PHARMACOLOGICAL INHIBITION OF THE PI3K/AKT/MTOR AND NF-KB CANCER PROMOTING PATHWAYS FOR TARGETED TREATMENT OF ACUTE MYELOID LEUKEMIA PATIENTS
(Abstract release date: 05/19/16)
EHA Library. Deslauriers A. 06/09/16; 132442; E893
Mr. Andre Deslauriers
Contributions
Contributions
Abstract
Abstract: E893
Type: Eposter Presentation
Background
Acute myeloid leukemia (AML) develops as a consequence of genetic aberrations in hematopoietic stem and progenitor cells causing a differentiation impairment and an accumulation of AML blast cells in the bone marrow. This results in bone marrow failure as well as depletion of normal blood cells. Standard treatment remains initial high-dose chemotherapy (anthracycline/cytarabine) and subsequent consolidation therapy (allogeneic transplantation), however AML patients retain a poor median 5-year survival rate, thus there is a need for more effective treatment modalities. Furthermore, due to the tremendous genetic and epigenetic heterogeneity of leukemia, it becomes important to define more personalized treatment schemes. One of the most common genetic aberration in AML is the translocation t(8;21), which forms the fusion protein and core-binding transcriptional repressor AML-ETO encoded by the fusion oncogene RUNX1-RUNX1T1. Using our bioinformatics screening of microarray gene expression datasets, aberrant signaling of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) and NF-kB pathways, involved in proliferation and survival advantages, has been identified as a causative agent of malignant transformation in t(8:21) AML patients.
Aims
The aim of this study was to use gene expression signatures associated with the t(8;21) AML subtype in order to define specific targets and evaluate the anti-leukemic activity of selected small molecule inhibitors against these targets, in a personalized treatment strategy. More specifically, the objective was to determine if a combinatorial treatment targeting the PI3K/Akt/mTOR and NF-kB pathways can block leukemic cell proliferation compared to normal cells, using a t(8;21)/TET2-/- AML model. AML-ETO has been shown not to be sufficient to induce leukemia and is often associated with other dominant negative mutations acquired in early progenitors, such as TET2, a methylcytosine dioxygenase, which is represented by our murine model.
Methods
The small molecule inhibitors GDC-0941, NVP-BEZ235, IKK-16, and BAY 11-7082, were used to investigate their effects on cellular proliferation in assays supporting clonogenic growth. For this, GFP+-sorted murine t(8;21)/TET2-/- cells and normal wild type bone marrow cells were plated in semi-solid methylcellulose, in parallel. Colony formation was evaluated after treatment with the inhibitors, either individually or in combination. Furthermore, pathway blockade was evaluated using specific biomarkers, protein phosphorylation and transcription factor translocation.
Results
In our study, we demonstrate that the small molecule inhibitors inactivated their respective targeted pathways, seen through specific biomarker analysis, and inhibited cellular growth and survival of the human t(8;21) leukemic cell line Kasumi-1. Furthermore, the in vitro assays supporting clonogenic growth of our murine t(8;21)/TET2-/- AML cells showed that the small molecule inhibitors hindered colony formation in a dose dependent manner, while combinatorial inhibition of PI3K/Akt/mTOR and NF-kB showed synergistic inhibition.
Conclusion
This study demonstrates that dual targeted therapy against the PI3K/mTOR axis and NF-kB signalling, may represent a novel therapeutic modality for t(8;21) AML. It also showed that identification of specific drivers of AML subtypes can be targeted in a personalized fashion, which could potentially be used in combination with standard chemotherapeutic regimens in order to reduce patient relapse and adapt treatment depending on AML subtype.
Session topic: E-poster
Keyword(s): Acute myeloid leukemia, MTOR, NF- B, PI3-K/AKT
Type: Eposter Presentation
Background
Acute myeloid leukemia (AML) develops as a consequence of genetic aberrations in hematopoietic stem and progenitor cells causing a differentiation impairment and an accumulation of AML blast cells in the bone marrow. This results in bone marrow failure as well as depletion of normal blood cells. Standard treatment remains initial high-dose chemotherapy (anthracycline/cytarabine) and subsequent consolidation therapy (allogeneic transplantation), however AML patients retain a poor median 5-year survival rate, thus there is a need for more effective treatment modalities. Furthermore, due to the tremendous genetic and epigenetic heterogeneity of leukemia, it becomes important to define more personalized treatment schemes. One of the most common genetic aberration in AML is the translocation t(8;21), which forms the fusion protein and core-binding transcriptional repressor AML-ETO encoded by the fusion oncogene RUNX1-RUNX1T1. Using our bioinformatics screening of microarray gene expression datasets, aberrant signaling of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) and NF-kB pathways, involved in proliferation and survival advantages, has been identified as a causative agent of malignant transformation in t(8:21) AML patients.
