PI3K GAMMA/DELTA AS A NOVEL TARGET FOR THE TREATMENT OF MULTIPLE MYELOMA
(Abstract release date: 05/21/15)
EHA Library. Piddock R. 06/12/15; 102772; PB1845
Disclosure(s): UEAMED
Rachel Piddock
Contributions
Contributions
Abstract
Abstract: PB1845
Type: Publication Only
Background
Inhibiting tumor proliferation by targeting specific tyrosine kinases has proved an effective and well tolerated strategy in a number of hematological malignancies. Phosphoinositide-3-kinases (PI3K) are an enzyme group that generates phosphatidylinositol 3, 4, 5-triphosphate which provides a membrane docking site for the tyrosine kinase AKT (also known as protein kinase B). The class 1 PI3K isoforms (p110α/β/γ/δ) are known to be involved in the carcinogenesis and chemotherapy resistance of many cancers types, with p110δ and p110γ specifically being enriched in the hematopoietic system. The aberrant activation of the PI3K-AKT pathway has previously been shown to be active in Multiple Myeloma (MM) where it functions as a pro-survival signaling pathway. IPI-145 (Duvelisib) is a PI3K p110δ and p110γ inhibitor which at 25mg twice a day dosing is reported to achieve a plasma steady-state concentration of 0.9 μM and plasma peak concentration (Cmax) of 2.4 μM.
Aims
Here we investigate the effects of IPI-145 on MM pro-survival signaling, proliferation and bone marrow stromal cell (BMSC) and SDF1 mediated plasma cell migration using drug concentrations achievable in vivo.
Methods
To investigate the role of PI3K p110δ and p110γ subunits in regulating MM survival and migration we used PI3K pharmacological inhibitor IPI-145 (PI3K δγ inhibitor) with LY295002 (Pan PI3K inhibitor) and CAL101/Idelalisib (PI3K p110δ inhibitor) as controls. CellTiter-Glo was used to measure survival and transwell permeable plates with 8.0µM pores for migration assays. Western blotting was used to examine the role of BMSC, SDF-1 and IL-6 in regulating AKT and MAPK activation in MM cells in response to PI3K δγ inhibition.
Results
The PI3K δγ inhibitor IPI-145 reduced survival of MM cells at 1uM. IPI-145 triggered cytoxicity was associated with pAKT inhibition. IPI-145 also inhibited MM cell growth in response to IL-6 and bone marrow stromal cell co-culture. Furthermore we found that IPI-145 inhibited the migration of MM cells responding to BMSC and SDF-1 stimulation. Finally, we report that IPI-145 can inhibit SDF-1 induced AKT phosphorylation and downstream signaling.
Summary
IPI-145 inhibits MM cell survival and migration at concentrations achievable in vivo. The results reported here provide a molecular mechanistic rationale for the clinical evaluation of IPI-145 in MM patients.
Keyword(s): Myeloma, PI3K
Type: Publication Only
Background
Inhibiting tumor proliferation by targeting specific tyrosine kinases has proved an effective and well tolerated strategy in a number of hematological malignancies. Phosphoinositide-3-kinases (PI3K) are an enzyme group that generates phosphatidylinositol 3, 4, 5-triphosphate which provides a membrane docking site for the tyrosine kinase AKT (also known as protein kinase B). The class 1 PI3K isoforms (p110α/β/γ/δ) are known to be involved in the carcinogenesis and chemotherapy resistance of many cancers types, with p110δ and p110γ specifically being enriched in the hematopoietic system. The aberrant activation of the PI3K-AKT pathway has previously been shown to be active in Multiple Myeloma (MM) where it functions as a pro-survival signaling pathway. IPI-145 (Duvelisib) is a PI3K p110δ and p110γ inhibitor which at 25mg twice a day dosing is reported to achieve a plasma steady-state concentration of 0.9 μM and plasma peak concentration (Cmax) of 2.4 μM.
Aims
Here we investigate the effects of IPI-145 on MM pro-survival signaling, proliferation and bone marrow stromal cell (BMSC) and SDF1 mediated plasma cell migration using drug concentrations achievable in vivo.
Methods
To investigate the role of PI3K p110δ and p110γ subunits in regulating MM survival and migration we used PI3K pharmacological inhibitor IPI-145 (PI3K δγ inhibitor) with LY295002 (Pan PI3K inhibitor) and CAL101/Idelalisib (PI3K p110δ inhibitor) as controls. CellTiter-Glo was used to measure survival and transwell permeable plates with 8.0µM pores for migration assays. Western blotting was used to examine the role of BMSC, SDF-1 and IL-6 in regulating AKT and MAPK activation in MM cells in response to PI3K δγ inhibition.
Results
The PI3K δγ inhibitor IPI-145 reduced survival of MM cells at 1uM. IPI-145 triggered cytoxicity was associated with pAKT inhibition. IPI-145 also inhibited MM cell growth in response to IL-6 and bone marrow stromal cell co-culture. Furthermore we found that IPI-145 inhibited the migration of MM cells responding to BMSC and SDF-1 stimulation. Finally, we report that IPI-145 can inhibit SDF-1 induced AKT phosphorylation and downstream signaling.
