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 Inhibiteur de cellules souches cancéreuses pluripotentes.

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Denis
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Nombre de messages : 15767
Date d'inscription : 23/02/2005

MessageSujet: Re: Inhibiteur de cellules souches cancéreuses pluripotentes.   Lun 17 Oct 2016 - 9:36

FDA grants Napabucasin orphan status for gastric cancer
Wednesday, June 29, 2016

Photo of Manish Shah, M.D. The FDA has granted an orphan drug designation to the STAT3-targeted agent napabucasin as a treatment for patients with gastric or gastroesophageal junction (GEJ) cancer, based on early-phase research showing antitumor activity for the agent when used in combination with weekly paclitaxel.

In a phase Ib/II study, the cancer stemness inhibitor showed an objective response rate (ORR) of 15% with a median progression-free survival (PFS) of 13 weeks. In those who did not receive a taxane in the metastatic setting, the ORR was 31% and the median PFS was 20.6 weeks. In those who received just 1 prior therapy that was not a taxane, the ORR was 50%.

Based on these findings, the investigational small molecule, also known as BBI608, is being evaluated in the phase III BRIGHTER trial as a second-line treatment for patients with gastric and GEJ cancer following platinum or fluoropyrimidine-based chemotherapy.

"In the US, only about 1 in 3 patients with gastric cancer survive five years after diagnosis, so there remains a significant need for innovation in this tumor type," Chiang J. Li, MD, President, CEO and chief medical officer of Boston Biomedical, the company developing the drug, said in a statement. "We hope that napabucasin, with a first-in-class mechanism of action, will help address this significant unmet medical need."

...

"This is an important second-line study of chemotherapy with or without a novel STAT3 inhibitor, which works as a stem cell or a stemness inhibitor," lead investigator Manish A. Shah, M.D., Bartlett Family Associate Professor in Gastrointestinal Oncology at Weill Cornell Medicine told OncLive. "Cancer stem cells are likely responsible for the development or recurrence and disease progression in patients with solid tumor malignancies, and for the first time we are now able to test agents that are really targeting the stemness phenotype."

The BRIGHTER study currently has an estimated primary completion date of August 2017. The study, which was launched in June 2014, is seeking to enroll 700 patients who experienced clinical or radiologic disease progression during first-line treatment for unresectable or metastatic disease or ≥6 months after finishing therapy (NCT02178956).

In addition to gastric cancer, napabucasin is also being explored as a potential treatment for patients with pancreatic cancer, ovarian cancer, triple-negative breast cancer, head and neck cancer, and colorectal cancer. These studies are assessing the agent in various combinations.

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La FDA accorde Napabucasin statut orphelin pour le cancer gastrique
Mercredi, 29 Juin, 2016

Photo de Manish Shah, MD La FDA a accordé une désignation de médicament orphelin à l'agent napabucasin ciblant STAT3 comme un traitement pour les patients atteints de cancer de jonction gastrique ou gastroesophageal (GEJ), basée sur la recherche de phase précoce présentant une activité antitumorale de l'agent lorsqu'il est utilisé en combinaison avec le paclitaxel hebdomadaire.

Dans une étude de phase Ib / II, l'inhibiteur de cellules souches du cancer a montré un taux de réponse objective (ORR) de 15% avec une médiane de survie sans progression (PFS) de 13 semaines. Dans ceux qui ne reçoivent pas un taxane dans le cadre métastatique, l'ORR était de 31% et la SSP médiane était de 20,6 semaines. Dans ceux qui ont reçu seulement 1 traitement antérieur qui n'a pas été un taxane, le taux de réponse était de 50%.

Sur la base de ces constatations, la petite molécule expérimentale, également connu sous le nom BBI608, est en cours d'évaluation dans la phase d'essai III BRIGHTER comme traitement de deuxième ligne pour les patients atteints de cancer gastrique et GEJ suivants une chimio à base de platine ou une chimiothérapie à base de fluoropyrimidine.

