Showing papers by "Axel Ullrich published in 2011"

The FGFR4-G388R Polymorphism Promotes Mitochondrial STAT3 Serine Phosphorylation to Facilitate Pituitary Growth Hormone Cell Tumorigenesis

Abstract: Pituitary tumors are common intracranial neoplasms, yet few germline abnormalities have been implicated in their pathogenesis. Here we show that a single nucleotide germline polymorphism (SNP) substituting an arginine (R) for glycine (G) in the FGFR4 transmembrane domain can alter pituitary cell growth and hormone production. Compared with FGFR4-G388 mammosomatotroph cells that support prolactin (PRL) production, FGFR4-R388 cells express predominantly growth hormone (GH). Growth promoting effects of FGFR4-R388 as evidenced by enhanced colony formation was ascribed to Src activation and mitochondrial serine phosphorylation of STAT3 (pS-STAT3). In contrast, diminished pY-STAT3 mediated by FGFR4-R388 relieved GH inhibition leading to hormone excess. Using a knock-in mouse model, we demonstrate the ability of FGFR4-R385 to promote GH pituitary tumorigenesis. In patients with acromegaly, pituitary tumor size correlated with hormone excess in the presence of the FGFR4-R388 but not the FGFR4-G388 allele. Our findings establish a new role for the FGFR4-G388R polymorphism in pituitary oncogenesis, providing a rationale for targeting Src and STAT3 in the personalized treatment of associated disorders.

Visceral obesity and inflammation markers in relation to serum prostate volume biomarkers among apparently healthy men.

Abstract: Eur J Clin Invest 2011; 41 (9): 987–994 Abstract Background Prostate disease incidence is expected to rise among developing nations secondary to increased prevalence of obesity and the elderly. Although many case–control studies have associated obesity to prostate cancer aggressiveness, few have correlated markers of prostate pathology to biomarkers of visceral obesity and insulin resistance, using an apparently healthy cohort. This study aims to fill this gap. Materials and methods The 219 consenting adult Arab men, aged 30–70 years, were included in this cross-sectional study. Demographics were noted and anthropometrics measured. Fasting blood samples were extracted, and glycaemic and lipid profile were determined using routine laboratory methods. Serum adipocytokines and inflammatory markers were measured using multiplex assays. Total prostate-specific antigen (tPSA), free PSA (fPSA), parathyroid-related protein (PTHrP) and endoglin were measured using enzyme-linked immunosorbent assays. Results Serum triglycerides and waist–hip ratio (WHR) were significantly and positively associated with circulating (tPSA) levels in all subjects (P < 0·01). Systolic blood pressure (SBP), adiponectin, active plasminogen activator inhibitor-1 (aPAI-1) and insulin-like growth factor-1 (IGF-1) had significant inverse associations to tPSA. Stepwise linear regression revealed that adiponectin, IGF-1, WHR and PTHrP explained 30% of variance in tPSA levels (P < 0·0001), while SBP, resistin and BMI explained 18·7% of variance in endoglin (P = 0·001). Conclusions The associations of adiponectin and WHR strengthen the link between insulin resistance and visceral adiposity to prostate volume markers among apparently healthy Arab men. Follow-up studies are needed to extend these preliminary findings so that early interventions can be provided to those at increased risk.

Kinases as targets for anti-diabetic therapy

Abstract: The present invention is related to compound capable of modulating the activity and/or expression of the protein kinases SCYL1, ADCK1, and GRK5, thereby enhancing the expression and/or release of insulin. The invention is further related to methods of identifying said compounds for the treatment of diseases of the carbohydrate metabolism. The invention is further related to methods of treatment of diseases of the carbohydrate metabolism, particularly diabetes mellitus type 2.

Marker for sunitinib resistance formation

Abstract: The present invention relates to marker for sunitinib resistance formation and modulators thereof for the prevention and reduction of sunitinib resistance of hyperproliferative cells, in particular cancer cells. Further, the present invention relates to compositions comprising agents suitable for anticancer therapy in combination with the modulators for treating proliferative diseases.

GRK5 Kinases as targets for anti-diabetic therapy

Abstract: The present invention is related to a compound capable of modulating the activity and/or expression of the protein kinase GRK5, thereby enhancing the expression and/or release of insulin. The invention is further related to methods of identifying said compounds for the treatment of diseases of the carbohydrate metabolism. The invention is further related to methods of treatment of diseases of the carbohydrate metabolism, particularly diabetes mellitus type 2.

Inhibitory anti-HER3 antibody for sensitizing melanoma metastases or refactory melanoma for treatment with chemotherapeeutic agents or radiation therapy

Abstract: The present invention relates to an inhibitor of HER3 for the treatment of melanoma, pharmaceutical compositions comprising such an inhibitor and a method for the diagnosis or prognosis of melanoma.