XL 184

http://www.exelixis.com/cabozantinib


une petite vidéo avec un commentaire en anglais que j'ai traduit ici :

Dans plusieurs sortes de cancer incluant thyroIde, et Met est régulé à la hausse comparé aux niveaux trouvé dans les tissus normaux. CE taux élevé de Met peut activer divers mécanismes incluant, l'amplification de gènes, un taux de transcription plus élevé et une surexpression de son ligand HGF.

L'activation de Met dans les cellules cancéreuse produit la croissance des cellules cancéreuses et le phénomène d'invasion des tissus. HGF son ligand est un vacteur de vascularisation (angiogenèse) comme VEGF.

L'hypoxie (manque ou abvsence d'oxygène pour les cellles cancéreuses dans la tumeur, peut promouvoir MEt qui repart la tumeur. Met est donc une voie de survie pour les cellules cancéreuses. Met facilite donc les métastases dans le corps. Exelixis fabrile cabozantinib qui ciblent en même temmps Met et VEGF2 et réduit la vascularisation.

DEs études précliniques ont montré que le médicament réduisait l'agressivité du cancer, réduisait les métatstases aux tissus mous et dans les os. Exelexis fait de nombreux essais clinique de son médicament.

p.s. le médicament va être essayé aussi contre les sarcomes

,,,Early results from clinical trials. The vast majority
of the clinical trials that aim to define the efficacy of
HGF/SF–MET therapeutics are currently in progress but
initial results from several studies have been made avail‐
able. Striking results with the MET antibody METMab in
combination with an EGFR inhibitor (erlotinib) have been
reported in patients with NSCLC.


Des résultats primaires dans les essais cliniques. La vaste majorité des essais clinques pour définir l'efficacité des thérapeuthiques HGF/SF-MET sont en cours mais des résultats i nitiaux sont rendus disponibles. Des résultats étonnants avec l'anticorps de MET MetMab en combinaison avec un inhibiteur de EGFR (erlotinib) ont été rapportés pour le cancer du :poumon" non à petites cellules.


As determined retro‐
Studies with the multi‐target MET inhibitor XL184
(also known as cabozantinib) have shown significant
activity against a number of solid tumours, including
breast cancer, NSCLC, melanoma and liver cancer.
Ovarian cancer displayed notable responses to XL184,
but the most remarkable response was seen in both soft
tissue and bone metastatic lesions in patients with meta‐
static castration‐resistant prostate cancer (CRPC).

Comme déterminé auparavant, les études avec XL184 ont montré une activité contre nombre de tumeurs solides
Le cancer de l' a enregistré de bonnes réponses au XL184, mais les plus remarquabble réponses ont été vues dans le cancer des tissus mous et des lésions fait par les métastases dans les os par le cancer de la

The success of XL184 against CRPC primary and metastatic
tumours marks a turning point for MET kinase inhibi‐
tors and their power to change terminal cancer prog‐
noses. XL184 also showed activity against medullary
thyroid cancer and the range of applications for this
drug may further expand.

Les succès de XL184 contre le cancer de la réfractaire et les métastases marque un point tournant pour les inhibiteurs de kinase MET et leur pouvoir de changer les pronostics mortels . Le xl184 montre aussi des activités contre le cancer de la thyroîde et le nombre d'applications de ce médicament peut s'étendre encore.

Finally, the multi‐target MET inhibitor XL880 has
been reported to cause tumour reduction in patients
with breast cancer with resistance to inhibitors of
EGFR (such as erlotinib) or EGFR and ERBB2 (such as
lapatinib) a result that mirrors those obtained with
MET and EGFR inhibitors in NSCLC. ...


Finalement, l'inhibiteur multi-cibles Met XL184 a été la cause de réduction de tumeurs chez des patientes avec le cancer du avec de la résistance au EGFR (erlotinib) ou egfr et ERBB2 (lapatinib) un résultat qui rappelle celui dans le cancer du

Eh bien, j'ai voue tout tes nouveaux articles, les avancés sont impressionnantes !!
J'espère que la Phase III réussira, car les métastases osseuses pour le sein et la prostate ( et poumon etc...) sont récurrentes et dangereuses et...

Il faut que ce traitement présenté ici, marche, c''est un grand espoir pour les malades, surtout qu'il soit sur le marché très rapidement.

Bonne journée,
ACHILLE

19 mai 2011

The experimental drug cabozantinib achieved high rates of disease control and shrunk or eliminated bone metastases in a range of advanced cancers, according to results from a phase II trial.

