Characterisation of novel AKT inhibitor in treatment of androgen sensitive prostate cancer

david cochrane, katie o'donovan, Heather Nesbitt, Stephanie McKeown, Jenny Worthington, martin o'rourke, Iain James, Declan McKenna

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

BackgroundAn upregulation of the AKT pathway has been associated with the progression to castrateresistant prostate cancer and loss of response to androgen deprivation therapy (ADT). TargetedAKT pathway inhibition is one strategy for increasing the clinical efficacy of prostate cancertherapeutics. Therefore, in this pre-clinical study, we investigated the effect of a novel AKTinhibitor ALM301 (ALMAC Discovery) on prostate tumour growth as a single agent and incombination with ADT.MethodIn vitro characterisation of ALM301 was performed using enzyme kinetic and drug biomarkerstudies. The in vitro effect of ALM301 on cell survival, proliferation, invasion, migration andtubule formation/angiogenic potential was analysed. The in vivo characterisation of ALM301 insingularity and in combination with ADT was performed in an LNCaP-luc Xenograft Balb-c (SCID)mouse model and the effects upon tumour biomarkers, tumour growth, metastasis andmolecular markers of malignant progression were assessed.ResultsALM301 was confirmed as an allosteric ATP-independent inhibitor of AKT, leading to repressionof the PI3K/AKT pathway. In vitro, ALM301 treatment significantly reduced the survival,proliferation, migration and invasive capacity of LNCaP cancer cells, as well as impacting on theability of endothelial cells to instigate tubule formation. In vivo, ALM301 was also shown tosuccessfully inhibit AKT and the subsequent activation of the PI3K/AKT pathway. ALM301, incombination with ADT, was shown to down-regulate molecular markers of malignantprogression and impact on a tumours ability to proliferate and metastasise to distal sites.ConclusionThe AKT inhibitor ALM301 successfully targets AKT pathway activation in prostate cancer cellsin vitro and in vivo, causing a potent inhibition of cell growth. Our results demonstrate thatcombination of ALM301 with ADT demonstrates significant delay of tumour growth andmetastatic progression.
LanguageEnglish
Title of host publicationUnknown Host Publication
Number of pages180
Publication statusPublished - Feb 2015
EventIrish Association for Cancer Research 2015 - Limerick
Duration: 1 Feb 2015 → …

Conference

ConferenceIrish Association for Cancer Research 2015
Period1/02/15 → …

Fingerprint

Androgens
Prostatic Neoplasms
Neoplasms
Growth
Phosphatidylinositol 3-Kinases
Prostate
Therapeutics
SCID Mice
Tumor Biomarkers
Heterografts
Cell Survival
Up-Regulation
Down-Regulation
Endothelial Cells
Pharmacokinetics
Adenosine Triphosphate
Cell Proliferation
Neoplasm Metastasis
Enzymes
In Vitro Techniques

Keywords

  • Prostate Cancer
  • AKT inhibition
  • ALM301
  • bicalutamide

Cite this

cochrane, D., o'donovan, K., Nesbitt, H., McKeown, S., Worthington, J., o'rourke, M., ... McKenna, D. (2015). Characterisation of novel AKT inhibitor in treatment of androgen sensitive prostate cancer. In Unknown Host Publication
cochrane, david ; o'donovan, katie ; Nesbitt, Heather ; McKeown, Stephanie ; Worthington, Jenny ; o'rourke, martin ; James, Iain ; McKenna, Declan. / Characterisation of novel AKT inhibitor in treatment of androgen sensitive prostate cancer. Unknown Host Publication. 2015.
@inproceedings{01fb39d3d6234cf0a33401cc8081beb0,
title = "Characterisation of novel AKT inhibitor in treatment of androgen sensitive prostate cancer",
abstract = "BackgroundAn upregulation of the AKT pathway has been associated with the progression to castrateresistant prostate cancer and loss of response to androgen deprivation therapy (ADT). TargetedAKT pathway inhibition is one strategy for increasing the clinical efficacy of prostate cancertherapeutics. Therefore, in this pre-clinical study, we investigated the effect of a novel AKTinhibitor ALM301 (ALMAC Discovery) on prostate tumour growth as a single agent and incombination with ADT.MethodIn vitro characterisation of ALM301 was performed using enzyme kinetic and drug biomarkerstudies. The in vitro effect of ALM301 on cell survival, proliferation, invasion, migration andtubule formation/angiogenic potential was analysed. The in vivo characterisation of ALM301 insingularity and in combination with ADT was performed in an LNCaP-luc Xenograft Balb-c (SCID)mouse model and the effects upon tumour biomarkers, tumour growth, metastasis andmolecular markers of malignant progression were assessed.ResultsALM301 was confirmed as an allosteric ATP-independent inhibitor of AKT, leading to repressionof the PI3K/AKT pathway. In vitro, ALM301 treatment significantly reduced the survival,proliferation, migration and invasive capacity of LNCaP cancer cells, as well as impacting on theability of endothelial cells to instigate tubule formation. In vivo, ALM301 was also shown tosuccessfully inhibit AKT and the subsequent activation of the PI3K/AKT pathway. ALM301, incombination with ADT, was shown to down-regulate molecular markers of malignantprogression and impact on a tumours ability to proliferate and metastasise to distal sites.ConclusionThe AKT inhibitor ALM301 successfully targets AKT pathway activation in prostate cancer cellsin vitro and in vivo, causing a potent inhibition of cell growth. Our results demonstrate thatcombination of ALM301 with ADT demonstrates significant delay of tumour growth andmetastatic progression.",
keywords = "Prostate Cancer, AKT inhibition, ALM301, bicalutamide",
author = "david cochrane and katie o'donovan and Heather Nesbitt and Stephanie McKeown and Jenny Worthington and martin o'rourke and Iain James and Declan McKenna",
year = "2015",
month = "2",
language = "English",
booktitle = "Unknown Host Publication",

}

cochrane, D, o'donovan, K, Nesbitt, H, McKeown, S, Worthington, J, o'rourke, M, James, I & McKenna, D 2015, Characterisation of novel AKT inhibitor in treatment of androgen sensitive prostate cancer. in Unknown Host Publication. Irish Association for Cancer Research 2015, 1/02/15.

