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P-67 IGF Targeting of the IGF-IR as a potential therapeutic strategy in endometrial cancer
Poster Presentations: IGF clinical/therapy
IGF clinical/therapy P-67 IGF Targeting of the IGF-IR as a potential therapeutic strategy in endometrial cancer Z. Attias1 ° , I. Bruchim2 , H. Werner1 . 1 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel, 2 Gynecologic Oncology Unit, Meir Medical Center, Kfar Saba, Israel Endometrial cancer is the most frequent gynecologic cancer in Western countries. The majority of the cases can be divided into two broad categories, based on clinic-pathological and molecular characteristics. Type I cancers, which represent more than 80% of the cases, exhibit an endometroid histology, are generally estrogen dependent, and have a good prognosis. Type II endometrial cancers, also termed uterine serous papillary endometrial cancer (USPC), have serous papillary or clear cell histology and have a poor prognosis. The insulin-like growth factors (IGFs), have been implicated in the etiology of a number of malignancies, including endometrial cancer. However, no study has so far evaluated the expression of the IGF system in USPC. Moreover, no study has addressed the potential impact of IGF-IR targeting in endometrial cancer. The aim of our research was to investigate the anti-proliferative potential of a targeted therapy approach against the IGF-IR in endometrial cancer. To assess the impact of IGF-IR inhibition on IGF-I-mediated signaling, ECC-1 and Ishikawa endometroid carcinoma cells and USPC-1 and USPC-2 serous papillary carcinoma cells were treated with IGF-I in the absence or presence of increasing amount of the selective IGF-IR inhibitor NVP-AEW-541 (Novartis Pharma, Basel, Switzerland). Results obtained showed that NVP-AEW-541 abolished the IGF-I-stimulated IGF-IR phosphorylation in all of the cell lines, whereas it abolished AKT and ERK phosphorylation only in ECC-1 and USPC-1 cells. Furthermore, in order to evaluate the effect of IGF-IR inhibition on apoptosis, the cells were treated with IGF-I in the absence or presence of the inhibitor. Results showed that addition of the IGF-IR inhibitor on top of IGF-I prevented from IGF-I from exerting its antiapoptotic effect in ECC-1, USPC-1 and USPC-2 cells. Furthermore, proliferation assays showed that the inhibitor NVPAEW-541 cause a significant decrease in proliferation rate compared to control cells in all of the cell lines. In summary, our results suggest that inhibition of IGF-IR signaling by AEW-541 abolished the antiapoptotic activity of IGF-IR and abrogated IGF-I-mediated signaling events. Taken together, these results indicate that specific IGF-IR inhibition is a potential proapoptotic tool in endometrial cancer cells. P-68 The GH−IGF axis in glycogen storage disease type 1 (GSD): Evidence of different growth patterns and IGF levels in patients with GSD1 A and GSD1 B R. Pivonello1 ° , D. Melis2 , G. Parenti2 , F. Balivo2 , R. Della Casa2 , M. Salerno2 , C. Di Somma1 , P. Piccolo2 , G. Sebastio2 , G. Andria2 , G. Lombardi1 , A. Colao1 . 1 Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy, 2 Department of Pediatrics, Federico II University, Naples, Italy Glycogen storage disease type 1 (GSD1) is associated with growth impairment. The aim of this study was to investigate the GH-IGF system in the two forms of GSD1, namely GSD1a and GSD1b. Seventeen patients with GSD1 (10 with GSD1a, 7 with GSD1b) and 34 BMI, sex and age-matched controls entered the study. GHIGF status, insulin levels and anti-pituitary (APA) antibody, were evaluated in patients and controls. The IGF-II methylation status at 11p15 region and IGF-II/ApaI genotype were also investigated in GSD1 patients. Height SDS was lower in both GSD1a and GSD1b
S47 patients than in controls (p < 0.005); short stature was detected in 10.0% of GSD1a and in 42.9% of GSD1b patients. Serum GH and ALS levels were lower whereas serum IGF-II, IGFBP1 and insulin levels higher in both GSD1a and GSD1b patients than in controls (p < 0.005). In GSD1b but not in GSD1a patients, serum total and free IGF-I were lower than in controls (p < 0.001). After GHRH plus arginine test, a significantly reduced GH response was found in both groups of patients compared to controls (p < 0.05); GH deficiency was diagnosed in 40% of GSD1a and 57% of GSD1b patients. Normal IGF-II methylation status and IGF-II/ApaI genotype distribution were detected in GSD1 patients. APA antibodies were detected in 42.8% GSD1b patients and in none of GSD1a patients. Serum IGF-II levels significantly correlated with height SDS in both group of patients (p < 0.05). In conclusion, this study demonstrated that GSD1a and GSD1b patients have a different impairment of GH-IGF axis: GSD1a patients have a frequent functional GH deficiency, whereas GSD1b patients have a high prevalence of short stature and an impairment of GH secretion, associated with IGF-I deficiency, probably due to the presence of anti-pituitary antibodies. The increased IGF-II levels might be a protective factor for the definitive stature in GSD1. P-69 Patients with liver cirrhosis have higher levels of bioactive IGF-I in ascites than in serum N. Jeyaratnaganthan1 , P. Holland-Fischer2 , H. Grønbæk2 , H. Vilstrup2 , J-W. Chen1 , A. Flyvbjerg1 , J. Frystyk1 ° . 