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Montreal, Canada

Chiappori A.,H. Lee Moffitt Cancer Center and Research Institute | Williams C.,Arlington Cancer Center | Adams J.W.,Arlington Cancer Center | Malik S.,Georgetown University | And 5 more authors.
Journal of Thoracic Oncology | Year: 2014

INTRODUCTION: The proapoptotic small-molecule pan-Bcl-2 inhibitor obatoclax mesylate (GX15-070) may enhance the cytotoxicity of chemotherapy in relapsed/refractory non-small-cell lung cancer (NSCLC). METHODS: Obatoclax was administered with docetaxel in patients with relapsed or refractory NSCLC - docetaxel as a 1-hour infusion on day 1 and obatoclax as a 24-hour infusion on days 1 and 2 - every 3 weeks for up to eight cycles. Four dose levels were evaluated in phase 1 (level 1: docetaxel 55 mg/m × 1 and obatoclax 30 mg × 2; levels 2-4: docetaxel 75 mg/m and obatoclax 30 mg, 45 mg, or 60 mg × 2) to identify dose-limiting toxicity and a phase 2 dose. In phase 2, response and tolerability were evaluated. RESULTS: Eighteen patients were included in phase 1. Two dose-limiting toxicities occurred during cycle 1: one febrile neutropenia each at dose levels 3 and 4. Maximum tolerated dose was not reached; 32 patients (including 3 from phase 1) were treated in phase 2 with docetaxel 75 mg/m and obatoclax 60 mg (median 2 cycles). Three patients (11%) had partial responses in phase 2; two demonstrated stable disease lasting 12 weeks or more. Median duration of response was 4.8 months. Overall, median progression-free survival was 1.4 months. Neutropenia (31%), febrile neutropenia (16%), and dyspnea (19%) were the most common grade 3/4 adverse events observed. CONCLUSIONS: Combined obatoclax mesylate plus docetaxel is tolerable in patients with NSCLC, but response was minimal and neutropenia was a common adverse event. Copyright © 2013 by the International Association for the Study of Lung Cancer. Source


Alavian K.N.,Yale University | Li H.,Yale University | Collis L.,BioCurrents Research Center | Bonanni L.,University of Chieti Pescara | And 17 more authors.
Nature Cell Biology | Year: 2011

Anti-apoptotic Bcl2 family proteins such as Bcl-x L protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-x L enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-x L interacts directly with the β-subunit of the F1 FO ATP synthase, decreasing an ion leak within the F1 FO ATPase complex and thereby increasing net transport of H + by F1 FO during F1 FO ATPase activity. By patch clamping submitochondrial vesicles enriched in F 1 FO ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-xL activity increases the membrane leak conductance. In addition, recombinant Bcl-x L protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-xL decreases the level of F1 FO enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x L-expressing neurons. © 2011 Macmillan Publishers Limited. All rights reserved. Source


Wei Y.,University of Texas M. D. Anderson Cancer Center | Kadia T.,University of Texas M. D. Anderson Cancer Center | Tong W.,University of Texas M. D. Anderson Cancer Center | Zhang M.,University of Texas M. D. Anderson Cancer Center | And 7 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Single-agent histone deacetylase inhibitors (HDACi) have limited clinical activity in human leukemia. Although the way HDACi exert their antileukemia effect is not fully understood, it is accepted that induction of apoptosis is important. We hypothesized, therefore, that combination of an HDACi with a proapoptotic agent, such as the Bcl-2 homology domain-3 mimetic GX15-070, could result in enhanced antileukemia activity. Experimental Design: We analyzed the cellular and molecular effects of two different HDACi (MGCD0103 and vorinostat) in combination with GX15-070 in leukemia cell lines and primary acute myelogenous leukemia cells. Results: We showed that the combination had synergistic antileukemia effect both in leukemia cell lines and in primary acute myelogenous leukemia cells. Using molecular markers and electron microscopy, we observed that in addition to apoptosis, autophagy accounts for the nonapoptotic decrease in cell viability, an effect that could be inhibited by chloroquine, an inhibitor of autophagy. Finally, we established a role for calpain activity in the induction of both autophagy and apoptosis by this combination. Conclusions: The combination of an HDACi and GX15-070 has synergistic antileukemia activity, and the effect is mediated by induction of apoptosis and autophagy. The combination should be studied in clinical trials of leukemia and the role of autophagy in leukemia therapy needs to be better understood. ©2010 AACR. Source


Arellano M.L.,Emory University | Borthakur G.,University of Texas M. D. Anderson Cancer Center | Berger M.,Gemin X Pharmaceuticals | Luer J.,Powered Inc. | Raza A.,Columbia University
Clinical Lymphoma, Myeloma and Leukemia | Year: 2014

Curative therapies are lacking for older patients with myelodysplastic syndrome (MDS). In this small phase II study, the B-cell lymphoma 2 (Bcl-2) inhibitor obatoclax (60 mg over 24 hours every 2 weeks) was feasible and relatively well tolerated, but had limited first-line activity in MDS.Background: Obatoclax mesylate is a small-molecule Bcl-2 homology domain-3 mimetic that neutralizes antiapoptotic Bcl-2erelated proteins. We evaluated obatoclax in untreated MDS patients with anemia/thrombocytopenia .Patients and Methods: Twenty-four patients with a bone marrow blast count of ≤ 10% and anemia (hemoglobin level < 10 g/dL) or thrombocytopenia (platelet count < 50 × 109/L) were eligible to receive intravenous obatoclax 60 mg over 24 hours every 2 weeks .Results: Response rate was 8% (2 patients; hematologic improvement). Disease stabilization/response was maintained ≥ 12 weeks in 50% (12 patients). Because the response rate was below a predetermined threshold, the study was terminated. Adverse events (any grade) included euphoric mood (63%; 15 patients), nausea (38%; 9 patients), and diarrhea (25%; 6 patients); Grade 3/4 adverse events included anemia (21%; 5 patients), thrombocytopenia (13%; 3 patients), and pneumonia (13%; 3 patients) .Conclusions: Obatoclax 60 mg every 2 weeks was feasible, but had limited first-line activity in MDS . © 2014 Elsevier Inc. All rights reserved. Source


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Gemin X Pharmaceuticals, Geminx Pharmaceuticals Canada Inc. and Gemin X Biotechnologies Inc. | Date: 2011-07-26

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