Aims
The aim of this study was to use gene expression signatures associated with the t(8;21) AML subtype in order to define specific targets and evaluate the anti-leukemic activity of selected small molecule inhibitors against these targets, in a personalized treatment strategy. More specifically, the objective was to determine if a combinatorial treatment targeting the PI3K/Akt/mTOR and NF-kB pathways can block leukemic cell proliferation compared to normal cells, using a t(8;21)/TET2-/- AML model. AML-ETO has been shown not to be sufficient to induce leukemia and is often associated with other dominant negative mutations acquired in early progenitors, such as TET2, a methylcytosine dioxygenase, which is represented by our murine model.
Methods
The small molecule inhibitors GDC-0941, NVP-BEZ235, IKK-16, and BAY 11-7082, were used to investigate their effects on cellular proliferation in assays supporting clonogenic growth. For this, GFP+-sorted murine t(8;21)/TET2-/- cells and normal wild type bone marrow cells were plated in semi-solid methylcellulose, in parallel. Colony formation was evaluated after treatment with the inhibitors, either individually or in combination. Furthermore, pathway blockade was evaluated using specific biomarkers, protein phosphorylation and transcription factor translocation.
Results
In our study, we demonstrate that the small molecule inhibitors inactivated their respective targeted pathways, seen through specific biomarker analysis, and inhibited cellular growth and survival of the human t(8;21) leukemic cell line Kasumi-1. Furthermore, the in vitro assays supporting clonogenic growth of our murine t(8;21)/TET2-/- AML cells showed that the small molecule inhibitors hindered colony formation in a dose dependent manner, while combinatorial inhibition of PI3K/Akt/mTOR and NF-kB showed synergistic inhibition.
Conclusion
This study demonstrates that dual targeted therapy against the PI3K/mTOR axis and NF-kB signalling, may represent a novel therapeutic modality for t(8;21) AML. It also showed that identification of specific drivers of AML subtypes can be targeted in a personalized fashion, which could potentially be used in combination with standard chemotherapeutic regimens in order to reduce patient relapse and adapt treatment depending on AML subtype.
Session topic: E-poster
Keyword(s): Acute myeloid leukemia, MTOR, NF- B, PI3-K/AKT
Abstract: E893
Type: Eposter Presentation
Background
Acute myeloid leukemia (AML) develops as a consequence of genetic aberrations in hematopoietic stem and progenitor cells causing a differentiation impairment and an accumulation of AML blast cells in the bone marrow. This results in bone marrow failure as well as depletion of normal blood cells. Standard treatment remains initial high-dose chemotherapy (anthracycline/cytarabine) and subsequent consolidation therapy (allogeneic transplantation), however AML patients retain a poor median 5-year survival rate, thus there is a need for more effective treatment modalities. Furthermore, due to the tremendous genetic and epigenetic heterogeneity of leukemia, it becomes important to define more personalized treatment schemes. One of the most common genetic aberration in AML is the translocation t(8;21), which forms the fusion protein and core-binding transcriptional repressor AML-ETO encoded by the fusion oncogene RUNX1-RUNX1T1. Using our bioinformatics screening of microarray gene expression datasets, aberrant signaling of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) and NF-kB pathways, involved in proliferation and survival advantages, has been identified as a causative agent of malignant transformation in t(8:21) AML patients.
Aims
The aim of this study was to use gene expression signatures associated with the t(8;21) AML subtype in order to define specific targets and evaluate the anti-leukemic activity of selected small molecule inhibitors against these targets, in a personalized treatment strategy. More specifically, the objective was to determine if a combinatorial treatment targeting the PI3K/Akt/mTOR and NF-kB pathways can block leukemic cell proliferation compared to normal cells, using a t(8;21)/TET2-/- AML model. AML-ETO has been shown not to be sufficient to induce leukemia and is often associated with other dominant negative mutations acquired in early progenitors, such as TET2, a methylcytosine dioxygenase, which is represented by our murine model.
Methods
The small molecule inhibitors GDC-0941, NVP-BEZ235, IKK-16, and BAY 11-7082, were used to investigate their effects on cellular proliferation in assays supporting clonogenic growth. For this, GFP+-sorted murine t(8;21)/TET2-/- cells and normal wild type bone marrow cells were plated in semi-solid methylcellulose, in parallel. Colony formation was evaluated after treatment with the inhibitors, either individually or in combination. Furthermore, pathway blockade was evaluated using specific biomarkers, protein phosphorylation and transcription factor translocation.
