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 La protéine sFRP-1

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Nombre de messages : 16202
Date d'inscription : 23/02/2005

MessageSujet: Re: La protéine sFRP-1   Mer 1 Aoû 2012 - 11:29

(July 31, 2012) — A potentially powerful new approach to treating two lethal metastatic cancers -- triple negative breast cancer and clear cell renal cell carcinoma, the most common form of kidney cancer -- has been discovered by researchers at Mayo Clinic in Florida. In the online issue of Molecular Cancer Therapeutics, they report that two drugs, romidepsin and decitabine, work cooperatively to activate a potent tumor suppressor gene that is silenced in these cancers. Once the gene, secreted frizzled related protein one or sFRP1, went to work after the drugs were used, the laboratory tumor cells stopped growing and died.

Une nouvelle approche potentiellement puissante pour traiter deux cancers métastasiques - le cancer du triplement négatif et le cancer du à cellules claires - a été découverte par les chercheurs de la clinique Mayo en Floride. Ils rapportent que deux médicaments ont été découvert, la romidepsine et la décitabine travaillent ensemble pour activer un puissant un puissant gène suppresseur de tumeurs qui est inactivé par ces cancers. Une fois que le gène relié à protéine sFRP1 est réactivé avec les médicaments, les tumeurs en laboratoire du moins arrêtent de grossir et meurent.

Both drugs are approved by the Food and Drug Administration to treat blood cancer and are being tested individually in numerous solid cancers in which sFRP1 is disabled. This study was the first to test the use of both in these metastatic cancers linked to sFRP1, and the results are very encouraging, says senior investigator John Copland, Ph.D., a Mayo Clinic molecular biologist.

Les deux médicaments sont approuvés par la FDA pour traiter le cancer du sang et ont été testé individuellement dans plusieurs cancers solides dans lequel sFRP1 est désactivé. l'étude était la première à tester ces deux médicaments ensemble et les résultats sont très encourageants.

"We now have the basis for a clinical trial aimed at providing effective therapy for two drug-resistant cancers and perhaps many more tumor types in the future," Dr. Copland says. In addition to breast and kidney cancer, sFRP1 is disabled in colon, ovarian, lung, liver and other tumor types.

"nous avons maintenant les bases d'un essai clinique visant à fournir une thérapie efficace pour deux résistances aux médicaments et peut-être à plusieurs types de cancers de plus. Le gène sFRP1 est désactivé dans le cancer du de l' du du ainsi que d'autres types de tumeurs..

Dr. Copland and his colleagues earlier discovered that sFRP1 was silenced in certain cancers. This new work demonstrates that its expression can be restored by romidepsin, which is a histone deacetylase inhibitor, and decitabine, a methyltranferase inhibitor. Both are epigenetic drugs, modifying genes in a way that affects whether they are turned on or off.

Le docteur Copland et ses collègues ont découvert plus tôt que le sFRP1 était désactivé dans certains cancers. CE nouveau travail démontre que son expression peut être restaurer avec romodepsin un inhibiteur d'histone deacetylase et decitabine un inhibiteur methyltransferase. Ce sont deux médicaments epigenetics qui modifient les gènes en les mettant à "on " ou à "off".

"Individually, each drug did not induce any form of cell death but, together, they killed all of the different cell lines of kidney and triple negative breast cancer that we tested in the laboratory," says lead investigator Simon Cooper, Ph.D., a Mayo Clinic molecular biologist who specializes in renal cancer.

Pris séparément, chaque médicament ne provoquent aucune mort de cellules cancéreuses mais ensemble ils ont tué toutes les différentes sortes de cellules du rein ou du cancer du sein triplement négatif qui ont été testées en laboratoire.

The two cancers affect up to 80,000 Americans each year and therapies to treat both, especially when they are advanced, have been very limited, says co-author Edith Perez, M.D., deputy director of Mayo Clinic Cancer Center.

"But now, not only do we have a very promising lead on future therapy, but if this combination treatment works as we hope it does, we will have a biomarker to be able to test which patients might benefit the most," she says. "In other words, a biopsy test could identify patients whose tumors had lost sFRP1 function."

