Neoadjuvant olaparib targets hypoxia to improve radioresponse in a homologous recombination-proficient breast cancer model

Gerben R Borst, Ramya Kumareswaran, Hatice Yücel, Seyda Telli, Trevor Do, Trevor McKee, Gaetano Zafarana, Jos Jonkers, Marcel Verheij, Mark J O'Connor, Sven Rottenberg, Robert G Bristow

Research output: Contribution to journalArticlepeer-review

Abstract

Clinical trials are studying the benefits of combining the PARP-1 inhibitor olaparib with chemotherapy and radiotherapy treatment in a variety of cancer increasing the therapeutic ratio for olaparib may come from its ability to modify the tumour microenvironment by targeting homologous recombination-deficient, hypoxic tumour clonogens, and/or increasing tumour-associated vasodilation to improve oxygenation. Herein, we investigated the effect of prolonged neoadjuvant exposure to olaparib on the tumor microenvironment using a genetically-engineered mouse p53-/- syngeneic breast cancer model, which is proficient in homology-directed DNA repair. We observed increased in vivo growth delay and decreased ex vivo clonogenic survival following pre-treatment with olaparib 50 mg/kg bid Olaparib for 7 days ending 48 hours prior to a radiation dose of 12Gy. This increased in vivo radioresponse was associated with a decreased hypoxic fraction. This study suggests that the radiation response in patients can be improved with limited toxicity if olaparib is given in a purely neoadjuvant setting to modify the tumor microenviroment prior to the start of the radiotherapy treatment. Consequently a significant gain can be achieved in therapeutic window and clinical studies are needed to confirm this preclinical data.

Original languageEnglish
Pages (from-to)87638-87646
Number of pages9
JournalOncotarget
Volume8
Issue number50
Early online date15 Sept 2017
DOIs
Publication statusPublished - 20 Oct 2017

Keywords

  • Hypoxia
  • Neoadjuvant treatment
  • Olaparib
  • Radiotherapy
  • Targeted therapy

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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