1 The Medical Research Laboratories & Medical Department M (Diabetes and Endocrinology), and 2 Medical Department V (Gastroenterology and Hepatology), Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark Background: It is well-documented that patients with liver cirrhosis have diminished hepatic IGF-I generation, resulting in very low circulating levels. In contrast, data on IGF-I levels in ascites are sparse. Aim: To compare the IGF-system in serum and ascites from cirrhotic patients. Methods & design: The study comprised 43 patients (12 females) with ascites and a remnant liver function of 58±10% of normal as measured by the galactose elimination capacity test. Serum and ascites were collected concomitantly in the fasting state. In 11 patients a second puncture was performed within the first week. Serum from age- and sex-matched controls (n = 11) were also included. All samples were assayed for total IGF-I and -II, bioactive IGF-I by a cell-based assay and IGFBP-2. Results: As expected, serum levels of total IGF-I, total IGF-II and bioactive IGF-I were 4- to 5-fold reduced in liver patients as compared to controls, whereas IGFBP-2 was 3.4-fold elevated (P). Conclusion: This study is the first to show that the concentration of bioactive IGF-I can be higher in an extra-vascular compartment than in serum. The stable ascites values indicate that one measurement is representative. As ascites total IGFs were markedly decreased, the high IGF-I bioactivity may reflect an increased IGFBP-proteolysis, which is currently being investigated. The pathophysiological perspective of the relatively high ascites IGF-I bioactivity is so far uncertain. P-70 Peripheral sensory neuropathy in type 2 diabetes is associated with increased IGFBP-1 L. K¨arvestedt ° , E. Sandberg, K. Brismar. Dept. of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Objective: To study peripheral sensory neuropathy in relation to the IGF-axis in a representative population-based cohort of subjects with type 2 diabetes (T2D). Research Design and Method: A geographically defined population, 141 subjects with T2D, 59% males and 41% females, mean age 62±7 years, diabetes duration 7±5.5 years, BMI 29.5±5 and HbA1c
IGF clinical/therapy P-67 IGF Targeting of the IGF-IR as a potential therapeutic strategy in endometrial cancer Z. Attias1 ° , I. Bruchim2 , H. Werner1 . 1 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel, 2 Gynecologic Oncology Unit, Meir Medical Center, Kfar Saba, Israel Endometrial cancer is the most frequent gynecologic cancer in Western countries. The majority of the cases can be divided into two broad categories, based on clinic-pathological and molecular characteristics. Type I cancers, which represent more than 80% of the cases, exhibit an endometroid histology, are generally estrogen dependent, and have a good prognosis. Type II endometrial cancers, also termed uterine serous papillary endometrial cancer (USPC), have serous papillary or clear cell histology and have a poor prognosis. The insulin-like growth factors (IGFs), have been implicated in the etiology of a number of malignancies, including endometrial cancer. However, no study has so far evaluated the expression of the IGF system in USPC. Moreover, no study has addressed the potential impact of IGF-IR targeting in endometrial cancer. The aim of our research was to investigate the anti-proliferative potential of a targeted therapy approach against the IGF-IR in endometrial cancer. To assess the impact of IGF-IR inhibition on IGF-I-mediated signaling, ECC-1 and Ishikawa endometroid carcinoma cells and USPC-1 and USPC-2 serous papillary carcinoma cells were treated with IGF-I in the absence or presence of increasing amount of the selective IGF-IR inhibitor NVP-AEW-541 (Novartis Pharma, Basel, Switzerland). Results obtained showed that NVP-AEW-541 abolished the IGF-I-stimulated IGF-IR phosphorylation in all of the cell lines, whereas it abolished AKT and ERK phosphorylation only in ECC-1 and USPC-1 cells. Furthermore, in order to evaluate the effect of IGF-IR inhibition on apoptosis, the cells were treated with IGF-I in the absence or presence of the inhibitor. Results showed that addition of the IGF-IR inhibitor on top of IGF-I prevented from IGF-I from exerting its antiapoptotic effect in ECC-1, USPC-1 and USPC-2 cells. Furthermore, proliferation assays showed that the inhibitor NVPAEW-541 cause a significant decrease in proliferation rate compared to control cells in all of the cell lines. In summary, our results suggest that inhibition of IGF-IR signaling by AEW-541 abolished the antiapoptotic activity of IGF-IR and abrogated IGF-I-mediated signaling events. Taken together, these results indicate that specific IGF-IR inhibition is a potential proapoptotic tool in endometrial cancer cells. P-68 The GH−IGF axis in glycogen storage disease type 1 (GSD): Evidence of different growth patterns and IGF levels in patients with GSD1 A and GSD1 B R. Pivonello1 ° , D. Melis2 , G. Parenti2 , F. Balivo2 , R. Della Casa2 , M. Salerno2 , C. Di Somma1 , P. Piccolo2 , G. Sebastio2 , G. Andria2 , G. Lombardi1 , A. Colao1 . 