Il reste un besoin important pour l'innovation dans ce type de tumeur," selon Chiang J. Li, MD, président, PDG et directeur médical de Boston biomédicale, la société de développement du médicament, qui a déclaré dans un communiqué. "Nous espérons que napabucasin, avec un mécanisme d'action nouveau dans sa catégorie, permettra de faire face à ce besoin médical non satisfait."


"Ceci est une étude de deuxième ligne importante de la chimiothérapie avec ou sans un inhibiteur de STAT3, qui fonctionne comme un inhibiteur de cellules souches" Selon l'investigateur principal Manish A. Shah, MD, professeure agrégée en oncologie gastro-intestinale au Weill Cornell Medicine dit OncLive. "Les cellules souches cancéreuses sont probablement responsables de l'élaboration ou la récidive et progression de la maladie chez les patients présentant des tumeurs malignes solides, et pour la première fois, nous sommes maintenant en mesure de tester des agents qui ciblent vraiment le phénotype de souche."

L'étude BRIGHTER a actuellement une date d'achèvement du primaire estimée à Août 2017. L'étude, qui a été lancé en Juin 2014, cherche à inscrire 700 patients qui ont connu la progression de la maladie clinique ou radiologique pendant le traitement de première ligne pour la maladie métastatique ou non résécable ou ≥6 mois après avoir terminé le traitement (NCT02178956).

En plus du cancer gastrique, napabucasin est également explorée comme un traitement potentiel pour les patients atteints d'un cancer du , de cancer de l' , de cancer du triple négatif, de cancer la tête et du , et du cancer du . Ces études évaluent l'agent dans diverses combinaisons.

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MessageSujet: Re: Inhibiteur de cellules souches cancéreuses pluripotentes.   Dim 29 Jan 2012 - 17:09

Cet article est daté de janvier 2011.


Dans des études précédentes, Dr. Joshi Alumkal a prouvé que (demethylase Lysine-spécifique 1) la protéine LSD1 est un conducteur de croissance de cellules de cancer de et survie et que LSD1 est upregulated dans les cancers agressifs de prostate. Ainsi, la suppression LSD1 pourrait fournir une occasion unique de contrôler la progression de cancer de prostate. Le travail de Dr. Alumkal's clarifiera les voies du gène LSD1 qui expliquent des effets de LSD1, et il évaluera de petits inhibiteurs de molécule de LSD1. Ses résultats mèneront la manière de mettre des épreuves cliniques d'I des inhibiteurs LSD1 dans les patients présentant la forme mortelle de cancer-le castration-résistant metastatic de prostate de cette maladie.

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MessageSujet: Re: Inhibiteur de cellules souches cancéreuses pluripotentes.   Dim 29 Jan 2012 - 16:24

(Jan. 27, 2012) — A collaborative anti-cancer research jointly conducted by The Hong Kong Polytechnic University (PolyU), Peking University Shenzhen Graduate School and Nevada Cancer Institute has led to the development of a novel class of chemical inhibitors that specifically target cancer cells with pluripotency.

Une collaboration entre l'université de Pékin et celle de Honk-Kong sur la recherche anti-cancer a donné une nouvelle classe de médicaments qui cible spécialement les cellules canécreuses pluripotentes.

This cutting-edge research has combined the effort of three research teams including one led by Dr Tao Ye, Associate Professor of PolyU's Department of Applied Biology and Chemical Technology. This breakthrough may help the selective removal of cancer stem cells and potentially provide a novel strategy to eradicate cancers.

C'est une recherche de pointe et une avancée qui pourrait aider à tuer sélectivement les cellules souches canécreuses et fournir une nouvelle stratégie pour éradiquer le cancer.

Cancer is a major cause of human death in China and all around the world. It is difficult to treat cause of the existence of cancer initiating cells/cancer stem cells. Although they exist in very few in numbers, cancer stem cells (CSCs) can proliferate and self-renew, and are pluripotent and multipotent, which have the capability to differentiate into various more heterogeneous cancer cells that constitute the entire tumor mass. As stem cells, they are more resistant to most conventional cancer therapies such as chemotherapy or radiotherapy due to their differences in the cell cycle regulation and DNA repair processes. They also act as the source for metastasis and recurring drug resistant cancers after conventional cancer therapy. Currently, there are no chemical inhibitors or other agents that can specifically and selectively target cancer stem cells. The development of compounds that target cancer stem cells is an unmet medical demand for the eradication of malignant cancers.