Non seulement nous avons quelque chose de très prometteur pour de futures thérapies mais si cela va comme on veut, nous aurons un biomarqueur pour tester chaque patient qui pourrait en bénéficier le plus. En d'autres mots, une biopsie pourrait identifier les patients qui ont perdu la fonction du gène sFRP1."

The approach to finding this potential new treatment strategy is novel, adds oncologist Michael Menefee, M.D., who is also a study co-author.

L'approche pour trouver ce traitement potentiel est nouvelle.

"This type of interdisciplinary preclinical research effort is important, not only because of the value of the science, but also because the drugs are already in the clinic and that will facilitate translational efforts and hopefully confirm the preclinical findings in patients with advanced malignancies," he said.

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MessageSujet: La protéine sFRP-1   Jeu 16 Aoû 2007 - 21:34

Researchers at Mayo Clinic Jacksonville have found that a key gene is often "silenced" in clear cell renal cell carcinoma, the most common type of kidney cancer, and when they restored that gene in human kidney cancer cells in culture and animal experiments, tumors stopped growing and many disappeared.

Les chercheurs de la clinique Mayo ont trouvé qu'un gène-clé est souvent rendu silencieux dans le cancer du rein et quand ce gène est restauré chez les animaux et dans les cellules de laboratoire, les tumeurs arrêtent de croitre et plusieurs disapraissent.

In the August 15 issue of Clinical Cancer Research, investigators report that suppression of this gene, which makes secreted Frizzled-Related Protein-1 (sFRP-1), appears to be one defining epigenetic event in the development and progression of clear cell renal carcinoma, which is responsible for at least 80 percent of kidney cancers. The researchers also found that sFRP-1 controlled 13 tumor-promoting genes along the powerful "Wnt" signaling pathway, whose activity has been linked to a number of different cancers, of which colon cancer is best known.

La suppression du gène qui secrète la protéine sFRP-1 est un évênement qui encourage le cancer du rein (80% de tous les cancers du rein) et sa progression. Cette protéine controle au moins 13 gènes qui promeuvent le cancer du rein dans le chemin cellulaire WNT qui est lié à différent cacners comme le cancer du

"For all intents and purposes, sFRP-1 acts as a key tumor suppressor gene in clear cell renal cell carcinoma — it puts a brake on Wnt, stopping dangerous oncogenic signaling to the cancer cell, thus blocking tumor growth and metastasis," explained the study's senior investigator, John A. Copland, Ph.D., a molecular biologist at Mayo Clinic Cancer Center. Michelle Gumz, Ph.D., a former postdoctoral researcher at Mayo Clinic, is the lead author of the study. She is now at the University of Florida.

The findings may also be relevant to other cancers, such as breast, ovarian, prostate, bladder, lung and colon cancers, in which loss of sFRP-1 function is common, Dr. Copland explained. "Through understanding the important role sFRP-1 plays, we may be able to eventually tailor human therapies to restore its function in this type of kidney cancer and in other cancers," he says.

Kidney cancer incidence and related deaths have been increasing by about 2 percent per year for the past six decades, for reasons that are not fully understood but may be related to smoking and other environmental factors. More than 50,000 new cases of the cancer are expected in 2007, with almost 13,000 deaths. Kidney cancer tumors are often found when they are advanced and extremely difficult to treat: two-year survival at that stage is only 12 percent whereas kidney cancer that has not yet spread has a five-year survival of up to 75 percent.

To aid diagnosis and treatment, Dr. Copland and a team of researchers have been developing a panel of biomolecular markers for kidney cancer. They are comparing tissue from renal cell tumors with normal kidney tissue from the same patient, searching for "master" genes that control signaling pathways that are involved in cancer development and progression. A master gene, if altered, would shut down the cascade of cancer-causing genes that it controls. "There are likely to be a number of molecular events that lead to cancer development, so we want to find as many genes as we can that we might shut down, like Wnt, or turn back on, like sFRP1," Dr. Copland says.

