ABSTRACT

No abstract

Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses. Mol Cancer Ther; 13(4); 880-9. Ó2014 AACR.

Chronic inflammation and malnutrition relate to increased risks for cardiovascular death. This study compared fasting glucose levels (FGL) and impaired fasting glucose (IFG) with malnutrition and inflammation in nondiabetic maintenance hemodialysis (MHD) patients to investigate the adverse affects and risks for mortality. In total, 693 MHD patients were enrolled in this study and followed up for 1 yr. Geographic, hematologic, biochemical, and dialysis-related data were collected. According to 1997 and 2003 definitions, all patients were classified into three groups: Diabetic, nondiabetic with IFG, and nondiabetic with normal FGL. More diabetic and nondiabetic with IFG group patients were malnourished ( 2 ϭ 24.55, P Ͻ 0.0001) and had inflammatory changes ( 2 ϭ 9.32, P ϭ 0.0095) than those with normal FGL. The IFG group had higher high-sensitivity C-reactive protein and ferritin and lower serum albumin, creatinine levels, and normalized protein catabolic rate than the normal FGL group. Age and parameters of nutrition and inflammation were associated with FGL. Stepwise multiple regression analysis demonstrated that FGL were negatively associated with serum albumin (P ϭ 0.0026) and positively correlated with Log high-sensitivity C-reactive protein (P ϭ 0.0004) in nondiabetic MHD patients. In addition, after 1 yr of follow-up, Cox multivariate analysis demonstrated that, after adjustment for other significant related factors, FGL (relative risk 1.049; 95% confidence interval 1.007 to 1.093; P ϭ 0.0232) or presence of IFG (relative risk 3.798; 95% confidence interval 1.168 to 12.344; P ϭ 0.0265) was a significant risk factor for 1-yr all-cause mortality of these patients. On the basis of these findings, basal FGL or presence of IFG, a preventive and treatable status, plays an important role in inflammation, malnutrition, and short-term mortality of nondiabetic MHD patients. 18: 238518: -239118: , 200718: . doi: 10.1681 Fasting glucose levels (FGL) are important for diagnosis of diabetes and impaired fasting glucose (IFG). 1 Diabetes is associated with increased incidence of cardiovascular disease (CVD) in both men and women in most racial and ethnic groups. 1,2 Individuals with IFG have increased risk for future diabetes and may also have increased risk for CVD. [3][4][5] Because IFG is associated with increased CVD risk, initiating preventive interventions is important for these patients. However, the clinical significance of FGL and IFG in maintenance hemodialysis (MHD) patients remains unclear. J Am Soc NephrolAccording to the US Renal Data System, the annual mortality rate for MHD patients is 25%, with nearly 50% of all reported MHD patient deaths being attributed to cardiovascular complications. 6 Although traditional risk factors for CVD are common in patients with ESRD, these factors alone may not explain the high prevalence of CVD. 7 Clinical