1 Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy, 2 Department of Pediatrics, Federico II University, Naples, Italy Glycogen storage disease type 1 (GSD1) is associated with growth impairment. The aim of this study was to investigate the GH-IGF system in the two forms of GSD1, namely GSD1a and GSD1b. Seventeen patients with GSD1 (10 with GSD1a, 7 with GSD1b) and 34 BMI, sex and age-matched controls entered the study. GHIGF status, insulin levels and anti-pituitary (APA) antibody, were evaluated in patients and controls. The IGF-II methylation status at 11p15 region and IGF-II/ApaI genotype were also investigated in GSD1 patients. Height SDS was lower in both GSD1a and GSD1b
S47 patients than in controls (p < 0.005); short stature was detected in 10.0% of GSD1a and in 42.9% of GSD1b patients. Serum GH and ALS levels were lower whereas serum IGF-II, IGFBP1 and insulin levels higher in both GSD1a and GSD1b patients than in controls (p < 0.005). In GSD1b but not in GSD1a patients, serum total and free IGF-I were lower than in controls (p < 0.001). After GHRH plus arginine test, a significantly reduced GH response was found in both groups of patients compared to controls (p < 0.05); GH deficiency was diagnosed in 40% of GSD1a and 57% of GSD1b patients. Normal IGF-II methylation status and IGF-II/ApaI genotype distribution were detected in GSD1 patients. APA antibodies were detected in 42.8% GSD1b patients and in none of GSD1a patients. Serum IGF-II levels significantly correlated with height SDS in both group of patients (p < 0.05). In conclusion, this study demonstrated that GSD1a and GSD1b patients have a different impairment of GH-IGF axis: GSD1a patients have a frequent functional GH deficiency, whereas GSD1b patients have a high prevalence of short stature and an impairment of GH secretion, associated with IGF-I deficiency, probably due to the presence of anti-pituitary antibodies. The increased IGF-II levels might be a protective factor for the definitive stature in GSD1. P-69 Patients with liver cirrhosis have higher levels of bioactive IGF-I in ascites than in serum N. Jeyaratnaganthan1 , P. Holland-Fischer2 , H. Grønbæk2 , H. Vilstrup2 , J-W. Chen1 , A. Flyvbjerg1 , J. Frystyk1 ° . 1 The Medical Research Laboratories & Medical Department M (Diabetes and Endocrinology), and 2 Medical Department V (Gastroenterology and Hepatology), Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark Background: It is well-documented that patients with liver cirrhosis have diminished hepatic IGF-I generation, resulting in very low circulating levels. In contrast, data on IGF-I levels in ascites are sparse. Aim: To compare the IGF-system in serum and ascites from cirrhotic patients. Methods & design: The study comprised 43 patients (12 females) with ascites and a remnant liver function of 58±10% of normal as measured by the galactose elimination capacity test. Serum and ascites were collected concomitantly in the fasting state. In 11 patients a second puncture was performed within the first week. Serum from age- and sex-matched controls (n = 11) were also included. All samples were assayed for total IGF-I and -II, bioactive IGF-I by a cell-based assay and IGFBP-2. Results: As expected, serum levels of total IGF-I, total IGF-II and bioactive IGF-I were 4- to 5-fold reduced in liver patients as compared to controls, whereas IGFBP-2 was 3.4-fold elevated (P). Conclusion: This study is the first to show that the concentration of bioactive IGF-I can be higher in an extra-vascular compartment than in serum. The stable ascites values indicate that one measurement is representative. As ascites total IGFs were markedly decreased, the high IGF-I bioactivity may reflect an increased IGFBP-proteolysis, which is currently being investigated. The pathophysiological perspective of the relatively high ascites IGF-I bioactivity is so far uncertain. P-70 Peripheral sensory neuropathy in type 2 diabetes is associated with increased IGFBP-1 L. K¨arvestedt ° , E. Sandberg, K. Brismar. Dept. of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Objective: To study peripheral sensory neuropathy in relation to the IGF-axis in a representative population-based cohort of subjects with type 2 diabetes (T2D). Research Design and Method: A geographically defined population, 141 subjects with T2D, 59% males and 41% females, mean age 62±7 years, diabetes duration 7±5.5 years, BMI 29.5±5 and HbA1c