Le médicament expérimental cabozantinib atteint de haut taux de controle de la maladie et rétrécit ou élimine les métastases osseuses dans beaucoup de cancers avancés selon les résultats d'une étude de phase II.

The overall response rate was only 9%, but cabozantinib monotherapy was shown to stabilize disease after 12 weeks in 76% of participants with liver cancer, 71% of those with prostate cancer, and 58% of those with ovarian cancer. The drug achieved disease control rates of 45% in melanoma, 45% in breast cancer, and 40% in non–small cell lung cancer.

Les réponses totales étaient seulement de 9% mais l'administration de cabozantinib a démontré être capable de stabiliser la maladie après 12 semaines pour 76% des particpants avec le cancer du , 71% des cancers de la 58% des cancers de . Le médicament a controlé la maladie dans 45% des cas de mélanomes , 45% des cas de cancer du et 40% du cancer du non à petites cellules.

Moreover, cabozantinib surprised investigators by shrinking or eliminating bone metastases in 59 of 68 people who entered the study with bone metastases. This outcome was most pronounced in castrate-resistant prostate cancer, with "complete or partial bone scan resolution" in 86% of prostate cancer patients, lead author Dr. Michael S. Gordon said during a press briefing at which the American Society of Clinical Oncology (ASCO) offered a preview of studies to be presented at its annual meeting in June.

De plus, le cabozantib a surpris les chercheurs en supprimant ou éliminant les métastases des os pour 59% à 68% des gens qui ont participés à l'étude . Ce résultat était plus prononcé pour les cancers résistants à l'hormono-thérapie (86% des patients avec le cancer de la ) C'est un docteur qui présentait un avant-goût de ce que la compagnie présenter à l'Asco qui annoncait cela.

The study has been expanded to include more patients with castrate-resistant prostate cancer and with platinum-resistant or refractory ovarian cancer, and phase III trials are contemplated.

L'étude de phase III va prendre plus de patients avec le cancer de la prostate et de cancers ovariens.

The findings suggest that cabozantinib, an oral tyrosine kinase inhibitor also known as XL184, may be effective across a range of solid tumors, possibly because of its action, which targets two pathways of tumor growth: vascular endothelial growth factor 2 (VEGF2) and MET.

Les découvertes montrent que le cabozantinib, un inhibiteur de tyrosine kinase, connu aussi sous le nom de XL184 pourrait être efficace pour des tumeurs solides possiblement à cause de son action qui cible 2 chemins cellulaires de croissance de la tumeur : VEGF2 et MET

"Cabozantinib demonstrated antitumor activity in 12 of 13 tumor types studied," said Dr. Gordon of Pinnacle Oncology Hematology in Scottsdale, Ariz. It also showed "unprecedented bone scan improvement," he added.

Le Cabozantinib a démontré de l'activité antitumeur dans 12 des 13 types de tumeurs étudiés et il a montré une amélioration des os sans précédent.

For their study, Dr. Gordon and his colleagues analyzed 398 patients with progressive measurable disease, and of whom 39% had bone metastases at enrollment.

All patients received cabozantinib 100 mg daily over 12 weeks in an open-label setting. At 12 weeks, patients with progressive disease (growth of 20% or more) were removed from the trial; patients with a partial response (shrinkage of 30% or more) stayed on the drug; and patients with stable disease were randomized to cabozantinib or placebo. This design, called a discontinuation trial, allows investigators to assess whether patients are "stable in spite or because of the drug," Dr. Gordon explained.

The findings on bone metastases were particularly striking, as they included patients with breast cancer, prostate cancer, and melanoma who experienced either partial or complete disappearance of the cancer on bone scans, often with improvement seen after 6 weeks of treatment. Improvement in bone scans was typically accompanied by relief of pain and less need for pain medications, a reduction in markers of bone reabsorption, and "sustained increases in hemoglobin in patients previously anemic," Dr. Gordon said.

The most common grade 3 or higher adverse events in the study were fatigue (9%), hand-foot syndrome (8%), and hypertension (5%). The discontinuation rate for adverse events was 12%.

Dr. Mark G. Kris, chief of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center, New York, and chair of cancer communications for ASCO, commented at the press conference that the cabozantinib findings showed "an evolution in targeted cancer therapies" that go after "not just one pathway but the entire network."

"Here we are attacking multiple targets MET and VEGF, and we saw some very important tumor shrinkages," in common types of cancer, Dr. Kris said, along with benefits including stronger bones and less pain among patients with bone metastases.

