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.
|Title of host publication||Unknown Host Publication|
|Publisher||Irish Association for Cancer Research|
|Number of pages||180|
|Publication status||Published - Feb 2015|
|Event||Irish Association for Cancer Research 2015 - Limerick|
Duration: 1 Feb 2015 → …
|Conference||Irish Association for Cancer Research 2015|
|Period||1/02/15 → …|
- Prostate Cancer
- AKT inhibition
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 Irish Association for Cancer Research.