Summary
IPI-145 inhibits MM cell survival and migration at concentrations achievable in vivo. The results reported here provide a molecular mechanistic rationale for the clinical evaluation of IPI-145 in MM patients.
Keyword(s): Myeloma, PI3K
Abstract: PB1845
Type: Publication Only
Background
Inhibiting tumor proliferation by targeting specific tyrosine kinases has proved an effective and well tolerated strategy in a number of hematological malignancies. Phosphoinositide-3-kinases (PI3K) are an enzyme group that generates phosphatidylinositol 3, 4, 5-triphosphate which provides a membrane docking site for the tyrosine kinase AKT (also known as protein kinase B). The class 1 PI3K isoforms (p110α/β/γ/δ) are known to be involved in the carcinogenesis and chemotherapy resistance of many cancers types, with p110δ and p110γ specifically being enriched in the hematopoietic system. The aberrant activation of the PI3K-AKT pathway has previously been shown to be active in Multiple Myeloma (MM) where it functions as a pro-survival signaling pathway. IPI-145 (Duvelisib) is a PI3K p110δ and p110γ inhibitor which at 25mg twice a day dosing is reported to achieve a plasma steady-state concentration of 0.9 μM and plasma peak concentration (Cmax) of 2.4 μM.
Aims
Here we investigate the effects of IPI-145 on MM pro-survival signaling, proliferation and bone marrow stromal cell (BMSC) and SDF1 mediated plasma cell migration using drug concentrations achievable in vivo.
Methods
To investigate the role of PI3K p110δ and p110γ subunits in regulating MM survival and migration we used PI3K pharmacological inhibitor IPI-145 (PI3K δγ inhibitor) with LY295002 (Pan PI3K inhibitor) and CAL101/Idelalisib (PI3K p110δ inhibitor) as controls. CellTiter-Glo was used to measure survival and transwell permeable plates with 8.0µM pores for migration assays. Western blotting was used to examine the role of BMSC, SDF-1 and IL-6 in regulating AKT and MAPK activation in MM cells in response to PI3K δγ inhibition.
Results
The PI3K δγ inhibitor IPI-145 reduced survival of MM cells at 1uM. IPI-145 triggered cytoxicity was associated with pAKT inhibition. IPI-145 also inhibited MM cell growth in response to IL-6 and bone marrow stromal cell co-culture. Furthermore we found that IPI-145 inhibited the migration of MM cells responding to BMSC and SDF-1 stimulation. Finally, we report that IPI-145 can inhibit SDF-1 induced AKT phosphorylation and downstream signaling.
Summary
IPI-145 inhibits MM cell survival and migration at concentrations achievable in vivo. The results reported here provide a molecular mechanistic rationale for the clinical evaluation of IPI-145 in MM patients.
Keyword(s): Myeloma, PI3K
Type: Publication Only
Background
Inhibiting tumor proliferation by targeting specific tyrosine kinases has proved an effective and well tolerated strategy in a number of hematological malignancies. Phosphoinositide-3-kinases (PI3K) are an enzyme group that generates phosphatidylinositol 3, 4, 5-triphosphate which provides a membrane docking site for the tyrosine kinase AKT (also known as protein kinase B). The class 1 PI3K isoforms (p110α/β/γ/δ) are known to be involved in the carcinogenesis and chemotherapy resistance of many cancers types, with p110δ and p110γ specifically being enriched in the hematopoietic system. The aberrant activation of the PI3K-AKT pathway has previously been shown to be active in Multiple Myeloma (MM) where it functions as a pro-survival signaling pathway. IPI-145 (Duvelisib) is a PI3K p110δ and p110γ inhibitor which at 25mg twice a day dosing is reported to achieve a plasma steady-state concentration of 0.9 μM and plasma peak concentration (Cmax) of 2.4 μM.
Aims
Here we investigate the effects of IPI-145 on MM pro-survival signaling, proliferation and bone marrow stromal cell (BMSC) and SDF1 mediated plasma cell migration using drug concentrations achievable in vivo.
Methods
To investigate the role of PI3K p110δ and p110γ subunits in regulating MM survival and migration we used PI3K pharmacological inhibitor IPI-145 (PI3K δγ inhibitor) with LY295002 (Pan PI3K inhibitor) and CAL101/Idelalisib (PI3K p110δ inhibitor) as controls. CellTiter-Glo was used to measure survival and transwell permeable plates with 8.0µM pores for migration assays. Western blotting was used to examine the role of BMSC, SDF-1 and IL-6 in regulating AKT and MAPK activation in MM cells in response to PI3K δγ inhibition.
Results
The PI3K δγ inhibitor IPI-145 reduced survival of MM cells at 1uM. IPI-145 triggered cytoxicity was associated with pAKT inhibition. IPI-145 also inhibited MM cell growth in response to IL-6 and bone marrow stromal cell co-culture. Furthermore we found that IPI-145 inhibited the migration of MM cells responding to BMSC and SDF-1 stimulation. Finally, we report that IPI-145 can inhibit SDF-1 induced AKT phosphorylation and downstream signaling.
Summary
IPI-145 inhibits MM cell survival and migration at concentrations achievable in vivo. The results reported here provide a molecular mechanistic rationale for the clinical evaluation of IPI-145 in MM patients.
Keyword(s): Myeloma, PI3K
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