Table 3.
Preclinical studies exploring the role of PI3K, AKT and/or mTOR inhibitors radiosensitising GBM.
| Author | Year | Type of Cancer | Experimental Model | Drug (s) Tested | Drug Category | Radiotherapy Dose | Summary Outcome |
|---|---|---|---|---|---|---|---|
| Shi et al. [98] | 2018 | GBM | In vitro (cell lines): A172, SHG44, and T98G In vivo (xenograft) |
NVP-BEZ235 | PI3K and mTOR inhibitor | 2 Gy | Higher p27 and lower Bcl-2 expression in cells treated with radiotherapy, temozolomide and NVP-BEZ235 Inhibited tumour growth and prolonged survival with combined treatment all three modalities |
| Djuzenova et al. [49] | 2016 | GBM | In vitro (cell lines): GaMG, SNB19 | PI-103 | PI3K, mTOR and DNA-PK inhibitor | 0, 2 Gy or 8 Gy | Enhanced radiosensitising effect following treatment Enhanced radiosensitisation to heat shock protein 90 inhibitor NVP-AUY922 |
| Choi et al. [94] | 2014 | GBM | In vitro (cell lines): U251, U87, T98G | PI-103 Rapamycin |
PI3K, mTOR and DNA-PK inhibitor mTOR inhibitor |
Variable range (0–8 Gy) |
Radiotherapy with drug increased cytotoxic effects No discernible radiosensitising effect with rapamycin |
| Del Alcazar et al. [90] | 2014 | GBM | In vitro (cell line): U87MG In vivo (xenograft): GBM9 + mice |
NVP-BEZ235 | PI3K and mTOR inhibitor | 0, 2 Gy or 10 Gy | Reduced expression of DNA-PKcs and ATM kinase Attenuated repair of radiotherapy induced DNA damage Sensitized tumours to temozolomide and radiotherapy |
| Kuger et al. [2,91] | 2013 | GBM | In vitro (cell lines): GaMG (PTEN wt, p53 mut), DK-MG (PTEN wt, p53 wt), U373 (PTEN mut, p53 mut), U87-MG (PTEN mut, p53 wt) | NVP-BEZ235 Schedule 1: 24hr before radiotherapy Schedule 2: 1 h before and for 48hr post radiotherapy | PI3K and mTOR inhibitor | Variable range (0–8 Gy) | Enhanced radiosensitivity under schedule 2 as opposed to schedule one Protracted DNA repair Prolonged G2/M arrest and apoptosis |
| Wang et al. [92] | 2013 | GBM | In vitro (cell line): SU-2 cells (Glioma stem cells) | NVP-BEZ235 | PI3K and mTOR inhibitor | Variable range (0–8 Gy) |
Autophagy, increased apoptosis Decreased DNA repair capacity G1 cell cycle arrest |
| Cerniglia et al. [74] | 2012 | GBM | In vitro (cell line): U251MG | NVP-BEZ235 | PI3K and mTOR inhibitor | Variable range (0–6 Gy) |
Radiosensitises cells and induces autophagy |
| Mukherjee et al. [93] | 2012 | GBM | In vitro (cell lines): U251, U118, LN18, T98G, LN229, SF188, 1BR3, AT5, M059K, M059 In vivo (xenograft): U87 + mice |
NVP-BEZ235 | PI3K and mTOR inhibitor | 0, 2 Gy or 10 Gy | Reduced expression of ATM and DNA-PKcs G2/M Arrest |
| Li et al. [95] | 2009 | GBM | In vitro (cell line): U87MG | SH-5 MK-2206 LY294002 |
AKT inhibitor AKT inhibitor PI3K and PI3K-like kinase inhibitor |
Variable range (0–9 Gy) | Enhanced radiosensitivity noted with all three agents |
| Kao et al. [96] | 2007 | GBM | In vitro (cell line): U251MG | LY294002 | PI3K and PI3K-like kinase inhibitor | Variable range (0–6 Gy) | Enhanced radiosensitivity following treatment |
| Nakamura et al. [97] | 2005 | GBM | In vitro (cell line): U251 MG | LY294002 Rapamycin |
PI3K and PI3K-like kinase inhibitor mTOR inhibitor |
Variable range (0–8 Gy) |
Low doses of LY294002 sensitized U251 MG to clinically relevant doses of radiation No effect observed with rapamycin |
| Shinohara et al. [99] | 2005 | GBM | In vitro (cell lines): GL261, endothelial cell line In vivo (xenograft): GL261 + mice |
Everolimus | mTOR inhibitor | Variable range (0–7 Gy) |
Reduced tumour growth by enhanced radiosensitisation of the tumour vascular endothelium |
| Eshleman et al. [100] | 2002 | GBM | In vitro (cell lines): U87, SKMG-3 In vitro (spheroids): U87 In vivo (xenograft): U87 + mice |
Rapamycin | mTOR inhibitor | Variable range (0–10 Gy) |
Rapamycin had no effect on cell lines However, the drug significantly enhanced the response to radiotherapy on xenograft and spheroids following treatment |