Anti-cancer potential of PI 3-kinase overactivation: a proof-of-concept investigation

BACKGROUND: The aberrant activation of PI 3-kinase (PI3K) signalling in cancer and inflammation has driven extensive PI3K pathway inhibitor drug development efforts.

In unpublished studies, we have now generated pharmacological agents that directly activate PI3K signalling, by selectively targeting the ubiquitously-expressed PI3Kα isoform.

Our unpublished data document that these PI3Kα activators may hold therapeutic potential in tissue regeneration and – paradoxically – also in a cancer setting.

Indeed, as part of our characterization of these activators, we have found that PI3K overactivation in metabolically-stressed solid tumour cell lines can result in cell death, a phenomenon we have named PI3K overactivation-induced cell death (PI3K-OCD). This contrasts with PI3K-inhibitors which are mainly cystostatic.

To use an analogy, if a cancer cell were a balloon full of air, a PI3K-activator would pump in extra air and make the balloon pop, while a PI3K-inhibitor would act by getting air out of the balloon, without destroying it.

PI3K-OCD is most likely due to metabolic exhaustion driven by PI3Kα-induced anabolic metabolism, which is already high in many cancer cells compared with normal cells, thereby enabling cancer-selective toxicity.

AIMS: Our 18-month-proposal aims to preclinically validate the principle of PI3K-OCD as an anti-cancer strategy, using a combination of genetic and pharmacological approaches of PI3Kα-activation.

AIM 1 – Improved tool compounds in our existing PI3Kα-activator collection AIM 2 – Validation of pharmacologically-induced PI3K-OCD using genetic approaches AIM 3 – In vivo anti-cancer activity of PI3Kα-activators in human xenograft models METHODS: cell- and mouse-based studies HOW THE RESULTS WILL BE USED: If the proposed target validation is successful, we will aim to: (1) proceed with an more extensive a medicinal drug development programme to create PI3Kα activators with increased potency and drug-like characteristics, for use in preclinical efficacy and toxicoloty models, and (2) undertake detailed mechanistic investigations to fully understand the underlying molecular mechanism of PI3K overactivation-induced cell death, to explore determinants of drug sensitivity as well as mechanism-based approaches and compounds for use in combination therapy.

NOTES: 1.

We have been invited to resubmit an MRC-DPFS application (submission Nov 2021) for a PI3Kα-activator programme for peripheral nerve regeneration, for which we have obtained sound preclinical evidence (unpublished). The timeframe of these efforts might align with potential access to improved PI3Kα activator compounds. 2.

We are also in conversation with CRUK-TDL (Stuart Farrow/Hamish Ryder) and CRUK Beatson (Justin Bower et al., Owen Sansom) for potential parallel involvement in this project.