Abstract
Radiotherapy is an important anti‐cancer treatment, but tumour recurrence remains a significant clinical problem. In an effort to improve outcomes further, targeted anti‐cancer drugs are being tested in combination with radiotherapy. Here, we have studied the effects of Akt inhibition with AZD5363. AZD5363 administered as an adjuvant after radiotherapy to FaDu and PE/CA PJ34 tumours leads to long‐term tumour control, which appears to be secondary to effects on the irradiated tumour microenvironment. AZD5363 reduces the downstream effectors VEGF and HIF‐1α, but has no effect on tumour vascularity or oxygenation, or on tumour control, when administered prior to radiotherapy. In contrast, AZD5363 given after radiotherapy is associated with marked reductions in tumour vascular density, a decrease in the influx of CD11b+ myeloid cells and a failure of tumour regrowth. In addition, AZD5363 is shown to inhibit the proportion of proliferating tumour vascular endothelial cells in vivo, which may contribute to improved tumour control with adjuvant treatment. These new insights provide promise to improve outcomes with the addition of AZD5363 as an adjuvant therapy following radiotherapy.
Highlights
Radiotherapy (RT) plays an important part in approximately 40% of all cancer cures (Price et al, 2008); relapses after RT are common and present an ongoing clinical challenge to further improve outcomes
It is known that Akt inhibition can alter the intrinsic radiosensitivity of tumour cells (Kim et al, 2005); we evaluated the effect of AZD5363 on a variety of cell lines in vitro
We investigated whether the anti-proliferative effect of AZD5363 seen with mouse endothelial cells might occur with the treatment of human vascular endothelial cells (HUVECs)
Summary
Radiotherapy (RT) plays an important part in approximately 40% of all cancer cures (Price et al, 2008); relapses after RT are common and present an ongoing clinical challenge to further improve outcomes. An increased understanding of potentially important molecular targets and signalling pathways involved in driving cancer has led to the development of novel therapeutics, which can be combined with RT to potentially improve tumour control and outcomes further (Bernier et al, 2004). One potential target is Akt, which is at the centre of the phosphatidylinositol-4,5bisphosphate 3-kinase (PI3K)/Akt pathway, known to have diverse cellular functions including those of survival, growth, proliferation, angiogenesis, glucose uptake and cellular metabolism (Cantley, 2002). Several potential mechanisms have been described by which Akt is involved in the response of tumours to RT suggesting the combination of RT with Akt inhibition may be an important therapeutic opportunity (Kim et al, 2006; Bussink et al, 2008; Schuurbiers et al, 2009). Akt is known to impact on the tumour microenvironment and to induce hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) expression, which in turn can affect the tumour vasculature and tumour response to RT (Kao et al, 2007; Jiang & Liu, 2009; Fokas et al, 2012)
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