Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2020; 11:1573-1574.

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 and Robert G. Bristow

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:87638-87646. https://doi.org/10.18632/oncotarget.20936

Metrics: PDF 1607 views  |   HTML 3311 views  |   ?  


Abstract

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

Correspondence to:

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

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 20936