Neoadjuvant olaparib targets hypoxia to improve radioresponse in a homologous recombination-proficient breast cancer model
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Gerben R. Borst1,2,3, Ramya Kumareswaran1,2, Hatice Yücel1,2,3, Seyda Telli1,2, Trevor Do1,2, Trevor McKee1,2, Gaetano Zafarana1,2, Jos Jonkers4, Marcel Verheij3, Mark J. O’Connor5, Sven Rottenberg4,6 and Robert G. Bristow1,2
1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
2Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, Canada
3Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Department of Radiation Oncology, Amsterdam, The Netherlands
4Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Department of Molecular Biology, Amsterdam, The Netherlands
5Oncology, Innovative Medicines and Early Development, AstraZeneca, Cambridge, United Kingdom
6Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
Gerben R. Borst, email: [email protected]
Keywords: neoadjuvant treatment, targeted therapy, radiotherapy, hypoxia, olaparib
Received: January 26, 2017 Accepted: July 09, 2017 Published: September 15, 2017
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.
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