GRK et arrestines : la piste thérapeutique ?

La phosphorylation d’un récepteur couplé aux protéines G (RCPG) par une kinase spécifique, nommée GRK (G protein-coupled receptor kinase), est une première étape qui participe, avec l’action des arrestines, à l’arrêt de la transmission du signal, au cours d’un processus appelé désensibilisation. Le dérèglement de ce mécanisme de protection cellulaire, mis en évidence dans différentes situations pathologiques, relève soit de mutations génétiques d’une GRK ou d’une arrestine, soit d’une variation de leur expression. Ce dérèglement a pour conséquence de modifier l’activité des RCPG qui interviennent dans de nombreuses fonctions vitales de l’organisme. Ainsi, dans la maladie d’Oguchi, la stimulation excessive de la rhodopsine par la lumière, due à la perte de fonction de la GRK1 ou de l’arrestine 1, conduit à des problèmes d’adaptation de la vision à l’obscurité. La mise au point d’un modèle de souris hypertendues, après transfection ciblée du gène de la GRK2 au niveau des vaisseaux, suggère fortement que l’augmentation de cette GRK participe, chez l’homme, au développement de l’hypertension associée à une baisse de l’effet vasodilatateur des récepteurs β-adrénergiques. L’idée de rétablir une activité RCPG normale en agissant sur ces mécanismes de désensibilisation a été couronnée de succès dans des modèles animaux de défaillance cardiaque chronique, et laisse supposer que la modulation de l’activité des GRK ou de la fonction des arrestines pourrait constituer une piste thérapeutique. Cependant, la réalisation d’essais chez l’homme devra encore attendre la découverte de molécules pharmacologiques efficaces et non toxiques.Phosphorylation of the agonist-activated form of G-protein-coupled receptors (GPCRs) by a protein kinase from the G-protein-coupled receptor kinase (GRK) family initiates, with arrestin proteins, a negative feedback process known as desensitization. Because these receptors are involved in so many vital functions, it seems likely that disorders affecting GRK- or arrestin-mediated regulation of GPCRs would contribute to, if not engender, disease. Traditionally, it is believed that the desensitization process protects the cell against an overstimulation; however, in certain situations, this process is maladjusted and participes in disease progression. For example, in Oguchi disease, excessive rhodopsin stimulation due to a functional loss of GRK1 or arrestin 1 leads to light sensitization and stationary night blindness. Also, transgenic mice with vascular smooth muscle-targeted overexpression of GRK2 showed an elevated resting blood pressure, suggesting that increase in GRK2 level in humans is involved in hypertension associated with a decreased effect of β-adrenergic receptor-mediated vasorelaxation. The restoration of normal GPCR function in modulating the desensitization process has been successfully demonstrated in animal models of heart failure, which indicates that targeting GRKs or arrestins may open a novel therapeutic strategy in human diseases with GPCR dysregulation. However, the few effective pharmacological compounds in this domain currently preclude human clinical tests

Intérêt de la TEP [tomographie par émission de positons] au 18FDG et de la réalisation d'une acquisition dédiée à la sphère ORL dans le bilan pré-thérapeutique des carcinomes épidermoïdes de la tête et du cou

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Mesure de la clairance pulmonaire du DTPA-TC99m (Aspects méthodologiques.Intérêt dans le suivi thérapeutique en oncologie hématologique)

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Impact de la tomographie par émission de positons dans la définition des volumes cibles pour l'irradiation des cancers bronchiques non à petites cellules

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Apport de la TEP-TDM à la Fluorocholine dans la prise en charge des récidives d'adénocarcinomes prostatiques traités initialement par radiothérapie externe ou curiethérapie (étude prospective sur 11 patients)

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Evaluation de la tomographie par émission de positons (TEP) au 18FDG double phase dans l'étude des tumeurs cérébrales

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Development of a nomogram combining clinical staging with (18)F-FDG PET/CT image features in non-small-cell lung cancer stage I-III.