Characterisation of novel AKT inhibitor in treatment of androgen sensitive prostate cancer. / cochrane, david; o'donovan, katie; Nesbitt, Heather; McKeown, Stephanie; Worthington, Jenny; o'rourke, martin; James, Iain; McKenna, Declan.

Unknown Host Publication. 2015.

Research output: Chapter in Book/Report/Conference proceedingConference contribution

TY - GEN

T1 - Characterisation of novel AKT inhibitor in treatment of androgen sensitive prostate cancer

AU - cochrane, david

AU - o'donovan, katie

AU - Nesbitt, Heather

AU - McKeown, Stephanie

AU - Worthington, Jenny

AU - o'rourke, martin

AU - James, Iain

AU - McKenna, Declan

PY - 2015/2

Y1 - 2015/2

N2 - BackgroundAn upregulation of the AKT pathway has been associated with the progression to castrateresistant prostate cancer and loss of response to androgen deprivation therapy (ADT). TargetedAKT pathway inhibition is one strategy for increasing the clinical efficacy of prostate cancertherapeutics. Therefore, in this pre-clinical study, we investigated the effect of a novel AKTinhibitor ALM301 (ALMAC Discovery) on prostate tumour growth as a single agent and incombination with ADT.MethodIn vitro characterisation of ALM301 was performed using enzyme kinetic and drug biomarkerstudies. The in vitro effect of ALM301 on cell survival, proliferation, invasion, migration andtubule formation/angiogenic potential was analysed. The in vivo characterisation of ALM301 insingularity and in combination with ADT was performed in an LNCaP-luc Xenograft Balb-c (SCID)mouse model and the effects upon tumour biomarkers, tumour growth, metastasis andmolecular markers of malignant progression were assessed.ResultsALM301 was confirmed as an allosteric ATP-independent inhibitor of AKT, leading to repressionof the PI3K/AKT pathway. In vitro, ALM301 treatment significantly reduced the survival,proliferation, migration and invasive capacity of LNCaP cancer cells, as well as impacting on theability of endothelial cells to instigate tubule formation. In vivo, ALM301 was also shown tosuccessfully inhibit AKT and the subsequent activation of the PI3K/AKT pathway. ALM301, incombination with ADT, was shown to down-regulate molecular markers of malignantprogression and impact on a tumours ability to proliferate and metastasise to distal sites.ConclusionThe AKT inhibitor ALM301 successfully targets AKT pathway activation in prostate cancer cellsin vitro and in vivo, causing a potent inhibition of cell growth. Our results demonstrate thatcombination of ALM301 with ADT demonstrates significant delay of tumour growth andmetastatic progression.

AB - BackgroundAn upregulation of the AKT pathway has been associated with the progression to castrateresistant prostate cancer and loss of response to androgen deprivation therapy (ADT). TargetedAKT pathway inhibition is one strategy for increasing the clinical efficacy of prostate cancertherapeutics. Therefore, in this pre-clinical study, we investigated the effect of a novel AKTinhibitor ALM301 (ALMAC Discovery) on prostate tumour growth as a single agent and incombination with ADT.MethodIn vitro characterisation of ALM301 was performed using enzyme kinetic and drug biomarkerstudies. The in vitro effect of ALM301 on cell survival, proliferation, invasion, migration andtubule formation/angiogenic potential was analysed. The in vivo characterisation of ALM301 insingularity and in combination with ADT was performed in an LNCaP-luc Xenograft Balb-c (SCID)mouse model and the effects upon tumour biomarkers, tumour growth, metastasis andmolecular markers of malignant progression were assessed.ResultsALM301 was confirmed as an allosteric ATP-independent inhibitor of AKT, leading to repressionof the PI3K/AKT pathway. In vitro, ALM301 treatment significantly reduced the survival,proliferation, migration and invasive capacity of LNCaP cancer cells, as well as impacting on theability of endothelial cells to instigate tubule formation. In vivo, ALM301 was also shown tosuccessfully inhibit AKT and the subsequent activation of the PI3K/AKT pathway. ALM301, incombination with ADT, was shown to down-regulate molecular markers of malignantprogression and impact on a tumours ability to proliferate and metastasise to distal sites.ConclusionThe AKT inhibitor ALM301 successfully targets AKT pathway activation in prostate cancer cellsin vitro and in vivo, causing a potent inhibition of cell growth. Our results demonstrate thatcombination of ALM301 with ADT demonstrates significant delay of tumour growth andmetastatic progression.

KW - Prostate Cancer

KW - AKT inhibition

KW - ALM301

KW - bicalutamide

M3 - Conference contribution

BT - Unknown Host Publication

ER -

cochrane D, o'donovan K, Nesbitt H, McKeown S, Worthington J, o'rourke M et al. Characterisation of novel AKT inhibitor in treatment of androgen sensitive prostate cancer. In Unknown Host Publication. 2015