According to Dr Ye, the potential clinical applications of new LSD1 inhibitors include the following:

(1) They can be used to treat malignant germ cell tumors such as teratoma/teratocarcinomas, embryonic carcinomas, seminomas, choriocarcinomas, and tumors of yolk sac. These tumors are usually treated by surgery or cis-platinum, but after initial treatment, these tumors always become resistant to platinum drugs. So far, the LSD1 inhibitors are highly effective towards these pluriptont cancers with stem cell properties.

(2) The LSD1 inhibitors may also be used to remove teratomas/embryonic carcinomas during stem cell-based therapy. One major problem in stem/iPS cell-based therapy is the formation of embryonic carcinomas, teratomas, or teratocarcinomas by incomplete differentiation of ES/iPS cells in the organs of recipients. Because LSD1 selectively inhibit these pluripotent embryonic carcinomas, teratomas, or teratocarcinomas, LSD1 inhibitors may help ensure the successful application of stem cell-based therapy.

(3) More importantly, since teratomas/embryonic carcinomas are pluripotent cancer stem cells, researchers will probe whether cancer stem cells of other types of major organ-specific cancers such as breast, ovarian, lung, and brain cancers are sensitive to these LSD1 inhibitors. Further studies indicated that LSD1 inhibitors can also be used to inhibit many cancer stem cell-like cells such as breast and ovarian cancers

D'une façon plus importante, parce que ces carcinomes sont des cellules souches canécreuses pluripotentes, les chercheurs vont tester si les cellules souches cancéreuses d'autres types de cancer plus inportants comme celui du , de l' , du du vont être sensibles aux inhibiteurs de LSD1.



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MessageSujet: Inhibiteur de cellules souches cancéreuses pluripotentes.   Mer 5 Mar 2008 - 14:18

(Mar. 5, 2008) — A protein that governs development of human embryonic stem cells (hESCs) also inhibits the growth and spread of malignant melanoma, the deadliest skin cancer, Northwestern University researchers have discovered. Metastatic melanoma, which develops from the transformation of skin pigment cells or melanocytes, has a death rate of more than 80 percent and a median survival of less than 7.5 months.

Une protéine qui se dirige le développement  des cellules souches embryonniques (hESCs) inhibe aussi la croissance et la métastatisaton du cancer de la  

The Northwestern scientists, led by researcher Mary J. C. Hendrix, M.D., additionally found that the protein, called Lefty, prevents aggressive breast cancer cells from metastasizing. Death from metastatic breast cancer exceeded 40,000 in 2007, with over 180,000 new cases diagnosed in the United States.

Cette protéine appelé "Lefty" arrête aussi le développement de formes agressives du cancer du

Importantly, Lefty is secreted only in hESCs, and not in any other stem cell type tested -- including stem cells isolated from amniotic fluid, cord blood or adult bone marrow -- or placental cells.

Lefty est secrété seulement par les cellules hESCs et non dans les autres types de cellules souches.

Results of the study, described in an article in the March 3rd online version of The Proceedings of the National Academy of Sciences, build on an elegant body of research by the Hendrix lab to identify the genes and cellular pathways involved in cancer metastasis.

Dr. Hendrix is president and scientific director of the Children's Memorial Research Center and professor in The Robert H. Lurie Comprehensive Cancer Center of Northwestern University and at the Feinberg School of Medicine. Lynne-Marie Postovit, who was first author on the study and a post-doctoral trainee in the Hendrix lab, is currently an assistant professor at the University of Western Ontario, Canada.

Embryonic stem cells are pluripotent, meaning they can become any of 200-plus cell types in the adult body, depending on the signals they receive from their microenvironment (surrounding cells, tissues and vasculature). During cancer progression, malignant cells also receive and release signals from their microenvironment, cues that promote tumor growth and metastasis.

