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 Inhibiteurs de parp + inhibiteurs de c-met.

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Nombre de messages : 16917
Date d'inscription : 23/02/2005

MessageSujet: Re: Inhibiteurs de parp + inhibiteurs de c-met.   Lun 18 Jan 2016 - 18:59

Findings from a new study reveal that the activity of PARP inhibitors, an emerging class of drugs being studied in cancer clinical trials, may be enhanced by combining them with inhibitors targeting the oncogene c-MET, which is overexpressed in many cancers. The findings resulting from in vitro and mouse model studies were published by Du et al in Nature Medicine.

Study lead investigator Mien-Chie Hung, PhD, Chair of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center, believes the study results may hold promise for future treatment of breast cancer and possibly other cancers.

“These findings may predict tumor resistance to PARP inhibitors, and suggest that treatment with a combination of c-MET and PARP inhibitors may benefit patients bearing tumors with high c-MET expression who do not respond to PARP inhibition alone,” said Dr. Hung.

Study Findings

While PARP inhibitors are still in the clinical trial phases for breast cancer, the U.S. Food and Drug Administration recently approved the PARP inhibitor olaparib (Lynparza) for treatment of women with ovarian cancer and BRCA mutations.

“BRCA1 and BRCA2 play essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition,” said Dr. Hung. “Combining c-MET and PARP1 inhibitors synergized to suppress growth of breast cancer cells. Similar synergistic effects were also observed in a lung cancer mouse model.”

Dr. Hung's team discovered that c-MET associates with and phosphorylates PARP1, which increases its enzymatic activity. This process essentially renders cancer cells resistant to PARP inhibition. By blocking c-MET's cancer-friendly interaction with PARP, cancer cells lose this resistance to the therapy.

“Our study findings raise the interesting possibility that cancer patients with tumors that overexpress c-MET may benefit from this combination therapy, regardless of cancer type,” concluded Dr. Hung.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


Les résultats d'une nouvelle étude révèlent que l'activité des inhibiteurs PARP, une nouvelle classe de médicaments à l'étude dans des essais cliniques sur le cancer, peut être améliorée en les combinant avec des inhibiteurs ciblant l'oncogène c-MET, qui est surexprimée dans de nombreux cancers. Les constatations résultant de des études in vitro et de modèle de la souris ont été publiés par Du et al dans Nature Medicine.

L'investigateur principal Mien-Chie Hung, Ph.D. estime que les résultats de l'étude peuvent tenir leurs promesses pour le futur traitement du cancer du et peut-être d'autres cancers.

«Ces résultats peuvent prédire la résistance de la tumeur aux inhibiteurs de PARP, et suggérer que le traitement avec une combinaison d'inhibiteurs de c-MET et d'inhibiteurs de PARP peuvent bénéficier aux patients porteurs de tumeurs à forte expression de c-MET qui ne répondent pas à l'inhibition de la PARP seul," a déclaré le Dr Hung .

Conclusions de l'étude

Alors que les inhibiteurs de PARP sont encore dans les phases d'essais cliniques pour le cancer du sein, la Food and Drug Administration américaine a récemment approuvé l'olaparib, un inhibiteur de PARP (Lynparza) pour le traitement des femmes atteintes de cancer de l'ovaire et de mutations BRCA.

"BRCA1 et BRCA2 jouent des rôles essentiels dans la réparation des cassures de l'ADN double brin, et une carence de protéines BRCA sensibilise les cellules cancéreuses à l'inhibition de la PARP," a déclaré le Dr Hung. "La combinaison de c-MET et des inhibiteurs de PARP1 ont une synergie pour supprimer la croissance des cellules cancéreuses du sein. DEs effets synergiques similaires ont également été observés dans un modèle murin de cancer du ".

L'équipe du Dr Hung a découvert que c-Met s'associe et phosphorylise PARP1 ce qui augmente son activité enzymatique. Ce procédé rend essentiellement les cellules cancéreuses résistantes à l'inhibition de la PARP. En bloquant l'interaction de c-MET avec PARP, les cellules cancéreuses perdent cette résistance à la thérapie.

"Nos résultats de l'étude soulèvent la possibilité intéressante que les patients cancéreux atteints de tumeurs qui surexpriment c-MET peuvent bénéficier de cette thérapie de combinaison, indépendamment du type de cancer», a conclu le Dr Hung.

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MessageSujet: Inhibiteurs de parp + inhibiteurs de c-met.   Lun 3 Nov 2008 - 1:32

(Nov. 3, 2008) — In trying to find out why HER2-positive breast cancer can be more aggressive than other forms of the disease, UC Davis Cancer Center researchers have surprisingly discovered that HER2 itself is the culprit. By shutting down its own regulator gene, HER2 creates a permissive environment for tumor growth.

