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

2.50
Hdl Handle:
http://hdl.handle.net/10541/620645
Title:
Akt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment.
Authors:
Searle, Emma J; Telfer, B; Mukherjee, Debayan; Forster, D; Davies, B; Williams, K; Stratford, I; Illidge, Timothy M ( 0000-0003-3191-7324 )
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.
Affiliation:
Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester
Citation:
Akt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment. 2017, EMBO Mol Med
Journal:
EMBO molecular medicine
Issue Date:
30-Oct-2017
URI:
http://hdl.handle.net/10541/620645
DOI:
10.15252/emmm.201707767
PubMed ID:
29084756
Type:
Article
Language:
en
ISSN:
1757-4684
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorSearle, Emma Jen
dc.contributor.authorTelfer, Ben
dc.contributor.authorMukherjee, Debayanen
dc.contributor.authorForster, Den
dc.contributor.authorDavies, Ben
dc.contributor.authorWilliams, Ken
dc.contributor.authorStratford, Ien
dc.contributor.authorIllidge, Timothy Men
dc.date.accessioned2017-11-21T21:47:28Z-
dc.date.available2017-11-21T21:47:28Z-
dc.date.issued2017-10-30-
dc.identifier.citationAkt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment. 2017, EMBO Mol Meden
dc.identifier.issn1757-4684-
dc.identifier.pmid29084756-
dc.identifier.doi10.15252/emmm.201707767-
dc.identifier.urihttp://hdl.handle.net/10541/620645-
dc.description.abstractRadiotherapy 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.en
dc.language.isoenen
dc.rightsArchived with thanks to EMBO molecular medicineen
dc.titleAkt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment.en
dc.typeArticleen
dc.contributor.departmentDivision of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchesteren
dc.identifier.journalEMBO molecular medicineen

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