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Date d'inscription : 23/02/2005

MessageSujet: Re: PD173074   Ven 7 Juin 2013 - 16:55

Novel abnormalities in the FGFR gene, called FGFR fusions, were identified in a spectrum of cancers, and preliminary results with cancer cells harboring FGFR fusions suggested that some patients with these cancers may benefit from treatment with FGFR inhibitor drugs, according to data published in Cancer Discovery, a journal of the American Association for Cancer Research.

De nouvelles anormalités dans le gène FGFR appelés Fusions FGFR ont été identifiés dans plusieurs cancers et les résultats préliminaires avec les cellules ayant les fusions FGFR suggèrent que certains patients avec ces cancers pourraient bénéficier de médicaments inhibant FGFR selon une étude publié dans Cancer Discovery.

FGFR genes are fibroblast growth factor receptors that play a role in key biologic processes of a human cell.

Les gènes FGFR sont des récepteurs de facteurs de croissance qui jouent un rôle-clé dans des processus biologiques de la cellules humaine.

“We found targetable FGFR gene fusions across a diverse array of cancer types. Although rare for any individual cancer type, if found in an individual patient, these fusions are likely a major driver of that patient’s cancer,” said Arul M. Chinnaiyan, MD, PhD, Director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor. “We were surprised to find so many different FGFR fusions in so many different cancers.

nous avons trouvé des gènes FGFR que l'on peut cibler dans plusieurs cancers. Même si c'est rare pour un type de cancer particulier lorsque ces fusions sont trouvés chez un patient ce sont ces fusions qui font le cancer avance. Nous avons été surpris de trouver tellement de différentes fusions dans tellement de cancers différents.

“This study demonstrates the benefit of broad-based sequencing efforts in personalized oncology. It has the potential to identify novel, rare mutations that are ‘actionable’ therapeutic targets,” Dr. Chinnaiyan added. “Such advances in sequencing technology facilitate rational precision therapies for individuals with late-stage cancer.”

Michigan Oncology Sequencing Program

The Michigan Oncology Sequencing Program facilitates integrative sequencing analysis of tumors from patients with advanced cancers. More than 100 patients have been enrolled since 2011. Through the project, researchers analyze the mutational landscape of each patient’s tumor and suggest clinical trials or approved drugs that might be appropriate for that patient, according to Dr. Chinnaiyan.

Plus de 100 patients ont été enrôlés depuis 2011. Les chercheurs ont analysé la mutation de chaque patient et approuver un médicament qui pourrait être approprié pour chacun.

He and his colleagues identified novel fusions of the gene FGFR2 in the tumors of four patients recruited to the Michigan Oncology Sequencing Program. Of these four patients, two had metastatic tumors of the bile duct, one had metastatic breast cancer, and one had metastatic prostate cancer.

Les chercheurs on tidentifié de nouvelles fusions du gène FGFR2 dans les tumeurs de 4 patients. Un de ses patients avait des tumeurs métastasés du conduit de la bile, une avait un cancer du métastasé et un avait un cancer de la métastasé .

To further analyze whether FGFR fusions are present across different types of cancers, the researchers extended their assessment and analyzed data generated from an internal cohort of 322 patients, as well as from a large cohort of 2,053 patients recruited to The Cancer Genome Atlas. They identified several distinct FGFR fusions in nine different types of cancers, including bladder cancer, brain cancer and lung cancer.

Ils ont identifié plusieurs fusions distinctes de FGFR dans 9 cancers différents incluant

Patients May Benefit from FGFR Kinase Inhibition

Dr. Chinnaiyan and colleagues then conducted studies using cancer cells and found that the different FGFR fusion proteins all seemed to drive cancer cell proliferation by activating FGFR signaling. The researchers were able to inhibit proliferation of the cells in vitro using the FGFR inhibitors PD173074 and pazopanib (Votrient). In addition, they injected mice with human cancer cells and found that the tumors grown in mice could be inhibited with PD173074.

Les chercheurs ont été capable d'inhiber la prolifération des cellules avec les inhibiteurs PD173074 et le Votrient. En plus, ils ont injecté des souris avec des cellules cancéreuses humaines et trouvé que les tumeurs qui croissaient dans le souris povaient être inhibées avec PD173074.

One of the four patients whose metastatic bile duct tumor failed to respond to conventional chemotherapy was recruited to an FGFR inhibitor trial, and he is currently undergoing treatment, according to Dr. Chinnaiyan.

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MessageSujet: Re: PD173074   Mer 11 Nov 2009 - 13:32

(Nov. 11, 2009) — A potential new drug for lung cancer has eliminated tumours in 50% of mice in a new study published November 10 in the journal Cancer Research. In the animals, the drug also stopped lung cancer tumours from growing and becoming resistant to treatment. The authors of the research, from Imperial College London, are now planning to take the drug into clinical trials, to establish whether it could offer hope to patients with an inoperable form of lung cancer.