En essayant de trouver pourquoi le cancer du HER2 positif peut être plus agressif que les autres formes de la maladie. Les chercheurs ont découvert que HER2 lui-même était le coupable. En fermant son propre gène régulateur, HER2 crée un environnement permisif pou la tumeur.

Building on recent research showing that the regulator — labeled LRIG1 and commonly called "Lig-1" — limits the growth-promoting signals of HER2, the research team set out to clarify the role of Lig-1 in breast cancer.

Le groupe de recherche a voulu aussi clarifié le rôle du régulateur LR1G1 appelé "Lig-1" qui limiterait la croissance du signal de croissance de HER2.

They found that, when compared to healthy breast tissue, the regulator is significantly suppressed.

Ils ont fait cette découverte en comparant l'occurence de lig-1 dasn des tissus sains.

"This suppression assists HER2 in its own over-expression and in driving the growth of cancer cells," said Colleen Sweeney, associate professor of biochemistry and molecular medicine and senior author of the study, which appears in this month's issue of Cancer Research. "HER2 is clearly taking an active role its own ability to be successful in promoting cancer."

"Cette suprression assist HER2 dans sa propre sur-expression et fait que le nombre de cellules cancéreuses devient incontrôlable. HEr2 joue clairement un rôle dans sa propre capacité à être efficace dans la promotion du cancer."

Sweeney added that the study results could lead to new treatments aimed at restoring or replacing functions of the regulator. This is good news for patients because, in addition to being more aggressive, HER2-positive breast cancer tends to be less responsive to currently available treatments. The gene is over-expressed in about one-quarter to one-third of breast cancer cases.

Les résultats de l'étude pourrait conduire à de nouveaux traitements ciblés en restaurant les fonctions du régulateur. Ce sont de bonnes nouvelles pour les patientes parce que, en plus d'être agressif, le cancer du sein testant positif au HER2 tend à répondre moins aux traitements. Ce gèn est sur-exprié dans 1/4 ou 1/3 des cas.

Sweeney and colleagues began by studying mouse models of breast cancer with genomes that carry extra copies of HER2. They noticed an excess of HER2 protein in the resulting tumors, but it was not over-expressed in adjacent healthy tissues that also carried extra copies of the HER2 gene.

"That suggested to us that extra copies of HER2 alone are not enough to explain its over-expression. If it was, HER2 would have been over-expressed in both normal and tumor tissues from these mice," she said.

Given that observation, the team set out to determine what, exactly, created the permissive environment for HER2 over-expression. Given its tumor-suppressor role, Lig-1 levels were compared in the mouse models.

They found that Lig-1 was greatly diminished in tumor tissues when compared to the normal tissues. The researchers next conducted a series of laboratory experiments using human breast cancer cell lines and a technique called RNA interference that allows for selective depletion of cellular proteins.

Interestingly, they found the same results in the human breast cancers that they found in mice. In fact, 60 percent of 67 tumors analyzed showed a loss of the Lig-1 protein and its levels were, on average, 33 percent lower in tumor tissue versus healthy breast tissue.

"There was a clear inverse relationship between Lig-1 and HER2," said Sweeney. "When we depleted Lig-1, cancer cells grew almost 50 percent faster, while the opposite occurred when we restored Lig-1 to healthy levels. We also found that depleting HER2 levels resulted in an increase in Lig-1 levels, while activating HER2 resulted in Lig-1 depletion."
According to Sweeney, the results may help explain why, even among patients with HER2-positive breast cancer, the disease process can vary dramatically.

"Il y avait une claire inversion des relations entre lig-1 et HER-2. Quand lig-1 diminuait, les cellules cacéreuses croisaient 50% plus vite, quand nous restaurions lig-1 au niveau des tissus sains, les cellules cancéreuses diminuaient à la même vitesse.
Activer HER2 correspond à des niveaux de lig-1 plus bas et diminuer HER2 résulte en augmentation pour lig-1."

"We think Lig-1 levels could be linked to prognosis. Patients with more of the regulator gene's functions intact are going to have a better outcome than those with less," she said.

Results of the current study further support the notion that Lig-1 serves as a tumor suppressor gene, though more work is needed to confirm this outcome. Sweeney and her team are gathering more evidence to support this theory and to determine whether or not Lig-1 levels are truly predictive of outcome for HER2-positive patients. If so, it will suggest that, while this type of test is not available today, these patients should in the future be screened for Lig-1 activity in order to better define treatment subgroups.

"It's clear that stratifying breast cancer patients as either HER2-positive or HER2-negative is not telling the whole story. This research takes us a step further in the right direction toward better understanding types of breast cancer and treatment targets for those different types," Sweeney said.

Dernière édition par Denis le Lun 18 Jan 2016 - 19:00, édité 1 fois
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