to help keep themselves alive by preventing cAMP from increasing," Insel said. "This paper provides a validation of the importance of the cAMP pathway as a target for drugs that might be used to treat CLL."

(Sep. 28, 2011) — Pre-clinical research has generated some very promising findings about a prototype drug for the treatment of chronic lymphocytic leukemia (CLL). The findings, from work carried out by scientists at NUI Galway, are published in this month's Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research.

Une étude pré-clinique a généré quelques découvertes très pometteuse au sujet d'un médicament potentiel pour la leucémie lymphatique chronique ou CLL.

The research introduced a molecule, or prototype drug, to blood samples from patients with the type of blood cancer known as CLL. The findings indicated that the prototype drug kills leukemia cells circulating in the blood, including cells with features often associated with chemotherapy resistance. Additionally, it was found that the molecule also has the potential to target dividing leukemia cells within lymph nodes. With current standard treatment, these cells can act as a reservoir of resistant cells, which can then give rise to relapse.

L'étude a découverte qu'une mélocule tue les cellules cancéreuses qui circulent dans le sang, incluant des cellules qui sont souvent associées à la résistance à la chimiothérapie. De plus, il a été découvert que la molécule a le potentiel de cibler les cellules de leucémie qui se divisent dans les nodules lymphatiques. Avec le traitement standard, ces cellules peuvent agir comme un réservoir pour les cellules résistantes ce qui peut donner lieu à une rechûte.

For the last two and half years, NUI Galway's Professor Corrado Santocanale, along with Professor Michael O'Dwyer and Professor Afshin Samali, among others, have been researching this molecule 'PHA-767491' for treating CLL.

La molécule s'appelle PHA-767491.

According to Professor Corrado Santocanale, who works in NUI Galway's National Centre for Biomedical Engineering (NCBES) and in the Centre for Chromosome Biology (CCB): "Generally, the prognosis for patients diagnosed with CLL, one of the commonest types of blood cancer, is not as positive as we would like. However these laboratory results provide some hope for the future, especially as related trials with patients are already underway."

Ces résultats de laboratoire fournissent de l'espoir.

The molecule is the parent compound of a drug now being tested in a phase one clinical trial led by Professor Michael O'Dwyer at the HRB Clinical Research Facility at NUI Galway. The success of the laboratory research was an important factor in developing the clinical trial.

Une molécule parente est testé en phase I

Frank Giles, Professor of Cancer Therapeutics and Director of the HRB Clinical Research Facility at NUI Galway, commented: "Enormous progress in anti-cancer therapy is being made as pre-clinical identification of an optimal target, the development of small molecule that modulate the target, and the conduct of early phase human studies, are becoming a seamless process. The conduct of these early studies is a top priority for our NUI Galway CRF and demonstrates Ireland's increasing strength in this critical biomedical sector."

Pre-clinical cancer biology research at NUI Galway encompasses multidisciplinary research clusters who are working to understand the underlying cellular and molecular mechanisms responsible for the initiation and progression of cancer, and to develop new and better cancer therapies. The University also has a strong translational and clinical research programme with the objective of translating research discoveries into improved patient care.