The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Mario I Vega - One of the best experts on this subject based on the ideXlab platform.

  • abstract 1735 Obatoclax enhances cddp and trail induced apoptosis in epithelial ovarian adenocarcinoma cells
    Cancer Research, 2013
    Co-Authors: Melisa Martinezpaniagua, Luis A Romerogonzalez, Yumei Anguianohernandez, Carolina Gonzaleztorres, Mario I Vega
    Abstract:

    Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. Ovarian cancer is the fifth cause of death in women and annually 13,850 deaths are reported in United States. Effective screening strategies are lacking and the majority of cases are diagnosed with advanced stage disease. Chemo is the conventional therapy after surgery but the initial response is between 60 to 80%, however, some patients that initially responded to the therapy suffer of recurrent disease or become resistant to the treatment. As a consequence, the overall 5 year survival is only about 30%. It is important to identify novel therapies for ovarian cancer to treat or sensitize tumor cells to the existence therapy. It has been suggested that the tumor cells become resistance due to an increased expression of antiapoptotic proteins especially from the Bcl2 family (Bcl-2, Bcl-XL, Mcl-1). Obatoclax is a small molecule that mimics the BH3 domain of the BH3 only family members and inhibits the effect of antiapoptotic Bcl-2 members. The objective of this study was to assess the susceptibility of ovarian cancer cell lines to chemo or immuno therapy mediated apoptosis by Obatoclax and also to elucidate the mechanism. Four different epithelial ovarian adenocarcinomas cell lines (SKOV3, NIH-OVCAR-3, TOV112D and TOV21G) were treated with different concentrations of Obatoclax (nM-μM), CDDP (5-50μg/ml) or TRAIL (50-1200ng/ml) alone or with a combination of treatment to assess the viability, measured by the XTT kit (Roche). Basal and cell treated total protein expressions were assessed by western. Induction of apoptosis was measured by TUNEL. As a single agent, Obatoclax or CDDP inhibited the viability of the cells in a dose response form; TRAIL did not show an evident response. The combination of the treatment after selecting the IC50 and IC20 response showed an increased inhibition of the viability. TUNEL positive cells were measured and the induction of apoptosis was mediated by a caspase dependent manner and PARP cleavage. Our data suggest that Obatoclax in combination with CDDP or TRAIL can enhance the induction of apoptosis in resistance cell lines, suggesting to be an optional treatment of patients with ovarian cancer. Citation Format: Melisa A. Martinez-Paniagua, Luis A. Romero-Gonzalez, Yu Mei Anguiano-Hernandez, Carolina Gonzalez-Torres, Mario I. Vega. Obatoclax enhances CDDP and trail-induced apoptosis in epithelial ovarian adenocarcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1735. doi:10.1158/1538-7445.AM2013-1735

  • abstract b48 resensitization to cddp or trail mediated apoptosis in ovarian cancer cells by Obatoclax
    Cancer Research, 2013
    Co-Authors: Melisa Martinezpaniagua, Luis A Romerogonzalez, Yumei Anguianohernandez, Carolina Gonzaleztorres, Mario I Vega
    Abstract:

    Ovarian cancer is the fifth cause of death in women, annually 13,850 deaths are reported in United States. Chemo is the conventional therapy after surgery but the initial response is between 60 to 80%, however, some patients that initially respond well to the therapy suffer recurrent disease or become resistant to the treatment. As a consequence, the overall 5 year survival is only 30%. There is a necessity to identify novel therapies for ovarian cancer or to discover drugs witch re sensitize tumor cells to existence therapy. It has been suggested that the resistance of the tumor cells is because of the increased expression of antiapoptotic proteins especially from the Bcl2 family (Bcl-2, Bcl-XL, Mcl-1). Obatoclax is a small molecule that mimics the BH3 domain of the BH3 only family members, inhibiting the effect of antiapoptotic Bcl-2 members. The objective of this study was to assess the susceptibility of ovarian cancer cell lines to chemo or immune therapy mediated apoptosis by Obatoclax and also to elucidate the mechanism. Some ovarian cancer cell lines were treated with different concentrations of Obatoclax, CDDP or TRAIL alone or in combinational treatment to assess the reduction of viability measured by the XTT kit (Roche). Basal and cell treated total protein expressions were assessed by western. Induction of apoptosis was measured by TUNEL. As a single agent, Obatoclax or CDDP inhibited the growth of ovarian cancer cell lines in a dose response manner, TRAIL was no having an evident response showing a plateau with the concentration used. The combinational treatment after selecting the IC50 and IC20 response showed an increased inhibition of the viability. The induction of apoptosis was mediated by a caspase dependent manner. Our data suggest that Obatoclax in combination with CDDP or TRAIL can re sensitize resistance cell lines to apoptosis and also it can be an optional treatment of patients with ovarian cancer. Citation Format: Melisa A. Martinez-Paniagua, Luis A. Romero-Gonzalez, Yu-Mei Anguiano-Hernandez, Carolina Gonzalez-Torres, Mario I. Vega. Resensitization to CDDP or trail-mediated apoptosis in ovarian cancer cells by Obatoclax. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B48.

