ONO-5390556 AS POTENTIAL TARGETED THERAPY FOR ACUTE MYELOID LEUKAEMIA WITH ETV6-NTRK3 FUSION GENE
(Abstract release date: 05/19/16)
EHA Library. Kozaki R. 06/09/16; 132452; E903
Disclosure(s): I am a employee of Ono Pharmaceuticals Co.,LTD.
Mr. Ryohei Kozaki
Contributions
Contributions
Abstract
Abstract: E903
Type: Eposter Presentation
Background
Chromosomal rearrangements that target NTRK1, NTRK2 and NTRK3 are rare but recurrent abnormalities observed in some types of cancer. Fusion variants for each NTRK gene have been described in cancers that give rise to constitutive activation of kinase domains that are believe to drive the oncogenic process. Translocation of NTRK3 and Ets family transcription factor 6 (ETV6), ETV6-NTRK3 appears with the greatest frequency across many cancer types, including acute myeloid leukaemia (AML), radiation-associated thyroid cancer, high grade gliomas, ductal carcinoma, fibrosarcomas, congenital mesoblastic nephroma and secretory breast carcinoma. Patients bearing ETV6-NTRK3 show resistant to chemotherapy, indicating that targeting active NTRK may be effective in the treatment of patients with this fusion.
Aims
ONO-5390556 is a highly potent and selective NTRK inhibitor with an IC50 in the sub-nmol/L range. We have examined the activity of ONO-5390556 against ETV6-NTRK3 bearing cell line, IMS-M2 models both in vitro and in vivo.
Methods
Response was assessed by oral administration of ONO-5390556 once daily for 26 days in mice bearing IMS-M2 cells that were subcutaneously injected into female SCID mice. To investigate the regulation of signaling pathways by ONO-5390556 in IMS-M2 cells, western blotting was performed.
Results
IMS-M2 cell lines showed reduced proliferation (IC50: 0.8 nmol/L) compared with Ba/F3 cells (IC50 not reached at 1000 nmol/L). In the IMS-M2 xenograft model, tumour growth inhibition at the final treatment day was 62.7% in the 0.6 mg/kg treatment group and 100% both in the 2 mg/kg and 6 mg/kg treatment groups respectively (All treatment groups: P<0.001 v.s. Vehicle). The treatment of ONO-5390556 was well tolerated in IMS-M2 bearing SCID mice with no body weight loss. Western blotting demonstrated a dose-dependent reduction in phosphorylation of the NTRK and the downstream signaling of NTRK pathway, ERK, AKT and PLCg1.
Conclusion
The dramatic and sustained response to NTRK inhibition in IMS-M2 cells provides a rationale for the mechanisms underlying the response. Our in vivo study therefore demonstrate that ONO-5390556 has significant activity against cells containing NTRK rearrangement and shows promise for the treatment of patients with ETV6-NTRK3 fusion gene positive AML.
Session topic: E-poster
Keyword(s): AML, ETV6, Fusion, Kinase inhibitor
Type: Eposter Presentation
Background
Chromosomal rearrangements that target NTRK1, NTRK2 and NTRK3 are rare but recurrent abnormalities observed in some types of cancer. Fusion variants for each NTRK gene have been described in cancers that give rise to constitutive activation of kinase domains that are believe to drive the oncogenic process. Translocation of NTRK3 and Ets family transcription factor 6 (ETV6), ETV6-NTRK3 appears with the greatest frequency across many cancer types, including acute myeloid leukaemia (AML), radiation-associated thyroid cancer, high grade gliomas, ductal carcinoma, fibrosarcomas, congenital mesoblastic nephroma and secretory breast carcinoma. Patients bearing ETV6-NTRK3 show resistant to chemotherapy, indicating that targeting active NTRK may be effective in the treatment of patients with this fusion.
Aims
ONO-5390556 is a highly potent and selective NTRK inhibitor with an IC50 in the sub-nmol/L range. We have examined the activity of ONO-5390556 against ETV6-NTRK3 bearing cell line, IMS-M2 models both in vitro and in vivo.
Methods
Response was assessed by oral administration of ONO-5390556 once daily for 26 days in mice bearing IMS-M2 cells that were subcutaneously injected into female SCID mice. To investigate the regulation of signaling pathways by ONO-5390556 in IMS-M2 cells, western blotting was performed.
Results
IMS-M2 cell lines showed reduced proliferation (IC50: 0.8 nmol/L) compared with Ba/F3 cells (IC50 not reached at 1000 nmol/L). In the IMS-M2 xenograft model, tumour growth inhibition at the final treatment day was 62.7% in the 0.6 mg/kg treatment group and 100% both in the 2 mg/kg and 6 mg/kg treatment groups respectively (All treatment groups: P<0.001 v.s. Vehicle). The treatment of ONO-5390556 was well tolerated in IMS-M2 bearing SCID mice with no body weight loss. Western blotting demonstrated a dose-dependent reduction in phosphorylation of the NTRK and the downstream signaling of NTRK pathway, ERK, AKT and PLCg1.
Conclusion
The dramatic and sustained response to NTRK inhibition in IMS-M2 cells provides a rationale for the mechanisms underlying the response. Our in vivo study therefore demonstrate that ONO-5390556 has significant activity against cells containing NTRK rearrangement and shows promise for the treatment of patients with ETV6-NTRK3 fusion gene positive AML.
