RESUMO
ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fator 4 Ativador da Transcrição/metabolismo , Animais , Antineoplásicos/uso terapêutico , Azacitidina/farmacologia , Compostos de Boro/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Imidazóis , Camundongos , Camundongos SCID , Piridinas , Pirimidinas , Fator de Transcrição CHOP/metabolismo , Transplante HeterólogoRESUMO
OBJECTIVE: To determine whether elevated levels of troponin T are associated with altered lipid profile. METHODS: Data were collected from 205 patients each of whom presented elevated troponin T levels. RESULTS: 195 patients presented with suspected myocardial infarction, 10 patients did not. Of which 68 had medium, 107 high and 20 presented with very high troponin T levels. The proportions were significantly different (p = 0.000215). Regression analysis showed that troponin T level was a useful quadratic predictor of total cholesterol (p = 0.000), triglycerides (p = 0.003), and low density cholesterol (p = 0.000); and a useful linear predictor of TC/HC ratio (p = 0.001). CONCLUSIONS: The occurrence of myocardial infarction is associated with elevated troponin T levels; troponin T is positively correlated with total cholesterol, triglycerides, LDL and TC/HC ratio and negatively correlated with HDL. TC/HC ratio was not found to be a useful predictor of the likelihood of MI.