  • mcl 1 and yy1 inhibition and induction of dr5 by the bh3 mimetic Obatoclax gx15 070 contribute in the sensitization of b nhl cells to trail apoptosis
    Cell Cycle, 2011
    Co-Authors: Melisa Martinezpaniagua, Sara Huertayepez, Stavroula Baritaki, Cesar Gonzalezbonilla, Benjamin Bonavida, Vianney Ortiznavarrete, Mario I Vega
    Abstract:

    The pan Bcl-2 family antagonist Obatoclax (GX15-070), currently in clinical trials, was shown to sensitize TRAIL-resistant tumors to TRAIL-mediated apoptosis via the release of Bak and Bim from Mcl-1 or Bcl-2/Bcl-XL complexes or by the activation of Bax, though other mechanisms were not examined. Herein, we hypothesize that Obatoclax-mediated sensitization to TRAIL apoptosis may also result from alterations of the apoptotic pathways. The TRAIL-resistant B-cell line Ramos was used as a model for investigation. Treatment of Ramos cells with Obatoclax significantly inhibited the expression of several members of the Bcl-2 family, dissociated Bak from Mcl-1 and inhibited the NFκB activity. Cells treated with Mcl-1 siRNA were sensitized to TRAIL apoptosis. We examined whether the sensitization of Ramos to TRAIL by Obatoclax resulted from signaling of the DR4 and/or DR5. Transfection with DR5 siRNA, but not with DR4 siRNA, sensitized the cells to apoptosis following treatment with Obatoclax and TRAIL. The signal...

  • abstract 3499 identification of a novel mechanism by which the bh3 mimetic Obatoclax sensitizes non hodgkin s lymphoma tumor cells to trail mediated apoptosis
    Cancer Research, 2011
    Co-Authors: Melisa Martinezpaniagua, Sara Huertayepez, Stavroula Baritaki, Cesar Gonzalezbonilla, Benjamin Bonavida, Mario I Vega
    Abstract:

    Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The BH3 mimetic chemical antagonist Obatoclax (GX15-070, Gemin X Pharmaceuticals) has been used in vitro and nowadays also in clinical trials for its potential therapeutic effects in both solid and lymph node malignancies. The effects of Obatoclax treatment alone or in combination with cytotoxic drugs results in the reversal of tumor cell resistance. Studies by us and others have reported that inhibition of over expressed anti-apoptotic gene products such as Bcl-2 and Bcl-XL can reverse resistance to TRAIL. Obatoclax was shown to sensitize TRAIL-resistant solid tumors to TRAIL-apoptosis, inhibiting diverse anti-apoptotic molecules like Bcl-2, Bcl-XL and Mcl-1 through direct binding. We hypothesized that treatment of B-NHL cell lines with Obatoclax will result in tumor cell sensitization to TRAIL apoptosis by a different mechanism. B-NHL Ramos cell line were treated with different concentrations of Obatoclax (7-28 nM) and TRAIL (2.5-20 ng/ml) resulting in significant potentiation of apoptosis and synergy. Western analysis revealed that treatment with Obatoclax resulted in significant inhibition of several members of the Bcl-2 family such as inhibition of Mcl-1, Bcl-XL, XIAP, and cIAP 1/2. In addition, Obatoclax dissociated Bak from Mcl-1 as determined by immunoprecipitation. We found that, Obatoclax inhibited the expression/activity of several members of the NF-κB pathway including phospho-p65, IKK2, and phosphor-IκB-α. The NF-κB activity inhibition by Obatoclax was assessed by EMSA. We examined whether Obatoclax-induced sensitization to TRAIL resulted from both signaling of DR4 and DR5. Treatment of Ramos cells with DR4 siRNA or DR5 siRNA and then treated with Obatoclax and TRAIL resulted in the sensitization of cells treated with DR4 siRNA but not DR5 siRNA. We have previously reported that DR5 is negatively regulated by the transcription repressor YY1, upstream of NF-κB. We found that Obatoclax inhibited YY1 transcription and expression. The direct role of YY1 inhibition by Obatoclax in both DR5 upregulation and sensitization to TRAIL was determined in transfected cells with YY1 siRNA. Such cells showed upregulation of DR5 and sensitivity to TRAIL apoptosis. The inhibitory effect of Obatoclax on Mcl-1 activity and the Mcl-1 direct role in sensitization was examined by treatment of cells with Mcl-1 siRNA. Such cells reversed their sensitivity to TRAIL-mediated apoptosis. Overall, the present findings reveal a new mechanism of Obatoclax-induced sensitization to TRAIL by inhibiting NF-κB and downstream Mcl-1 and YY1. Both Mcl-1 and YY1 play a direct role in tumor cells sensitization to TRAIL mediated apoptosis. The present findings identify several new therapeutic targets modified by Obatoclax whose modifications can reverse tumor cell resistance to TRAIL mediated apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3499. doi:10.1158/1538-7445.AM2011-3499

