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Akt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment.

Authors
  • Searle, Emma J1, 2, 3
  • Telfer, Brian A1
  • Mukherjee, Debayan2, 3
  • Forster, Duncan M4
  • Davies, Barry R5
  • Williams, Kaye J1, 6, 7
  • Stratford, Ian J1
  • Illidge, Tim M8, 3
  • 1 Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK.
  • 2 Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester, UK.
  • 3 Christie Hospital Manchester Academic Health Sciences Centre University of Manchester, Manchester, UK.
  • 4 Division of Informatics, Imaging & Data Sciences, School of Health Sciences, University of Manchester, Manchester, UK.
  • 5 IMED Oncology Biotech Unit AstraZeneca, Cambridge, UK.
  • 6 CRUK-EPSRC Cancer Imaging Centre in Cambridge and Manchester, Cambridge, UK.
  • 7 CRUK-EPSRC Cancer Imaging Centre in Cambridge and Manchester, Manchester, UK.
  • 8 Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester, UK [email protected]
Type
Published Article
Journal
EMBO Molecular Medicine
Publisher
EMBO
Publication Date
Oct 30, 2017
Identifiers
DOI: 10.15252/emmm.201707767
PMID: 29084756
Source
Medline
Keywords
License
Unknown

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.

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