To find out which genes are activated and which are silent, in normal versus cancerous kidney tissues, the research team used three independent sets of patient kidney tissue samples from Mayo Clinic College of Medicine, in Jacksonville, and from The University of Texas M. D. Anderson Cancer Center in Houston. In one sample, they found that gene expression of sFRP-1 was "down-regulated," or turned down low or off, in 15 of 15 patients. They also found that activity of the gene decreased as much as 70 times the level seen in normal tissue.

In a second set of 33 patient samples, the researchers looked for evidence of messenger RNA (mRNA) activity; mRNA, transcribed from sFRP-1, is the blueprint that cells need to produce sFRP-1 proteins. Every stage of kidney cancer showed decreases in sFRP-1 mRNA, some as much as 140-fold.

Investigators then searched for differences between sFRP-1 protein levels in normal versus cancerous cells within another set of 39 matched patient samples. They found that 70 percent of the cancerous samples showed a total loss of sFRP-1 proteins, and the other 30 percent had very little of the vital protein in cells. "The take home message is that there was almost a complete loss of sFRP-1 protein in most of the renal cell carcinoma samples we studied," Dr. Copland says. "If no protein is being produced, the Wnt signaling pathway is free to activate other molecules that can cause cancer."

Finally, researchers used a common experimental technique to see what would happen if they reactivated sFRP-1 in tumor cells. They had discovered that, in clear cell renal carcinoma, sFRP-1 is silenced through a process known as methylation, blocking the ability of transcription factors and proteins from binding on and activating genes, thus "silencing" them.

Restoring sFRP-1 protein expression by a technique of transfecting the sFRP1 gene into human renal cancer cells was remarkably effective, Dr. Copland says. Growth of tumors decreased by at least 90 percent in sFRP1 transfected patient-derived cancer cells in the laboratory, he said, and Wnt regulated oncogenes, such as c-myc, were suppressed compared to untreated cells.

In mice, tumors in which sFRP-1 function had been restored for seven weeks were an average of 3 percent the size of tumors in untreated animals and many tumors disappeared completely. "This was a dramatic reduction," Dr. Gumz says. "Our report is the first to show anti-tumor activity of sFRP-1 in an animal model and to clearly implicate Wnt as an oncogenic signaling pathway in renal cell carcinoma."

Understanding and targeting the Wnt signaling pathway with drugs has been a goal of researchers worldwide, Dr. Copland says. "There are at least 20 known Wnt molecules and five members of the sFRP family, and we are slowly beginning to understand how they work together." Anti-methylation agents are now being tested in various clinical trials, he added, saying, "Given results of this study, that kind of strategy might be useful. There are few effective therapeutic options for metastatic clear cell renal cell carcinoma that result in increased longevity and quality of life. Restoration of sFRP-1 function represents a possible therapeutic target."

The findings might also be helpful in identifying which type of kidney cancer a patient has developed. The researchers found that loss of sFRP-1 is common in clear cell renal cell carcinoma as well as in the next most common form of renal cell carcinoma, the papillary subtype. But loss of this gene is not seen in chromophobe renal cell carcinoma and benign oncocytoma. "Although biopsies are not performed for renal cell carcinoma currently, creating molecular signatures unique to the subtype of renal cell carcinoma using genes such as sFRP1 and removing a small piece of tumor tissue by biopsy could save some patients from surgical removal of a benign mass," Dr. Copland says.

The study was funded by National Cancer Institute grants, the James and Esther King Biomedical Program of the Florida Department of Health, and the Dr. Ellis and Dona Brunton Rare Cancer Research Fund. Co-authors include, from Mayo Clinic College of Medicine, Jacksonville: Pamela A. Kreinest, Dr. April C. Childs, Leandra S. Belmonte, Shauna N. LeGrand, Dr. Kevin J. Wu, Dr. Alexander S. Parker; from Mayo Clinic College of Medicine, Rochester, Minn.: Dr. Hongzhi Zou and Dr. David A. Ahlquist; Dr. Christopher G. Wood, from the University of Texas M. D. Anderson Cancer Center, Houston, Texas; Dr. Bruce A. Luxon and Mala Sinha, from the University of Texas Medical Branch; Galveston, Texas; and Dr. L-Z Sun, from the University of Texas Health Science Center, San Antonio, Texas.
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