  • mechanism of Obatoclax gx15 070 bcl 2 family inhibitor induced sensitization of b nhl cells to trail mediated apoptosis inhibition of the nf κb survival pathway and the dr5 transcription repressor yin yang1 yy1
    Blood, 2008
    Co-Authors: Melisa Martinez Paniagua, Sara Huertayepez, Stavroula Baritaki, Mario I Vega, Bonilla Gonzalez, Vanessa Suarez, James R Berenson, Benjamin Bonavida
    Abstract:

    Patients with B-NHL respond initially to treatment with rituximab (chimeric anti- CD20 monoclonal antibody) in combination with CHOP. However, a subset of patients does not respond or develop refractoriness to further treatments. Therefore, there is an urgent need to develop novel therapeutic strategies to treat unresponsive patients. We have explored the potential therapeutic efficacy of TRAIL though, most tumors and cell lines are resistant to TRAIL-induced apoptosis. Our previous findings and those of others have demonstrated that the overexpression of anti-apoptotic gene products such as Bcl-2, BclXL, and Mcl-1 regulates resistance to TRAIL and thus, inhibition of these gene products reverses resistance. Hence, we hypothesized that treatment of B-NHL cell lines with the Bcl-2 family inhibitor, Obatoclax (GX15-070; Gemin X Pharmaceuticals, Malvern, PA) will result in tumor cell sensitization to TRAIL apoptosis. We have used the B-NHL Ramos cell line as model. Treatment of Ramos cells with various concentrations of Obatoclax (7–28 nM) and TRAIL (2.5–20 ng/ml) resulted in significant potentiation of apoptosis and the combination treatment was synergistic. We then explored the mechanism of Obatoclax-induced sensitization to TRAIL. Treatment of Ramos cells with Obatoclax inhibited NF-κB activity and downstream anti-apoptotic gene products regulated by NF- κB (example Bcl-xl, Mcl-1 and XIAP) as assessed by western. Since Obatoclax inhibited NF-κB activity, we explored its effect on the transcription repressor YY1 and DR5 expression. Treatment of Ramos with Obatoclax significantly inhibited YY1 expression concomitantly with upregulation of total and surface DR5 expression that are regulated by NF-κB. The direct role of YY1 in the regulation of resistance to TRAIL was demonstrated by treatment of Ramos with siRNA YY1. Such treated cells showed upregulation of DR5 expression and sensitization to TRAIL apoptosis. The sensitization by Obatoclax resulted in activation of both Type I and Type II apoptotic pathways when used in combination with TRAIL. These findings establish a novel mechanism of Obatoclax-induced gene modification aside from its direct inhibition of Bcl-2 family. Further, our findings with Obatoclax are different from those recently reported by Song et al., [JBC 2008; July 3 (Epub ahead of print)] demonstrating that ABT-737, a small molecule Bcl-2 inhibitor, potentiated TRAIL-induced apoptosis via activation of NF-κB and NF-κB-induced upregulation of DR5 transcription via NF-κB DNA binding site on the DR5 promoter. It is possible that Obatoclax and ABT-737 mediate their sensitization to TRAIL via distinct mechanisms. In summary, our findings demonstrate the potential therapeutic application of Obatoclax in combination with TRAIL or agonist DR4/DR5 antibodies in the reversal of tumor cell resistance to TRAIL.

Aaron D Schimmer - One of the best experts on this subject based on the ideXlab platform.

  • a multicenter phase i ii study of Obatoclax mesylate administered as a 3 or 24 hour infusion in older patients with previously untreated acute myeloid leukemia
    PLOS ONE, 2014
    Co-Authors: Aaron D Schimmer, Azra Raza, Thomas H Carter, David F Claxton, Harry P Erba, Daniel J Deangelo, Martin S Tallman, Carolyn A Goard, Gautam Borthakur
    Abstract:

    Purpose An open-label phase I/II study of single-agent Obatoclax determined a maximum tolerated dose (MTD) and schedule, safety, and efficacy in older patients (≥ 70 yr) with untreated acute myeloid leukemia (AML). Experimental design Phase I evaluated the safety of Obatoclax infused for 3 hours on 3 consecutive days (3 h × 3 d) in 2-week cycles. Initial Obatoclax dose was 30 mg/day (3 h × 3 d; n = 3). Obatoclax was increased to 45 mg/day (3 h × 3 d) if ≤ 1 patient had a dose-limiting toxicity (DLT) and decreased to 20 mg/day (3 h × 3 d) if DLT occurred in ≥ 2 patients. In the phase II study, 12 patients were randomized to receive Obatoclax at the dose identified during phase I (3 h × 3 d) or 60 mg/day administered by continuous infusion over 24 hours for 3 days (24 h × 3 d) to determine the morphologic complete response rate. Results In phase I, two of three patients receiving Obatoclax 30 mg/day (3 h × 3 d) experienced grade 3 neurologic DLTs (confusion, ataxia, and somnolence). Obatoclax was decreased to 20 mg/day (3 h × 3 d). In phase II, no clinically relevant safety differences were observed between the 20 mg/day (3 h × 3 d; n = 7) and 60 mg/day (24 h × 3 d; n = 5) arms. Neurologic and psychiatric adverse events were most common and were generally transient and reversible. Complete response was not achieved in any patient. Conclusions Obatoclax 20 mg/day was the MTD (3 h × 3 d) in older patients with AML. In the schedules tested, single-agent Obatoclax was not associated with an objective response. Evaluation in additional subgroups or in combination with other chemotherapy modalities may be considered for future study. Trial registration ClinicalTrials.gov NCT00684918.

  • an evidence based review of Obatoclax mesylate in the treatment of hematological malignancies
    Core Evidence, 2013
    Co-Authors: Carolyn A Goard, Aaron D Schimmer
    Abstract:

    Obatoclax mesylate is an intravenously-administered drug under investigation in Phase I and II clinical trials as a novel anticancer therapeutic for hematological malignancies and solid tumors. Obatoclax was developed as a pan-inhibitor of antiapoptotic members of the B cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2) family of proteins, which control the intrinsic or mitochondrial pathway of apoptosis. Resistance to apoptosis through dysregulation of BCL-2 family members is commonly observed in hematological malignancies, and can be linked to therapeutic resistance and poor clinical outcomes. By inhibiting pro-survival BCL-2 family proteins, including MCL-1, Obatoclax is proposed to (1) trigger cell death as a single agent, and (2) potentiate the anticancer effects of other therapeutics. Preclinical investigations have supported these proposals and have provided evidence suggestive of a promising therapeutic index for this drug. Phase I trials of Obatoclax mesylate in leukemia and lymphoma have defined well-tolerated regimens and have identified transient neurotoxicity as the most common adverse effect of this drug. In these studies, a limited number of objective responses were observed, along with hematological improvement in a larger proportion of treated patients. Published Phase II evaluations in lymphoma and myelofibrosis, however, have not reported robust single-agent activity. Emerging evidence from ongoing preclinical and clinical investigations suggests that the full potential of Obatoclax mesylate as a novel anticancer agent may be realized (1) in rational combination treatments, and (2) when guided by molecular predictors of therapeutic response. By understanding the molecular underpinnings of Obatoclax response, along with optimal therapeutic regimens and indications, the potential of Obatoclax mesylate for the treatment of hematological malignancies may be further clarified.

  • phase ii study of Obatoclax mesylate gx15 070 a small molecule bcl 2 family antagonist for patients with myelofibrosis
    Clinical Lymphoma Myeloma & Leukemia, 2010
    Co-Authors: Sameer A Parikh, Aaron D Schimmer, Hagop M Kantarjian, William V Walsh, Ekatherine Asatiani, Khaled Elshami, Elliott F Winton, Srdan Verstovsek
    Abstract:

    Abstract Background Myelofibrosis (MF) is a disease characterized by the overexpression of the antiapoptotic BCL-2 family of proteins (eg, BCL-X L and MCL-1). Patients and Methods We conducted a multicenter, open-label, noncomparative phase II study of Obatoclax mesylate, a small-molecule pan–BCL-2 antagonist, in patients with MF. Obatoclax was administered as a 24-hour infusion (on an outpatient basis) every 2 weeks at a fixed dose of 60 mg. Results A total of 22 patients were enrolled, with a median age of 63 years (range, 43-89 years). Twelve were men, and all 22 patients were previously treated (median of 2 previous therapies). Ten patients (45%) had a Lille score of 1, and 9 patients (41%) had a Lille score of 2. Thirteen (59%) were red blood cell transfusion dependent. A median of 7 cycles of Obatoclax were administered. No patient achieved complete or partial response according to International Working Group criteria. One patient (4%) demonstrated a clinical improvement (in terms of hemoglobin and platelet count) after 7 cycles of therapy. The improvement was sustained for 4 cycles of therapy, after which he underwent allogeneic stem cell transplantation. The most common adverse events included low-grade ataxia and fatigue in 50% of the patients. Dose reduction because of toxicity was required in 1 patient, whereas 2 patients were taken off the study because of grade 3 ataxia and grade 3 heart failure. Grade 3/4 anemia and thrombocytopenia were evident in 6 (27%) and 4 (18%) patients, respectively. Conclusion Obatoclax exhibits no significant clinical activity in patients with MF at the dose and schedule evaluated.

  • a phase i study of the pan bcl 2 family inhibitor Obatoclax mesylate in patients with advanced hematologic malignancies
    Clinical Cancer Research, 2008
    Co-Authors: Aaron D Schimmer, Hagop M Kantarjian, Susan Obrien, Bruce D Cheson, Joseph Brandwein, Mark D Minden, Karen W L Yee, Farhad Ravandi, Francis J Giles, Andre C Schuh
    Abstract:

    Purpose: The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, Obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose. Experimental Design: Forty-four patients with refractory leukemia or myelodysplasia were treated with Obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies. Results: A total of 306 infusions of Obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence. Conclusions: Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.

  • a phase i trial of the small molecule pan bcl 2 family inhibitor Obatoclax mesylate gx15 070 administered by continuous infusion for up to four days to patients with hematological malignancies
    Blood, 2007
    Co-Authors: Aaron D Schimmer, Hagop M Kantarjian, Susan Obrien, Bruce D Cheson, Joseph Brandwein, Mark D Minden, Karen W L Yee, Andre C Schuh, Vikas Gupta, Jean Viallet
    Abstract:

    Obatoclax antagonizes the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It is active in chronic lymphocytic leukemia(CLL; O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m 2 given over 3 h every 3 weeks with DLT of grade 3 infusional CNS toxicities. We evaluated prolonged infusions to minimize these toxicities while maintaining clinical activity. An initial trial established a Phase II dose of 28 mg/m 2 over 24 h every 2 weeks with dose limiting toxicities (DLTs) at 40 mg/m 2 and responses in 4/8 MDS patients (Borthakur et al., ASH 2006). We report on 21 patients who received Obatoclax 20–28 mg/m 2 /24 h weekly (n=9) or 20 mg/m 2 /24 h for 2, 3 or 4 consecutive days every 2–3 weeks (n=12). The final dose level of 28 mg/m 2 /24 h for 4 days is now open. Median age was 61 (range 26–75) and 11 patients were male. Diagnoses included: acute myelogenous leukemia (AML; 13), myelodysplastic syndromes (MDS; 6), acute lymphocytic leukemia (ALL; 1) and CLL (1). A total of 180 infusions of 24 h were administered. The most common adverse events (AE) were euphoric mood (57%), fatigue (57%), febrile neutropenia (43%), gait disturbance (43%), chills (33%), diarrhea (33%), nausea (33%), somnolence (33%), dizziness (29%). All were of Grades 1–2 with the exception of 7 grade 3 AEs of febrile neutropenia (unrelated to Obatoclax administration) and 1 each of diarrhea, fatigue and gait disturbance. There were no DLTs. Multiple day infusions were well tolerated; for the 20 mg/m 2 /24 h x 4days dose level, 4/6 patients received ≥ 4 cycles, with two ongoing at this time. Plasma concentrations of Obatoclax reached a steady state before end of infusion. Mean C max values at 20 mg/m 2 /24 h during1x24, 2x24, 3x24,4x24 h, and 28 mg/m 2 /24 h during 1x24 h infusions was 15.3, 8.4, 10.1, 15.7 and 10.8 ng/mL, respectively. The mean AUC (0–tlast) values at 20 mg/m 2 /24 h associated with 1x24, 2x24, 3x24, 4x24 h, and 28 mg/m 2 /24 h associated with 1x24 h infusions were 264.3, 396.9, 624.3, 1109.3 and 211.1 ng · hr/mL, respectively, increasing as expected with the duration of the infusion. One patient with treatment-related AML with a t(9;11)(p22;q23) translocation achieved a cytogenetic complete response (CR) with complete hematological recovery and transfusion independence on Day 9 following the start of weekly 24 h infusions of Obatoclax. This CR was sustained > 8 months while the patient received a total of 35 weekly infusions of 20 mg/m 2 without cumulative toxicities. Conclusions: Obatoclax can be administered by prolonged infusions without eliciting novel or cumulative toxicities. The dramatic response observed in a patient with AML with immediate recovery of peripheral blood counts supports that the cytotoxic effects of Obatoclax are specific to malignant cells while sparing normal bone marrow, as did our earlier reports of improvement in cytopenias in patients with MDS and CLL. The infusional schedules described here will be attractive to combine with standard chemotherapy regimens for AML and other indications to improve treatment outcomes where they may be limited by overexpression of Bcl-2 family members.

Gregory James Gores - One of the best experts on this subject based on the ideXlab platform.

  • a bax mediated mechanism for Obatoclax induced apoptosis of cholangiocarcinoma cells
    Cancer Research, 2010
    Co-Authors: Rory L Smoot, Steven F Bronk, Frank A Sinicrope, Boris Blechacz, Nathan W Werneburg, Alphonse E Sirica, Gregory James Gores
    Abstract:

    Apoptosis induction by BH3 mimetics is a therapeutic strategy for human cancer. These mimetics exert single-agent activity in cells "primed" for cell death. Primed cells are dependent upon antiapoptotic Bcl-2 proteins for survival and are characterized by the ability of the BH3 mimetic to induce cytochrome c release from their isolated mitochondria. Our aim was to examine the single-agent activity of Obatoclax, a BH3 mimetic in cholangiocarcinoma cell lines. In clonogenic assays, inhibition of colony formation was observed by Obatoclax treatment. Despite single-agent activity by Obatoclax, the mitochondria from these cells did not release cytochrome c after incubation with this BH3 mimetic. However, immunofluorescence and cell fractionation studies identified Bax activation and translocation to mitochondria after treatment with Obatoclax. shRNA targeted knockdown of Bax doubled the IC50 for Obatoclax but did not abrogate its cytotoxicity, whereas knockdown of Bak did not alter the IC50. In a cell-free system, Obatoclax induced an activating conformational change of Bax, which was attenuated by a site-directed mutagenesis of a previously identified protein activation site. Finally, the drug also elicited a significant in vivo response in a rodent model of this disease. In conclusion, single-agent Obatoclax treatment results in Bax activation, which contributes, in part, to cell death in cholangiocarcinoma cells. These data indicate that BH3 mimetics may also function as direct activators of Bax and induce cytotoxicity in cells not otherwise primed for cell death.

  • bh3 only protein mimetic Obatoclax sensitizes cholangiocarcinoma cells to apo2l trail induced apoptosis
    Molecular Cancer Therapeutics, 2008
    Co-Authors: Justin L Mott, Ruben A Mesa, Steven F Bronk, Scott H. Kaufmann, Gregory James Gores
    Abstract:

    Human cholangiocarcinomas evade apoptosis by overexpression of Mcl-1. The drug Obatoclax (GX15-070) inhibits antiapoptotic members of the Bcl-2 family including Mcl-1. The purpose of this study is to determine if Obatoclax sensitizes human cholangiocarcinoma cells to apoptosis. The human cholangiocarcinoma cell lines, KMCH, KMBC, and TFK, were employed for these studies. Protein expression was assessed by immunoblot and protein-protein interactions detected by coprecipitation of the polypeptide of interest with S-tagged Mcl-1. Activation of Bak and Bax was observed by immunocytochemistry with conformation-specific antisera. Obatoclax induced minimal apoptosis alone; however, it increased apoptosis 3- to 13-fold in all three cancer cell lines when combined with Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Obatoclax did not alter cellular expression of Bid, Bim, Puma, Noxa, Bak, Bax, Mcl-1, or cFLIP. Mcl-1 binding to Bak was readily identified in untreated cells, and this association was disrupted by treating the cells with Obatoclax. Additionally, Bim binding to Mcl-1 was markedly decreased by Obatoclax treatment. We also identified alterations in Bak and Bax conformation following treatment with Obatoclax plus Apo2L/TRAIL but not with either Apo2L/TRAIL or Obatoclax alone. In conclusion, Obatoclax releases Bak and Bim from Mcl-1 and sensitizes human cholangiocarcinoma cells to Apo2L/TRAIL-induced apoptosis. Obatoclax is a potentially promising adjunctive agent for the treatment of this cancer. [Mol Cancer Ther 2008;7(8):2339–47]

  • bh3 only protein mimetic Obatoclax sensitizes cholangiocarcinoma cells to apo2l trail induced apoptosis
    Molecular Cancer Therapeutics, 2008
    Co-Authors: Justin L Mott, Ruben A Mesa, Steven F Bronk, Scott H. Kaufmann, Gregory James Gores
    Abstract:

    Human cholangiocarcinomas evade apoptosis by overexpression of Mcl-1. The drug Obatoclax (GX15-070) inhibits antiapoptotic members of the Bcl-2 family including Mcl-1. The purpose of this study is to determine if Obatoclax sensitizes human cholangiocarcinoma cells to apoptosis. The human cholangiocarcinoma cell lines, KMCH, KMBC, and TFK, were employed for these studies. Protein expression was assessed by immunoblot and protein-protein interactions detected by coprecipitation of the polypeptide of interest with S-tagged Mcl-1. Activation of Bak and Bax was observed by immunocytochemistry with conformation-specific antisera. Obatoclax induced minimal apoptosis alone; however, it increased apoptosis 3- to 13-fold in all three cancer cell lines when combined with Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Obatoclax did not alter cellular expression of Bid, Bim, Puma, Noxa, Bak, Bax, Mcl-1, or cFLIP. Mcl-1 binding to Bak was readily identified in untreated cells, and this association was disrupted by treating the cells with Obatoclax. Additionally, Bim binding to Mcl-1 was markedly decreased by Obatoclax treatment. We also identified alterations in Bak and Bax conformation following treatment with Obatoclax plus Apo2L/TRAIL but not with either Apo2L/TRAIL or Obatoclax alone. In conclusion, Obatoclax releases Bak and Bim from Mcl-1 and sensitizes human cholangiocarcinoma cells to Apo2L/TRAIL-induced apoptosis. Obatoclax is a potentially promising adjunctive agent for the treatment of this cancer.

Jean Viallet - One of the best experts on this subject based on the ideXlab platform.

  • phase i dose finding studies of Obatoclax gx15 070 a small molecule pan bcl 2 family antagonist in patients with advanced solid tumors or lymphoma
    Clinical Cancer Research, 2010
    Co-Authors: Jimmy J Hwang, Mark S Berger, Jean Viallet, John Kuruvilla, David S Mendelson, Michael J Pishvaian, John F Deeken, John Marshall
    Abstract:

    Purpose: Two phase I, single-agent studies were conducted to determine the dose and regimen of Obatoclax, an antagonist of all BCL-2 antiapoptotic proteins, for evaluation in phase II trials. The two studies, GX001 and GX005, evaluated the safety and tolerability of weekly 1-hour and 3-hour infusions of Obatoclax, respectively. Experimental Design: Eligible patients in both studies were adults with solid tumor or lymphoma and performance status 0-1 for whom standard therapies were not appropriate. In the GX001 study an accelerated dose titration design was initially used with subsequent cohorts of three to six patients with 40% dose increments between levels. In the GX005 study three to six patients entered at each dose level with 40% dose increments between levels. Results: Thirty-five patients were enrolled in studies GX001 ( n = 8) and GX005 ( n = 27). Clinically significant central nervous system (CNS) toxicity was observed using the 1-hour infusion schedule. The Obatoclax maximum tolerated dose (MTD) in GX001 was 1.25 mg/m 2 due to these infusional CNS events. The 3-hour infusion schedule studied in GX005 had improved tolerability, and the Obatoclax MTD was 20 mg/m 2 . One patient in GX005 with relapsed non-Hodgkin9s lymphoma achieved partial response of 2 months9 duration, and one patient with relapsed non-Hodgkin9s lymphoma had stable disease for 18 months. Conclusions: The 1-hour infusion schedule of Obatoclax was associated with neuropsychiatric dose-limiting toxicities at relatively low doses (MTD, 1.25 mg/m 2 ). The 3-hour i.v. infusion of Obatoclax administered once weekly to patients with solid tumors was better tolerated (MTD, 20 mg/m 2 ), and evidence of clinical activity was observed. Clin Cancer Res; 16(15); 4038–45. ©2010 AACR.

  • phase i study of Obatoclax mesylate gx15 070 a small molecule pan bcl 2 family antagonist in patients with advanced chronic lymphocytic leukemia
    Blood, 2009
    Co-Authors: Susan Obrien, David F Claxton, Jean Viallet, Michael Crump, Stefan Faderl, Thomas J Kipps, Michael J Keating, Bruce D Cheson
    Abstract:

    Obatoclax mesylate is a small molecule pan-Bcl-2 antagonist with in vitro activity against chronic lymphocytic leukemia (CLL) cells. Obatoclax was administered to patients with advanced CLL at doses ranging from 3.5 to 14 mg/m(2) as a 1-hour infusion and from 20 to 40 mg/m(2) as a 3-hour infusion every 3 weeks. Twenty-six patients received a total of 74 cycles. Dose-limiting reactions were neurologic (somnolence, euphoria, ataxia) and associated with the infusion. The maximum tolerated dose (MTD) was 28 mg/m(2) over 3 hours every 3 weeks. One (4%) of 26 patients achieved a partial response. Patients with anemia (3/11) or thrombocytopenia (4/14) experienced improvements in hemoglobin and platelet counts. Circulating lymphocyte counts were reduced in 18 of 26 patients with a median reduction of 24%. Overall, the maximum plasma concentration (C(max)) and area under the curve (AUC) values of Obatoclax were dose proportional. Activation of Bax and Bak was demonstrated in peripheral blood mononuclear cells, and induction of apoptosis was related to overall Obatoclax exposure, as monitored by the plasma concentration of oligonucleosomal DNA/histone complexes. Obatoclax mesylate has biologic activity and modest single-agent activity in heavily pretreated patients with advanced CLL. Further evaluation in less heavily pretreated patients and in combination with other therapeutic agents is warranted. This trial has been registered with http://clinicaltrials.gov under identifier NCT00600964.

  • mechanisms of antileukemic activity of the novel bcl 2 homology domain 3 mimetic gx15 070 Obatoclax
    Cancer Research, 2008
    Co-Authors: Marina Konopleva, Julie C Watt, Rooha Contractor, Twee Tsao, David Harris, Zeev Estrov, William G Bornmann, Hagop M Kantarjian, Jean Viallet, Ismael Samudio
    Abstract:

    In this study, we investigated the mechanism of apoptosis induction of Obatoclax (GX15-070), a novel Bcl-2 homology domain-3 (BH3) mimetic, in acute myeloid leukemia (AML) cell lines and primary AML samples. Obatoclax inhibited cell growth of HL-60, U937, OCI-AML3, and KG-1 cell lines. Apoptosis induction contributed to the observed antiproliferative effects at concentrations of this agent that mirror its affinity for antiapoptotic Bcl-2 proteins. We show that Obatoclax can promote the release of cytochrome c from isolated leukemia cell mitochondria and that apoptosis induced by this agent is preceded by the release of Bak from Mcl-1, liberation of Bim from both Bcl-2 and Mcl-1, and the formation of an active Bak/Bax complex. Notably, apoptosis was diminished, but not fully prevented, in the absence of Bak/Bax or Bim, suggesting that Obatoclax has additional targets that contribute to its cytotoxicity. At growth inhibitory doses that did not induce apoptosis or decrease viability, Obatoclax induced an S-G(2) cell-cycle block. Obatoclax induced apoptosis in AML CD34+ progenitor cells with an average IC(50) of 3.59 +/- 1.23 micromol/L although clonogenicity was inhibited at concentrations of 75 to 100 nmol/L. Obatoclax synergized with the novel BH3 mimetic ABT-737 to induce apoptosis in OCI-AML3 cells and synergistically induced apoptosis in combination with AraC in leukemic cell lines and in primary AML samples. In conclusion, we show that Obatoclax potently induces apoptosis and decreases leukemia cell proliferation and may be used in a novel therapeutic strategy for AML alone and in combination with other targeted agents and chemotherapeutics.

  • small molecule Obatoclax gx15 070 antagonizes mcl 1 and overcomes mcl 1 mediated resistance to apoptosis
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: Mai Nguyen, Anne Roulston, Richard C Marcellus, Laurent Belec, Jean Viallet, Mark A Watson, Lucile Serfass, S Murthy R Madiraju, Daniel Goulet, Xavier Billot
    Abstract:

    Elevated expression of members of the BCL-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells. Small molecule Obatoclax (GX15-070), which is predicted to occupy a hydrophobic pocket within the BH3 binding groove of BCL-2, antagonizes these members and induces apoptosis, dependent on BAX and BAK. Reconstitution in yeast confirmed that Obatoclax acts on the pathway and overcomes BCL-2-, BCL-XL-, BCL-w-, and MCL-1-mediated resistance to BAX or BAK. The compound potently interfered with the direct interaction between MCL-1 and BAK in intact mitochondrial outer membrane and inhibited the association between MCL-1 and BAK in intact cells. MCL-1 has been shown to confer resistance to the BCL-2/BCL-XL/BCL-w-selective antagonist ABT-737 and to the proteasome inhibitor bortezomib. In both cases, this resistance was overcome by Obatoclax. These findings support a rational clinical development opportunity for the compound in cancer indications or treatments where MCL-1 contributes to resistance to cell killing.

  • a phase i trial of the small molecule pan bcl 2 family inhibitor Obatoclax mesylate gx15 070 administered by continuous infusion for up to four days to patients with hematological malignancies
    Blood, 2007
    Co-Authors: Aaron D Schimmer, Hagop M Kantarjian, Susan Obrien, Bruce D Cheson, Joseph Brandwein, Mark D Minden, Karen W L Yee, Andre C Schuh, Vikas Gupta, Jean Viallet
    Abstract:

    Obatoclax antagonizes the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It is active in chronic lymphocytic leukemia(CLL; O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m 2 given over 3 h every 3 weeks with DLT of grade 3 infusional CNS toxicities. We evaluated prolonged infusions to minimize these toxicities while maintaining clinical activity. An initial trial established a Phase II dose of 28 mg/m 2 over 24 h every 2 weeks with dose limiting toxicities (DLTs) at 40 mg/m 2 and responses in 4/8 MDS patients (Borthakur et al., ASH 2006). We report on 21 patients who received Obatoclax 20–28 mg/m 2 /24 h weekly (n=9) or 20 mg/m 2 /24 h for 2, 3 or 4 consecutive days every 2–3 weeks (n=12). The final dose level of 28 mg/m 2 /24 h for 4 days is now open. Median age was 61 (range 26–75) and 11 patients were male. Diagnoses included: acute myelogenous leukemia (AML; 13), myelodysplastic syndromes (MDS; 6), acute lymphocytic leukemia (ALL; 1) and CLL (1). A total of 180 infusions of 24 h were administered. The most common adverse events (AE) were euphoric mood (57%), fatigue (57%), febrile neutropenia (43%), gait disturbance (43%), chills (33%), diarrhea (33%), nausea (33%), somnolence (33%), dizziness (29%). All were of Grades 1–2 with the exception of 7 grade 3 AEs of febrile neutropenia (unrelated to Obatoclax administration) and 1 each of diarrhea, fatigue and gait disturbance. There were no DLTs. Multiple day infusions were well tolerated; for the 20 mg/m 2 /24 h x 4days dose level, 4/6 patients received ≥ 4 cycles, with two ongoing at this time. Plasma concentrations of Obatoclax reached a steady state before end of infusion. Mean C max values at 20 mg/m 2 /24 h during1x24, 2x24, 3x24,4x24 h, and 28 mg/m 2 /24 h during 1x24 h infusions was 15.3, 8.4, 10.1, 15.7 and 10.8 ng/mL, respectively. The mean AUC (0–tlast) values at 20 mg/m 2 /24 h associated with 1x24, 2x24, 3x24, 4x24 h, and 28 mg/m 2 /24 h associated with 1x24 h infusions were 264.3, 396.9, 624.3, 1109.3 and 211.1 ng · hr/mL, respectively, increasing as expected with the duration of the infusion. One patient with treatment-related AML with a t(9;11)(p22;q23) translocation achieved a cytogenetic complete response (CR) with complete hematological recovery and transfusion independence on Day 9 following the start of weekly 24 h infusions of Obatoclax. This CR was sustained > 8 months while the patient received a total of 35 weekly infusions of 20 mg/m 2 without cumulative toxicities. Conclusions: Obatoclax can be administered by prolonged infusions without eliciting novel or cumulative toxicities. The dramatic response observed in a patient with AML with immediate recovery of peripheral blood counts supports that the cytotoxic effects of Obatoclax are specific to malignant cells while sparing normal bone marrow, as did our earlier reports of improvement in cytopenias in patients with MDS and CLL. The infusional schedules described here will be attractive to combine with standard chemotherapy regimens for AML and other indications to improve treatment outcomes where they may be limited by overexpression of Bcl-2 family members.

Alberto Chiappori - One of the best experts on this subject based on the ideXlab platform.