Results
In our study, we demonstrate that the small molecule inhibitors inactivated their respective targeted pathways, seen through specific biomarker analysis, and inhibited cellular growth and survival of the human t(8;21) leukemic cell line Kasumi-1. Furthermore, the in vitro assays supporting clonogenic growth of our murine t(8;21)/TET2-/- AML cells showed that the small molecule inhibitors hindered colony formation in a dose dependent manner, while combinatorial inhibition of PI3K/Akt/mTOR and NF-kB showed synergistic inhibition.
Conclusion
This study demonstrates that dual targeted therapy against the PI3K/mTOR axis and NF-kB signalling, may represent a novel therapeutic modality for t(8;21) AML. It also showed that identification of specific drivers of AML subtypes can be targeted in a personalized fashion, which could potentially be used in combination with standard chemotherapeutic regimens in order to reduce patient relapse and adapt treatment depending on AML subtype.
Session topic: E-poster
Keyword(s): Acute myeloid leukemia, MTOR, NF- B, PI3-K/AKT
Type: Eposter Presentation
Background
Acute myeloid leukemia (AML) develops as a consequence of genetic aberrations in hematopoietic stem and progenitor cells causing a differentiation impairment and an accumulation of AML blast cells in the bone marrow. This results in bone marrow failure as well as depletion of normal blood cells. Standard treatment remains initial high-dose chemotherapy (anthracycline/cytarabine) and subsequent consolidation therapy (allogeneic transplantation), however AML patients retain a poor median 5-year survival rate, thus there is a need for more effective treatment modalities. Furthermore, due to the tremendous genetic and epigenetic heterogeneity of leukemia, it becomes important to define more personalized treatment schemes. One of the most common genetic aberration in AML is the translocation t(8;21), which forms the fusion protein and core-binding transcriptional repressor AML-ETO encoded by the fusion oncogene RUNX1-RUNX1T1. Using our bioinformatics screening of microarray gene expression datasets, aberrant signaling of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) and NF-kB pathways, involved in proliferation and survival advantages, has been identified as a causative agent of malignant transformation in t(8:21) AML patients.
Aims
The aim of this study was to use gene expression signatures associated with the t(8;21) AML subtype in order to define specific targets and evaluate the anti-leukemic activity of selected small molecule inhibitors against these targets, in a personalized treatment strategy. More specifically, the objective was to determine if a combinatorial treatment targeting the PI3K/Akt/mTOR and NF-kB pathways can block leukemic cell proliferation compared to normal cells, using a t(8;21)/TET2-/- AML model. AML-ETO has been shown not to be sufficient to induce leukemia and is often associated with other dominant negative mutations acquired in early progenitors, such as TET2, a methylcytosine dioxygenase, which is represented by our murine model.
Methods
The small molecule inhibitors GDC-0941, NVP-BEZ235, IKK-16, and BAY 11-7082, were used to investigate their effects on cellular proliferation in assays supporting clonogenic growth. For this, GFP+-sorted murine t(8;21)/TET2-/- cells and normal wild type bone marrow cells were plated in semi-solid methylcellulose, in parallel. Colony formation was evaluated after treatment with the inhibitors, either individually or in combination. Furthermore, pathway blockade was evaluated using specific biomarkers, protein phosphorylation and transcription factor translocation.
Results
In our study, we demonstrate that the small molecule inhibitors inactivated their respective targeted pathways, seen through specific biomarker analysis, and inhibited cellular growth and survival of the human t(8;21) leukemic cell line Kasumi-1. Furthermore, the in vitro assays supporting clonogenic growth of our murine t(8;21)/TET2-/- AML cells showed that the small molecule inhibitors hindered colony formation in a dose dependent manner, while combinatorial inhibition of PI3K/Akt/mTOR and NF-kB showed synergistic inhibition.
Conclusion
This study demonstrates that dual targeted therapy against the PI3K/mTOR axis and NF-kB signalling, may represent a novel therapeutic modality for t(8;21) AML. It also showed that identification of specific drivers of AML subtypes can be targeted in a personalized fashion, which could potentially be used in combination with standard chemotherapeutic regimens in order to reduce patient relapse and adapt treatment depending on AML subtype.
Session topic: E-poster
Keyword(s): Acute myeloid leukemia, MTOR, NF- B, PI3-K/AKT
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