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Integrin-Linked Kinase Inhibitor KP-392 Demonstrates Clinical Benefitsin an Orthotopic Human Non-small Cell Lung Cancer Model  Jiang Liu, MD, Penny C.

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Presentation on theme: "Integrin-Linked Kinase Inhibitor KP-392 Demonstrates Clinical Benefitsin an Orthotopic Human Non-small Cell Lung Cancer Model  Jiang Liu, MD, Penny C."— Presentation transcript:

1 Integrin-Linked Kinase Inhibitor KP-392 Demonstrates Clinical Benefitsin an Orthotopic Human Non-small Cell Lung Cancer Model  Jiang Liu, MD, Penny C. Costello, PhD, Nhu-An Pham, MSc, Melania Pintillie, MSc, Mogjan Jabali, PhD, Jasbinder Sanghera, PhD, Ming-Sound Tsao, MD, Michael R. Johnston, MD  Journal of Thoracic Oncology  Volume 1, Issue 8, Pages (October 2006) DOI: /S (15) Copyright © 2006 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 (A) ILK activity was measured in H460 cells after 3-hour incubation with KP-392 or solvent (control). Background levels included reagents without cells. All treatments were performed in triplicate; error bars represent ±SD of each sample group. KP-392 significantly inhibited the ILK activity derived from the H460 cells in this biochemical assay. (B) Detection of decreasing amounts of phospho-PKB/AKT by Western analysis resulted from a dose-dependent effect of KP-392 inhibition on ILK. Cell lysates were harvested after 3 hours of drug incubation. There was a significant decrease in phospho-PKB/AKT (SER473) at 100 μM drug. (C, D) Immunocytochemical analysis of DMSO control (C) and KP-392–treated (D) H460 cells. Phospho-PKB (Ser-473) level was significantly reduced following 3 hours of treatment with KP-392. Journal of Thoracic Oncology 2006 1, DOI: ( /S (15) ) Copyright © 2006 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 Kaplan–Meier survival curves of vehicle-treated control animals and three treatment arms, including cisplatin alone, KP-392 alone, and cisplatin + KP-392. Both KP-392 alone and cisplatin + KP-392 significantly prolonged survival compared with vehicle controls (p = and p < , respectively). The combined cisplatin + KP-392 regimen showed better survival than cisplatin treatment alone (p < ). Journal of Thoracic Oncology 2006 1, DOI: ( /S (15) ) Copyright © 2006 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 Image analysis was performed on H & E stained whole-tumor sections for the quantification of percent area of necrosis. Whiskers plot the minimum and maximum value, and a box plots the first quantile, median, and third quantile. The median for KP-392–treated animals is higher than vehicle-treated controls but not significant (p = 0.11). Journal of Thoracic Oncology 2006 1, DOI: ( /S (15) ) Copyright © 2006 International Association for the Study of Lung Cancer Terms and Conditions

5 FIGURE 4 A representative ILK-labeled tissue array image (A), captured using a Sprint Scan 35 Plus (Polaroid, Waltham, MA), shows groups of six cores per tumor specimen. An image of a typical core from an array stained with ILK shows moderate to intense expression in tumor and stromal cells (B), 20× objective lens. Journal of Thoracic Oncology 2006 1, DOI: ( /S (15) ) Copyright © 2006 International Association for the Study of Lung Cancer Terms and Conditions

6 FIGURE 5 An IHC score was applied to evaluate phospho–protein kinase B (Ser473) and phospho– extracellular signal-regulated kinase (Thr202/Thr204) in tissue arrays (A). A box plots the first quantile, median, and third quantile, and whiskers plot the minimum and maximum value. The median value of nuclear phospho–protein kinase B staining in KP-392–treated animals is significantly less than control, p < Representative images from the control tissue array (B and C) specimens showing intense and weak phospho–protein kinase B stain, respectively (40× objective lens, ScanScope CS, Aperio Technologies, Vista, CA). Journal of Thoracic Oncology 2006 1, DOI: ( /S (15) ) Copyright © 2006 International Association for the Study of Lung Cancer Terms and Conditions

7 FIGURE 6 Physical health of animals evaluated by skin coat condition, respiratory movement, and mobility at day 30 following tumor implantation. They were scored as 0 (normal), 1 (mild condition), 2 (moderate condition), 3 (severe condition), or 4 (critical condition). No animal reached condition 4 in accordance with the humane end point established by animal care regulations. The data are presented as mean ± SD. (A) Percentage of animals reaching grade 3 for skin coat condition. (B) Percentage of animals reaching grade 3 for respiratory distress. (C) Percentage of animals reaching grade 3 for mobility/activity. Journal of Thoracic Oncology 2006 1, DOI: ( /S (15) ) Copyright © 2006 International Association for the Study of Lung Cancer Terms and Conditions

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