International audienceOur goal was to develop a nomogram by exploiting intratumour heterogeneity on CT and PET images from routine (18)F-FDG PET/CT acquisitions to identify patients with the poorest prognosis. This retrospective study included 116 patients with NSCLC stage I, II or III and with staging (18)F-FDG PET/CT imaging. Primary tumour volumes were delineated using the FLAB algorithm and 3D Slicer™ on PET and CT images, respectively. PET and CT heterogeneities were quantified using texture analysis. The reproducibility of the CT features was assessed on a separate test-retest dataset. The stratification power of the PET/CT features was evaluated using the Kaplan-Meier method and the log-rank test. The best standard metric (functional volume) was combined with the least redundant and most prognostic PET/CT heterogeneity features to build the nomogram. PET entropy and CT zone percentage had the highest complementary values with clinical stage and functional volume. The nomogram improved stratification amongst patients with stage II and III disease, allowing identification of patients with the poorest prognosis (clinical stage III, large tumour volume, high PET heterogeneity and low CT heterogeneity). Intratumour heterogeneity quantified using textural features on both CT and PET images from routine staging (18)F-FDG PET/CT acquisitions can be used to create a nomogram with higher stratification power than staging alone

FFCD 1709-SIRTCI phase II trial: Selective internal radiation therapy plus Xelox, Bevacizumab and Atezolizumab in liver-dominant metastatic colorectal cancer

International audienceAbstract The cellular prion protein PrP C partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrP C and CAV1 across cancer. Using cell-based assays, we show that PrP C regulates the expression of and interacts with CAV1. PrP C additionally controls the expression of the amyloid precursor protein APP and of the Aβ generating enzyme BACE1, and regulates the levels of Aβ, whose accumulation is a central event in Alzheimer’s disease. We further identify DKK1 and DKK3, involved in both Alzheimer’s disease and cancer progression, as targets of the PrP C -dependent axis. Finally, we establish that antibody-mediated blocking of the Aβ-PrP C interaction delays the growth of prostate cancer cell line-derived xenografts and prevents the development of metastases. Our data additionally support an enrichment of the Aβ-PrP C -dependent pathway in the basal subtype of prostate cancer, associated with anti-hormonal therapy resistance, and in mesenchymal colon cancer, associated with poor prognosis. Thus, based on a parallel with neurodegenerative diseases, our results bring to light an Aβ-PrP C axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer

FFCD 1709-SIRTCI phase II trial: Selective internal radiation therapy plus Xelox, Bevacizumab and Atezolizumab in liver-dominant metastatic colorectal cancer

International audienceAbstract The cellular prion protein PrP C partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrP C and CAV1 across cancer. Using cell-based assays, we show that PrP C regulates the expression of and interacts with CAV1. PrP C additionally controls the expression of the amyloid precursor protein APP and of the Aβ generating enzyme BACE1, and regulates the levels of Aβ, whose accumulation is a central event in Alzheimer’s disease. We further identify DKK1 and DKK3, involved in both Alzheimer’s disease and cancer progression, as targets of the PrP C -dependent axis. Finally, we establish that antibody-mediated blocking of the Aβ-PrP C interaction delays the growth of prostate cancer cell line-derived xenografts and prevents the development of metastases. Our data additionally support an enrichment of the Aβ-PrP C -dependent pathway in the basal subtype of prostate cancer, associated with anti-hormonal therapy resistance, and in mesenchymal colon cancer, associated with poor prognosis. Thus, based on a parallel with neurodegenerative diseases, our results bring to light an Aβ-PrP C axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer

FFCD 1709-SIRTCI phase II trial: Selective internal radiation therapy plus Xelox, Bevacizumab and Atezolizumab in liver-dominant metastatic colorectal cancer

International audienceAbstract The cellular prion protein PrP C partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrP C and CAV1 across cancer. Using cell-based assays, we show that PrP C regulates the expression of and interacts with CAV1. PrP C additionally controls the expression of the amyloid precursor protein APP and of the Aβ generating enzyme BACE1, and regulates the levels of Aβ, whose accumulation is a central event in Alzheimer’s disease. We further identify DKK1 and DKK3, involved in both Alzheimer’s disease and cancer progression, as targets of the PrP C -dependent axis. Finally, we establish that antibody-mediated blocking of the Aβ-PrP C interaction delays the growth of prostate cancer cell line-derived xenografts and prevents the development of metastases. Our data additionally support an enrichment of the Aβ-PrP C -dependent pathway in the basal subtype of prostate cancer, associated with anti-hormonal therapy resistance, and in mesenchymal colon cancer, associated with poor prognosis. Thus, based on a parallel with neurodegenerative diseases, our results bring to light an Aβ-PrP C axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer