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Sauveur Michel Maira - One of the best experts on this subject based on the ideXlab platform.
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abstract 4472 nvp bkm120 a pan class i pi3k inhibitor impairs microvascular permeability and tumor growth as detected by dce mri and ifp measurements via radio telemetry comparison with nvp BEZ235
Cancer Research, 2010Co-Authors: Christian Schnell, Carlos Garciaecheverria, Samuel Arnal, Mike Becquet, Peter R Allegrini, Charles Voliva, Robert Cozens, Sauveur Michel MairaAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Tumor blood vessels are distinctly abnormal in structure and function. When compared to normal vessels, they are enlarged and tortuous and leaky, poorly covered by pericytes and with a defective basement membrane. VEGF is a prominent cytokine responsible for the hyperpermeable state of tumor microvasculature to plasma macromolecules. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway functions downstream of VEGF and can activate the production of the free radical gas nitric oxide (NO) through the enzyme endothelial NO synthase (eNOS), a key player for the in vivo biological activity of VEGF. In the present study, we investigated the effect of NVP-BKM120, a novel, synthetic low molecular mass compound, which potently inhibits class I PI3K activity, on vascular leakage in tumors and its impact on tumor progression in an orthotopic breast cancer model (BN472) in syngeneic rats. Effects on the vasculature were investigated in normal and tumor tissues with a variety of technologies: dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), tumor interstitial fluid pressure (IFP) measurements in conscious animals via radio-telemetry and a modified Miles assay, representing non invasive, minimally invasive and invasive methods, respectively. Tumor histology and western blots were used to confirm pathway inhibition. For comparison, the effect of NVP-BEZ235, a potent pan class I PI3K and mTOR activity inhibitor, was assessed head-to-head in the same experiments. BKM120 induced significant decreases in VEGF-induced vascular leakage in normal and tumor tissues. These effects were similar to those obtained following BEZ235 treatment. Western blot of total ear lysates from treated mice clearly demonstrated pathway inhibition. The inhibition of vessel permeability observed with BEZ235 and BKM120 correlated with their respective anti-tumor activities, IFP change and Ktrans (vascular permeability transfer constant measured by DCE-MRI) decrease. In conclusion, our data demonstrate that in BN472 tumors, BKM120 significantly decreases tumor microvascular leakage similar to BEZ235 at equipotent antitumor dose. Changes in Ktrans may be a useful independent clinical surrogate biomarker for NVP-BKM120 efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4472.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Susan Wee, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
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identification and characterization of nvp BEZ235 a new orally available dual phosphatidylinositol 3 kinase mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Molecular Cancer Therapeutics, 2008Co-Authors: Sauveur Michel Maira, Christian Schnell, Saskia Brachmann, Christine Fritsch, Frederic Stauffer, Josef Brueggen, Pascal Furet, Patrick Chene, Alain De Pover, Kevin SchoemakerAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.
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identification and characterization of nvp BEZ235 a new orally available dual phosphatidylinositol 3 kinase mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Molecular Cancer Therapeutics, 2008Co-Authors: Sauveur Michel Maira, Christian Schnell, Christine Fritsch, Frederic Stauffer, Josef Brueggen, Pascal Furet, Patrick Chene, Alain De Pover, Saskia Brachmann, Kevin SchoemakerAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5- c ]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G1 arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials. [Mol Cancer Ther 2008;7(7):1–13 [Mol Cancer Ther 2008;7(7):1851–13]
Christian Schnell - One of the best experts on this subject based on the ideXlab platform.
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abstract 4472 nvp bkm120 a pan class i pi3k inhibitor impairs microvascular permeability and tumor growth as detected by dce mri and ifp measurements via radio telemetry comparison with nvp BEZ235
Cancer Research, 2010Co-Authors: Christian Schnell, Carlos Garciaecheverria, Samuel Arnal, Mike Becquet, Peter R Allegrini, Charles Voliva, Robert Cozens, Sauveur Michel MairaAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Tumor blood vessels are distinctly abnormal in structure and function. When compared to normal vessels, they are enlarged and tortuous and leaky, poorly covered by pericytes and with a defective basement membrane. VEGF is a prominent cytokine responsible for the hyperpermeable state of tumor microvasculature to plasma macromolecules. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway functions downstream of VEGF and can activate the production of the free radical gas nitric oxide (NO) through the enzyme endothelial NO synthase (eNOS), a key player for the in vivo biological activity of VEGF. In the present study, we investigated the effect of NVP-BKM120, a novel, synthetic low molecular mass compound, which potently inhibits class I PI3K activity, on vascular leakage in tumors and its impact on tumor progression in an orthotopic breast cancer model (BN472) in syngeneic rats. Effects on the vasculature were investigated in normal and tumor tissues with a variety of technologies: dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), tumor interstitial fluid pressure (IFP) measurements in conscious animals via radio-telemetry and a modified Miles assay, representing non invasive, minimally invasive and invasive methods, respectively. Tumor histology and western blots were used to confirm pathway inhibition. For comparison, the effect of NVP-BEZ235, a potent pan class I PI3K and mTOR activity inhibitor, was assessed head-to-head in the same experiments. BKM120 induced significant decreases in VEGF-induced vascular leakage in normal and tumor tissues. These effects were similar to those obtained following BEZ235 treatment. Western blot of total ear lysates from treated mice clearly demonstrated pathway inhibition. The inhibition of vessel permeability observed with BEZ235 and BKM120 correlated with their respective anti-tumor activities, IFP change and Ktrans (vascular permeability transfer constant measured by DCE-MRI) decrease. In conclusion, our data demonstrate that in BN472 tumors, BKM120 significantly decreases tumor microvascular leakage similar to BEZ235 at equipotent antitumor dose. Changes in Ktrans may be a useful independent clinical surrogate biomarker for NVP-BKM120 efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4472.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Susan Wee, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
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identification and characterization of nvp BEZ235 a new orally available dual phosphatidylinositol 3 kinase mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Molecular Cancer Therapeutics, 2008Co-Authors: Sauveur Michel Maira, Christian Schnell, Saskia Brachmann, Christine Fritsch, Frederic Stauffer, Josef Brueggen, Pascal Furet, Patrick Chene, Alain De Pover, Kevin SchoemakerAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.
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identification and characterization of nvp BEZ235 a new orally available dual phosphatidylinositol 3 kinase mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Molecular Cancer Therapeutics, 2008Co-Authors: Sauveur Michel Maira, Christian Schnell, Christine Fritsch, Frederic Stauffer, Josef Brueggen, Pascal Furet, Patrick Chene, Alain De Pover, Saskia Brachmann, Kevin SchoemakerAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5- c ]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G1 arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials. [Mol Cancer Ther 2008;7(7):1–13 [Mol Cancer Ther 2008;7(7):1851–13]
Saskia Brachmann - One of the best experts on this subject based on the ideXlab platform.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Susan Wee, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
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identification and characterization of nvp BEZ235 a new orally available dual phosphatidylinositol 3 kinase mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Molecular Cancer Therapeutics, 2008Co-Authors: Sauveur Michel Maira, Christian Schnell, Saskia Brachmann, Christine Fritsch, Frederic Stauffer, Josef Brueggen, Pascal Furet, Patrick Chene, Alain De Pover, Kevin SchoemakerAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.
Carlos Garciaecheverria - One of the best experts on this subject based on the ideXlab platform.
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combination therapy targeting both tumor initiating and differentiated cell populations in prostate carcinoma
Clinical Cancer Research, 2010Co-Authors: Anna Dubrovska, Jimmy Elliott, Richard J Salamone, Sungeun Kim, Lindsey Aimone, John R Walker, James D Watson, Maira Sauveurmichel, Carlos Garciaecheverria, Charles Y ChoAbstract:Purpose: The cancer stem cell hypothesis predicts that standard prostate cancer monotherapy eliminates bulk tumor cells but not a tumor-initiating cell population, eventually leading to relapse. Many studies have sought to determine the underlying differences between bulk tumor and cancer stem cells. Experimental Design: Our previous data suggest that the PTEN/PI3K/AKT pathway is critical for the in vitro maintenance of CD133 + /CD44 + prostate cancer progenitors and, consequently, that targeting PI3K signaling may be beneficial in treatment of prostate cancer. Results: Here, we show that inhibition of PI3K activity by the dual PI3K/mTOR inhibitor NVP-BEZ235 leads to a decrease in the population of CD133 + /CD44 + prostate cancer progenitor cells in vivo . Moreover, the combination of the PI3K/mTOR modulator NVP-BEZ235, which eliminates prostate cancer progenitor populations, and the chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors in a prostate cancer xenograft model than monotherapy. Conclusion: This combination treatment ultimately leads to the expansion of cancer progenitors with a PTEN E91D mutation, suggesting that the analysis of PTEN mutations could predict therapeutic response to the dual therapy. Clin Cancer Res; 16(23); 5692–702. ©2010 AACR.
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abstract 4472 nvp bkm120 a pan class i pi3k inhibitor impairs microvascular permeability and tumor growth as detected by dce mri and ifp measurements via radio telemetry comparison with nvp BEZ235
Cancer Research, 2010Co-Authors: Christian Schnell, Carlos Garciaecheverria, Samuel Arnal, Mike Becquet, Peter R Allegrini, Charles Voliva, Robert Cozens, Sauveur Michel MairaAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Tumor blood vessels are distinctly abnormal in structure and function. When compared to normal vessels, they are enlarged and tortuous and leaky, poorly covered by pericytes and with a defective basement membrane. VEGF is a prominent cytokine responsible for the hyperpermeable state of tumor microvasculature to plasma macromolecules. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway functions downstream of VEGF and can activate the production of the free radical gas nitric oxide (NO) through the enzyme endothelial NO synthase (eNOS), a key player for the in vivo biological activity of VEGF. In the present study, we investigated the effect of NVP-BKM120, a novel, synthetic low molecular mass compound, which potently inhibits class I PI3K activity, on vascular leakage in tumors and its impact on tumor progression in an orthotopic breast cancer model (BN472) in syngeneic rats. Effects on the vasculature were investigated in normal and tumor tissues with a variety of technologies: dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), tumor interstitial fluid pressure (IFP) measurements in conscious animals via radio-telemetry and a modified Miles assay, representing non invasive, minimally invasive and invasive methods, respectively. Tumor histology and western blots were used to confirm pathway inhibition. For comparison, the effect of NVP-BEZ235, a potent pan class I PI3K and mTOR activity inhibitor, was assessed head-to-head in the same experiments. BKM120 induced significant decreases in VEGF-induced vascular leakage in normal and tumor tissues. These effects were similar to those obtained following BEZ235 treatment. Western blot of total ear lysates from treated mice clearly demonstrated pathway inhibition. The inhibition of vessel permeability observed with BEZ235 and BKM120 correlated with their respective anti-tumor activities, IFP change and Ktrans (vascular permeability transfer constant measured by DCE-MRI) decrease. In conclusion, our data demonstrate that in BN472 tumors, BKM120 significantly decreases tumor microvascular leakage similar to BEZ235 at equipotent antitumor dose. Changes in Ktrans may be a useful independent clinical surrogate biomarker for NVP-BKM120 efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4472.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Susan Wee, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
Christine Fritsch - One of the best experts on this subject based on the ideXlab platform.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
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specific apoptosis induction by the dual pi3k mtor inhibitor nvp BEZ235 in her2 amplified and pik3ca mutant breast cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Saskia Brachmann, Carlos Garciaecheverria, Christian Schnell, Irmgard Hofmann, Christine Fritsch, Heidi Lane, Shaowen Wang, Susan Wee, Sauveur Michel MairaAbstract:NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
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identification and characterization of nvp BEZ235 a new orally available dual phosphatidylinositol 3 kinase mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Molecular Cancer Therapeutics, 2008Co-Authors: Sauveur Michel Maira, Christian Schnell, Saskia Brachmann, Christine Fritsch, Frederic Stauffer, Josef Brueggen, Pascal Furet, Patrick Chene, Alain De Pover, Kevin SchoemakerAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.
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identification and characterization of nvp BEZ235 a new orally available dual phosphatidylinositol 3 kinase mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Molecular Cancer Therapeutics, 2008Co-Authors: Sauveur Michel Maira, Christian Schnell, Christine Fritsch, Frederic Stauffer, Josef Brueggen, Pascal Furet, Patrick Chene, Alain De Pover, Saskia Brachmann, Kevin SchoemakerAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5- c ]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G1 arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials. [Mol Cancer Ther 2008;7(7):1–13 [Mol Cancer Ther 2008;7(7):1851–13]