ABSTRACT
PURPOSE: Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of cancers including multiple myeloma (MM). In this study, we describe GTx-134, a novel small-molecule inhibitor of IGF-1R and insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM. EXPERIMENTAL DESIGN: The activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples. Downstream effector proteins and correlation with apoptosis was evaluated. Cytotoxcity in bone marrow stroma coculture experiments was assessed. Finally, the in vivo efficacy was evaluated in a human myeloma xenograft model. RESULTS: GTx-134 inhibited the growth of 10 of 14 myeloma cell lines (<5 µmol/L) and induced apoptosis. Sensitivity to GTx-134 correlated with IGF-1R signal inhibition. Expression of MDR-1 and CD45 were associated with resistance to GTx-134. Coculture with insulin-growth factor-1 (IGF-1) or adherence to bone marrow stroma conferred modest resistance, but did not overcome GTx-134-induced cytotoxicity. GTx-134 showed in vitro synergies when combined with dexamethasone or lenalidomide. Further, GTx-134 enhanced the activity of PD173074, a fibroblast growth factor receptor 3 (FGFR3) inhibitor, against t(4;14) myeloma cells. Therapeutic efficacy of GTx-134 was shown against primary cells and xenograft tumors. Although dysregulation of glucose homeostasis was observed in GTx-134-treated mice, impairment of glucose tolerance was modest. CONCLUSIONS: These studies support the potential therapeutic efficacy of GTx-134 in MM. Further, they provide a rationale for clinical application in combination with established antimyeloma treatments and novel targeted therapies.
Subject(s)
Antineoplastic Agents/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Multiple Myeloma/metabolism , Receptor, IGF Type 1/antagonists & inhibitors , Sulfones/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Drug Synergism , Female , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/toxicity , Humans , Mice , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Signal Transduction/drug effects , Stromal Cells/drug effects , Stromal Cells/metabolism , Sulfones/chemistry , Sulfones/toxicity , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To explore the relationships between fall risk factors and care plan intervention and implementation. DESIGN: Observational cohort study. SETTING: Nursing homes in Central Ontario, Canada. PARTICIPANTS: Residents (n = 635) of 8 nursing homes across Ontario, Canada. MEASUREMENTS: Chart reviews and observational rounds on nursing units were carried out to examine how well nursing staff (1) identified fall risk, (2) documented nursing care plan interventions, and (3) implemented nursing care plan interventions in residents who had fallen in the preceding year. RESULTS: Of the 635 fallers, two thirds (65.9%) had a history of falls. A total of 94 fallers across the 8 facilities had no fall risk care plan included in their medical record, despite having fallen previously. Only 63.46% of nursing care plan interventions were successfully implemented. Shorter length of stay (P < .001; odds ratio [OR] 0.09; 95% confidence interval [CI] 0.04-0.23), fall history (P = .002; OR 2.14; 95% CI 1.32-3.46), and those who are widowed (P = .001; OR 2.53; 95% CI 1.43-4.48) and divorced (P = .03; OR 2.16; 95% CI 1.06-4.40) predicted a higher likelihood of falls. CONCLUSION: This study revealed significant breakdowns in care related to the lack of documented care plan interventions for residents with a history of falls, and lack of implementation in cases where care plan interventions were made. Policies and procedures to improve the selection and implementation of care plan interventions may result in substantial improvements in nursing home safety.