The study was funded by Exelixis, the manufacturer of cabozantinib. Dr. Gordon said that he did not own stock in Exelixis or have other conflicts of interest. Several of his coauthors disclosed stock ownership in and/or employment with Exelixis.

Sur le cancer de la glande thyroïde (MTC) le médicament semble bien et il est maintenant en phase III d'essais clinique.

(Oct. 27, 2008) — Preliminary trials of a new multi-kinase inhibitor have indicated it has impressive tumour shrinkage activity in patients with a difficult to treat type of thyroid cancer. The results have put the drug's development on a fast track, prompting the accelerated initiation of a large phase III trial.

Les essais préliminaires d'un nouvel inhibiteur de multi-kinase ont indiqué une régression impressionnante de tumeurs chez des patients avec un type de cancer de la glande thyroïde difficille à traiter. Les érsultats ont mis le médicament sous un développement (fast track) accélérant la mise ne place d'un essai phase III.


The compound, XL184, targets cell growth and migration, as well as blood vessel growth (angiogenesis), through inhibition of MET kinase, VEGFR and RET kinase.

La molécule XL184 cible la croissance de la cellule et sa migration aussi bien que l'angiogenèse et ce par le moyen de l'inhibition de la MET kinase, du VEGFR et de la RET kinase.

In a study presented October 23 at the 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva, 84 patients with a variety of advanced tumours that were not amenable to standard therapy were administered XL184 for either the first five days of a 14-day cycle or daily throughout the cycle. The group included 36 patients with advanced medullary thyroid cancer, for which no treatment is known to work. Response to the drug was assessed at 28 days and subsequently every eight weeks.

Dans un rassemblement à Genève, on a présenté une étude sur 84 patients acec une variété de cancers avancés qui n'étaient plus soignables.On leur a administré de xl184 .Le groupe incluait 36 patients avec un cancer de la thyroïde avancé pour lesquels aucun traitement n'était connu.

The impact on tumour shrinkage was particularly notable in the medullary thyroid cancer patients, where the overall disease control rate – the percentage of patients with either a partial response to the drug or prolonged stable disease for more than three months – was 84% in the 25 patients who have been followed for at least three months, said the study's presenter, Professor Steven Sherman, chair of the Department of Endocrine Neoplasia and Hormonal Disorders at M.D. Anderson Cancer Center in Houston (Texas, USA).

L'impact sur ces malades a été particulièrement remarquable. 84% de ces malades ont eu soit une réponse positive (diminution de la tumeur ) soit une stabilisation de la maladie.


"Partial response, where tumours shrink by at least 30%, was achieved in 55% of the 22 patients with measurable disease who have been followed for at least three months. Most of the others experienced prolonged stable disease beyond three months, and for most of these patients there was actually tumour shrinkage. That is an impressive result for an early trial in this type of cancer," Professor Sherman said.

Une réponse partielle, une diminution de la tumeur d'au moins 30% a été atteint pour 55% des patients avec une tumeur mesurable. La plupart des autres ont vu une stabilisation de la maldie pour 3 mois. C'est un résultat impressionnant pour un essai de ce type.

Three of the medullary thyroid cancer patients had unmeasurable disease. Tumour biomarkers such as plasma calcitonin and CEA dropped significantly after therapy in most of the patients.

Of the 84 patients, including patients with diverse cancers, disease stabilisation for at least three months was seen in 28 cases. In sixteen of those cases, the disease was stable for six months or more, the study found. The most common adverse effects of the drug included diarrhoea (24%), nausea (18%) and fatigue (15%).

In a preclinical study presented on Friday at the conference, XL184 showed encouraging results in boosting sensitivity to erlotinib and gefitinib in drug-resistant lung cancer. Gefitinib and erlotinib belong to a class of targeted drugs that zero in on the epidermal growth factor receptor (EGFR) gene, which is mutated in many non-small cell lung cancers. MET kinase, which is inhibited by XL184, is implicated in the resistance to EGFR kinase inhibitors.

In the study, mice were grafted with human EGFR mutant and MET amplified non-small cell lung cancer tumours that were made resistant to gefitinib.

"Neither agent was effective alone, but tumour regression occurred in all animals when they were treated with a combination of erlotinib and XL184," said the mouse study's leader, Professor Pasi Janne, an assistant professor of medicine at Harvard University Medical School in Boston (Massachusetts, USA).

A clinical trial has now been initiated, testing XL184 with or without erlotinib in non-small cell lung cancer patients who have developed resistance to erlotinib. The phase III trial of XL184 in medullary thyroid cancer patients involves using the drug alone. XL184 is also being studied in glioblastoma.