Strategies to maximise the effects of bicalutamide in androgen sensitive prostate cancer

Abstract

An upregulation of the AKT pathway has been associated with the progression to castrate resistant prostate cancer and loss of response to androgen deprivation therapy (ADT). Targeted AKT pathway inhibition is one strategy for increasing the clinical efficacy of prostate cancer therapeutics. Therefore, in this pre-clinical study, we investigated the effect of a novel AKT inhibitor ALM301 (Almac Discovery) on prostate tumour growth as a single agent and in combination with ADT.

In vitro characterisation of ALM301 was performed using enzyme kinetic and drug biomarker studies. The in vitro effect of ALM301 on cell survival, proliferation, invasion, migration and tubule formation/angiogenic potential was analysed. The in vivo characterisation of ALM301 in singularity and in combination with ADT was performed in an LNCaP-luc xenograft (SCID) mouse model and the effects upon tumour biomarkers, tumour growth, metastasis and molecular markers of malignant progression were assessed.

ALM301 was confirmed as an allosteric inhibitor of AKT, leading to repression of 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 the ability of endothelial cells to instigate tubule formation. In vivo, ALM301 was also shown to successfully inhibit AKT and the subsequent activation of the PI3K/AKT pathway. ALM301, in combination with ADT, was shown to down-regulate molecular markers of malignant progression and impact on a tumours ability to proliferate and metastasise to distal sites.

The AKT inhibitor ALM301 successfully targets AKT pathway activation in prostate cancer cells in vitro and in vivo, causing a potent inhibition of cell growth. Our results demonstrate that combination of ALM301 with ADT demonstrates significant delay of tumour growth and metastatic progression.

Date of Award	May 2016
Original language	English
Supervisor	Declan McKenna (Supervisor), Heather Nesbitt (Supervisor) & Stephanie Mc Keown (Supervisor)