Un nouveau traitement potentiel pour le cancer du a éliminé les tumeurs chez la moitié des souris sous traitement. Pour ces animaux, le médicament a aussi arrêté le développement des tumeurs au il les a arrêté de croitre et de devenir résistantes aux traitements. Les chercheurs veulent maintenant essater ce traitement sur l'humain dans des essais cliniques pour établir si vraiment le médicament peut offrir un espoir pour certaines formes de cancer du poumon inopérable.

One in five people with lung cancer have small cell lung cancer and only three per cent of these people are expected to survive for five years. With this form of lung cancer, tumours spread quickly so it is rarely possible to remove the tumours surgically. Because of this, small cell lung cancer is treated with chemotherapy, with or without additional radiotherapy. Initially, the treatment often appears to work, reducing the size of the tumours. However, the tumours usually grow back rapidly and then become resistant to further treatment.

The researchers behind today's study have identified a drug that, in some mice, was able to completely shrink tumours away. In the mouse models, it was also able to stop tumours from growing and it helped other forms of chemotherapy to work more effectively. If the drug proves successful in humans, the researchers hope that it could help patients with this kind of lung cancer to live longer.

Si le traitement est aussi efficace chez l'humain, les chercheurs espèrent qu'il pourra aider les patients à vivre plus longtemps.

In small cell lung cancer, tumours spread quickly because the tumour cells grow and divide faster than normal cells. Previous research carried out by the Imperial team showed that these tumour cells proliferate faster because they are fuelled by a growth hormone called FGF-2. This growth hormone also triggers a survival mechanism in the tumour cells that makes them become resistant to chemotherapy.
In today's study, the researchers looked at the effect of a drug called PD173074, which blocks the receptor that FGF-2 uses to attach to the tumour cells. The drug stopped cancer cells from proliferating and from becoming resistant to treatment in 'test-tube' laboratory models. In one animal model of small cell lung cancer, the drug eliminated tumours in 50% of mice and in a second, similar mouse model, the drug enhanced the effect of standard chemotherapy.

Dans l'étude, les chercheurs ont regardé l'effet d'un médicament appelé PD173074 qui bloque le récepteur que FGF-2 utilise pour s'attacher aux tumeurs cancéreuses. Le médicament a arrêté la prolifération et la résistance aux thérapies dans les éprouvettes de laboratoire. Chez un animal modèle du cancer du à petites cellules, le médicament a éliminé 505 des tumeurs et sur un second animal il a amélioré l'effet de la chimio thérapie.

Professor Michael Seckl, corresponding author of the study who heads the Section of Molecular Oncology and Lung Cancer Research at Imperial College London, said: "Lung cancer is the most common cancer killer in the world and over 100 people in the UK are diagnosed with the disease every day. Around one in five of those people will have small cell lung cancer. Although it responds to chemotherapy initially, the tumours soon become resistant to treatment and sadly nearly all people with the disease do not survive.
"We urgently need to develop new treatments for this disease. Our new research in mice suggests that it may be possible to develop the drug PD173074 into a new targeted therapy for small cell lung cancer. We hope to take this drug, or a similar drug that also stops FGF-2 from working, into clinical trials next year to see if it is a successful treatment for lung cancer in humans. An added bonus of this drug is that it could be taken orally, which would make it less invasive than some other forms of cancer therapy," added Professor Seckl.
The researchers first studied the effect of PD173074 in the lab, on cells taken from human tumours. The drug stopped cells from proliferating and prevented FGF-2 from triggering their survival mechanism, so the cells could be killed with standard chemotherapy agents. The effect of the drug was dose-dependent, so the more drug the researchers added to the cells, the less the cells proliferated.

The researchers then studied PD173074 in mice using two different types of human small cell lung cancer tumours. They tested the drug on its own and alongside the standard chemotherapy agent cisplatin, which is frequently used to treat patients with the disease. In the first mouse model, PD173074 given on its own killed off tumours in 50 per cent of the mice and these mice remained disease-free for at least one year. In the second mouse model, both PD173074 and cisplatin alone slowed down tumour growth. When the drugs were combined, they slowed down tumour growth significantly faster than either drug on its own.

The researchers also used PET scanning to show that the drug reduced DNA synthesis in the tumours, which indicates that the drug was preventing cell proliferation. The researchers also found that the rate of cell death, or apoptosis, in the tumours increased after the drug was given to the mice.
PD173074 was developed in 1998 to stop blood vessels from forming around tumours. Today's research is the first to show this drug has a therapeutic effect on tumours in mice.
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MessageSujet: PD173074   Mer 3 Sep 2008 - 9:55

Researchers at the Translational Genomics Research Institute (TGen) today announced a new approach to treating endometrial cancer patients that not only stops the growth of tumors, but kills the cancer cells.

Les chercheurs ont annoncé une nouvelle approche pour combattre le cancer de l'endomètre (1) qui non seulement arrête la croissance des tumeurs mais tue aussi les cellules cancéreuses.

In a potentially major breakthrough, TGen scientists and collaborators at Washington University School of Medicine in St. Louis discovered that introducing a particular inhibitor drug can turn "off'' receptors responsible for the growth of tumors in a significant number of patients with endometrial cancer.