Les cellules souches embryonniques sont pluripotentes ce qui veut dre qu'elles peuvent se transformer en 200 types de cellules dépendamment du signal qu'elles recoivent de leur micro environnement (les cellules qui les entourent, les tissus et les veines) Durant la progression du cancer les cellules cancéreuses recoivent et relâchent égalemet des signaux de la part et vers leur environnement.

Groundbreaking work by Hendrix and colleagues is elucidating how, by becoming more like unspecialized stem cells, aggressive melanoma cells gain enhanced abilities to migrate, invade and metastasize while remaining virtually undetected by the immune system.

Les travaux du docteur Hendrix élucident comment, en devenant plus comme des cellules non-spécialisées, les cellules du mélanome augmentent leur capacité à migrer et envahir d'autres tissus alors qu'elle restent indétecter par le système immunitaire.

Hendrix and co-researchers previously demonstrated that a three-dimensional matrix conditioned by hESCs induced metastatic melanoma cells to revert to a normal, skin cell-like type with the ability to form colonies in the manner of hESCs (Postovit and Seftor et al, Stem Cells 24:501-505, 2006).

Hendrix avait déja démntré qu'une matrice tri-dimentionnelle conditionnée par des hESCs renversait le processus du mélanome et faisait que les cellules de la peau revenaient à la normale.

"This observation allowed us to appreciate the powerful influence of the hESC microenvironment on the reprogramming of metastatic melanoma cells," Hendrix said.

In subsequent experiments, Hendrix, Postovit and co-researchers found that aggressive melanoma and breast cancer produce a "morphogenic" protein called Nodal, which is essential for human embryonic stem cell pluripotency (Topczewska et al, Nature Medicine 12:925-932, 2006). Other researchers have found that Nodal also is present in testicular cancer.

"Thus, Nodal may serve as a prognostic marker of aggressive behaviors in human cancers," Hendrix said.

As described in the PNAS study, the Lefty protein inhibits production of Nodal and therefore plays a major role in embryonic cell differentiation and development -- under normal circumstances.

Hendrix and colleagues discovered that metastatic tumor cells do not express Lefty, allowing them to overproduce Nodal in an unregulated manner.

However, when the group exposed metastatic tumor cells to the microenvironment of hESCs containing Lefty, they witnessed dramatically reduced Nodal expres​sion(production) in these cancer cells together with decreased tumor cell growth and invasiveness and an increase in apoptosis, or programmed cell suicide.

Although exposure to a hESC microenvironment inhibited Nodal expression and tumor growth in both metastatic melanoma and breast cancer cells, the breast cancer cells underwent more complex reprogramming. Melanoma cells responded to the hESC-derived factors within three days, but breast cancer cells required two additional days to achieve the most significant reduction in Nodal.

This discrepancy is likely due to differences in signaling mechanisms between the two cell types. Yet, despite the inherent differences between melanoma cells and breast cancer cells, these divergent tumor types both underwent cell suicide following exposure to the hESC microenvironment.

"The remarkable similarity of the responses of the two tumor types is likely attributable to the commonality of plasticity (for example, the aberrant and unregulated expression of Nodal) that indiscriminately unifies highly aggressive cancer cells, regardless of their tissue of origin," Hendrix said.

"Further, the tumor suppressive effects of the hECs microenvironment, by neutralizing the expression of Nodal in aggressive tumor cells, provide previously unexplored novel therapeutic modalities for cancer treatment," Hendrix said.

However, while findings from the study suggest that hESC-derived Lefty may have potential to prevent metastasis, it is not the only tumor suppressive factor within the embryonic microenvironment.

Observations from the study highlight the potential utility of isolating factors within the hESC microenvironment responsible for influencing tumor cell fate and reversing the cancerous properties of metastatic tumor cells, such as melanoma and breast cancer.


Dernière édition par Denis le Lun 17 Oct 2016 - 9:37, édité 3 fois
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MessageSujet: Re: Inhibiteur de cellules souches cancéreuses pluripotentes.   Aujourd'hui à 12:26

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