Session topic: E-poster
Keyword(s): AML, ETV6, Fusion, Kinase inhibitor
Abstract: E903
Type: Eposter Presentation
Background
Chromosomal rearrangements that target NTRK1, NTRK2 and NTRK3 are rare but recurrent abnormalities observed in some types of cancer. Fusion variants for each NTRK gene have been described in cancers that give rise to constitutive activation of kinase domains that are believe to drive the oncogenic process. Translocation of NTRK3 and Ets family transcription factor 6 (ETV6), ETV6-NTRK3 appears with the greatest frequency across many cancer types, including acute myeloid leukaemia (AML), radiation-associated thyroid cancer, high grade gliomas, ductal carcinoma, fibrosarcomas, congenital mesoblastic nephroma and secretory breast carcinoma. Patients bearing ETV6-NTRK3 show resistant to chemotherapy, indicating that targeting active NTRK may be effective in the treatment of patients with this fusion.
Aims
ONO-5390556 is a highly potent and selective NTRK inhibitor with an IC50 in the sub-nmol/L range. We have examined the activity of ONO-5390556 against ETV6-NTRK3 bearing cell line, IMS-M2 models both in vitro and in vivo.
Methods
Response was assessed by oral administration of ONO-5390556 once daily for 26 days in mice bearing IMS-M2 cells that were subcutaneously injected into female SCID mice. To investigate the regulation of signaling pathways by ONO-5390556 in IMS-M2 cells, western blotting was performed.
Results
IMS-M2 cell lines showed reduced proliferation (IC50: 0.8 nmol/L) compared with Ba/F3 cells (IC50 not reached at 1000 nmol/L). In the IMS-M2 xenograft model, tumour growth inhibition at the final treatment day was 62.7% in the 0.6 mg/kg treatment group and 100% both in the 2 mg/kg and 6 mg/kg treatment groups respectively (All treatment groups: P<0.001 v.s. Vehicle). The treatment of ONO-5390556 was well tolerated in IMS-M2 bearing SCID mice with no body weight loss. Western blotting demonstrated a dose-dependent reduction in phosphorylation of the NTRK and the downstream signaling of NTRK pathway, ERK, AKT and PLCg1.
Conclusion
The dramatic and sustained response to NTRK inhibition in IMS-M2 cells provides a rationale for the mechanisms underlying the response. Our in vivo study therefore demonstrate that ONO-5390556 has significant activity against cells containing NTRK rearrangement and shows promise for the treatment of patients with ETV6-NTRK3 fusion gene positive AML.
Session topic: E-poster
Keyword(s): AML, ETV6, Fusion, Kinase inhibitor
Type: Eposter Presentation
Background
Chromosomal rearrangements that target NTRK1, NTRK2 and NTRK3 are rare but recurrent abnormalities observed in some types of cancer. Fusion variants for each NTRK gene have been described in cancers that give rise to constitutive activation of kinase domains that are believe to drive the oncogenic process. Translocation of NTRK3 and Ets family transcription factor 6 (ETV6), ETV6-NTRK3 appears with the greatest frequency across many cancer types, including acute myeloid leukaemia (AML), radiation-associated thyroid cancer, high grade gliomas, ductal carcinoma, fibrosarcomas, congenital mesoblastic nephroma and secretory breast carcinoma. Patients bearing ETV6-NTRK3 show resistant to chemotherapy, indicating that targeting active NTRK may be effective in the treatment of patients with this fusion.
Aims
ONO-5390556 is a highly potent and selective NTRK inhibitor with an IC50 in the sub-nmol/L range. We have examined the activity of ONO-5390556 against ETV6-NTRK3 bearing cell line, IMS-M2 models both in vitro and in vivo.
Methods
Response was assessed by oral administration of ONO-5390556 once daily for 26 days in mice bearing IMS-M2 cells that were subcutaneously injected into female SCID mice. To investigate the regulation of signaling pathways by ONO-5390556 in IMS-M2 cells, western blotting was performed.
Results
IMS-M2 cell lines showed reduced proliferation (IC50: 0.8 nmol/L) compared with Ba/F3 cells (IC50 not reached at 1000 nmol/L). In the IMS-M2 xenograft model, tumour growth inhibition at the final treatment day was 62.7% in the 0.6 mg/kg treatment group and 100% both in the 2 mg/kg and 6 mg/kg treatment groups respectively (All treatment groups: P<0.001 v.s. Vehicle). The treatment of ONO-5390556 was well tolerated in IMS-M2 bearing SCID mice with no body weight loss. Western blotting demonstrated a dose-dependent reduction in phosphorylation of the NTRK and the downstream signaling of NTRK pathway, ERK, AKT and PLCg1.
Conclusion
The dramatic and sustained response to NTRK inhibition in IMS-M2 cells provides a rationale for the mechanisms underlying the response. Our in vivo study therefore demonstrate that ONO-5390556 has significant activity against cells containing NTRK rearrangement and shows promise for the treatment of patients with ETV6-NTRK3 fusion gene positive AML.
Session topic: E-poster
Keyword(s): AML, ETV6, Fusion, Kinase inhibitor
{{ help_message }}
{{filter}}