Dans une percé majeure dans les connaissances, Les scientifiques de St-Louis Missouri ont découvert qu'en employant un médicamnet inhibiteur, ils pouvaient bloquer le récepteur responsable pour la croissance des tumeurs chez un nombre significatif de patientes aux prises avec le cancer de l'endomètre.

And, they found that the inhibitor drug proved effective even in cancer tumors containing a commonly occurring mutant gene, PTEN, previously associated with resistance to drug treatment.

Et, ils ont trouvé que le médicament inhibiteur était efficace même en présence du gène PTEN muté qui a été pourtant reconnu comme résistant aux médicaments.

TGen's findings appear September 1 in a paper published as a priority report by Cancer Research, a Philadelphia-based peer-reviewed journal dedicated to original cancer research.

A clinical trial based on the TGen study will start within the next year.

Un essai clinique basé sur ces découvertes sera initié cette année.

Dr. Pamela Pollock, an associate investigator in TGen's Cancer and Cell Biology Division and the paper's senior author, led a team that used the latest genome-scanning technology to sequence 116 endometrioid endometrial tumor samples. This work was done in association with Dr. Paul Goodfellow, an expert in endometrial cancer and a professor in the departments of Surgery and of Obstetrics and Gynecology at Washington University.

Pollock and colleagues in May 2007 announced that they had discovered previously unrecognized alterations in the fibroblast growth factor receptor 2 (FGFR2) gene. The altered FGFR2 is present in the cancer cells of nearly 15 percent of women with endometrioid endometrial tumors. These kinds of tumors represent 80 percent of all endometrial cancers.

Les scientifiques ont découvert précédemment des altérations inconnus dans le gène FGFR2. Cette altération du gène FGFR2 est présente dans 15% des femmes avec le cancer endométria.

By introducing a commercially available inhibitor drug, PD173074, TGen researchers showed that they could stop the growth of tumors, and even kill cancer cells, in cases where the tumors contained the altered FGFR2 gene. The altered gene causes the receptors to get stuck in the "on'' position and signal the endometrial cells to grow out of control.

Le médicament PD173074 pourrait arrêter la croissasnce des tumeurs et même tuer les cellules cancéreuses dans les cas ou le cancer contient le gène altéré en question

"These findings could accelerate the development of new treatments for endometrial cancer because there are already drugs in clinical trials that inhibit FGFR2 function,'' Pollock said.

Current treatment of endometrial cancer can involve surgical removal of the uterus, radiation and chemotherapy. While many women are successfully treated with these approaches, about 15 percent of those with endometrioid endometrial cancer have persistent or recurring tumors that are resistant to current drug therapies. Mutations in several genes previously have been identified in endometrial tumors, but they have not been suitable drug targets – until now.

"This targeted approach holds great promise for patients with uterine cancer (endometrioid endometrial) tumors that contain the FGFR2 mutation," said TGen physician-in-chief, Dr. Daniel Von Hoff, "and offers yet another powerful example of how genomic medicine is changing the way we look at and treat cancer."

Goodfellow agreed, "The discovery that endometrial cancer cells die when treated with an FGFR2 inhibitor - even when they carry other genetic abnormalities common in uterine cancers - suggests anti-FGFR2 therapies have great potential.''

The researchers' already established ties with the National Cancer Institute, which will assist with the clinical trials, should speed the development of new therapies, Goodfellow said. "Our collaborative group's strong ties with the NCI's Gynecologic Oncology Group will allow us to rapidly take our findings from the lab to patients.''

Endometrial cancer, which invades the inner wall of the uterus, is the most common gynecological cancer in the United States. This year more than 40,000 women will be diagnosed and nearly 7,500 women will die of the disease, according to the American Cancer Society (ACS).

Among women, only breast, lung and colon cancers strike with more frequency. And while endometrial cancer is slow to develop, and often is not detected until after age 60, nearly one in eight women who are diagnosed die within five years, according to the ACS.

Le cancer de l'endomètre est lent à se développer et n,est pas détecter souvent avant 60 ans.

Pollock plans to start clinical trials with an FGFR inhibitor in endometrial cancer patients within a year. The trials will be conducted in collaboration with Dr. Matthew Powell, a gynecologic oncologist and assistant professor of Obstetrics and Gynecology at Washington University School of Medicine.

Targeted drug therapy is a relatively new approach to cancer treatment that is based on identifying the abnormalities in cancer cells that cause them to grow uncontrollably. It involves treating tumors with drugs that specifically inhibit the activity of these genetic abnormalities.

This approach of targeted therapy allows oncologists to match the therapy to the specific genetic signature of each patient's tumor, a strategy that has been effective in multiple cancer types, including breast cancer, lung cancer and chronic myelogenous leukemia.

The study was funded, in part, by a two-year, $100,000 ($50,000 per year) grant from the Cary, N.C.-based, V Foundation for Cancer Research. The foundation is named in remembrance of famed North Carolina State basketball coach and award-winning broadcaster Jimmy Valvano, a cancer research advocate who died of Metastatic Adenocarcinoma in 1993.

(1) Définition endomètre : Revêtement interne de l'utérus

Dernière édition par Denis le Ven 18 Déc 2009 - 13:37, édité 3 fois
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