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

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

doi:10.18632/oncotarget.20936

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.

Highlights

Majority of the cancer patients undergo radiation therapy as a primary or adjuvant treatment for their cancers but may fail due to tumour clonogen radioresistance leading to poor local control and secondary metastases
Clinical trials are studying the benefits of combining the poly (ADP-ribose) polymerase (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
It has been shown that interference with DNA repair caused by PARP-1 inhibitors can result in radiosensitization of tumor cells when given concurrently with radiation in vitro and in vivo [12,13,14]

Summary

Introduction

Majority of the cancer patients undergo radiation therapy as a primary or adjuvant treatment for their cancers but may fail due to tumour clonogen radioresistance leading to poor local control and secondary metastases. PARP-1 inhibitors are of specific interest because they target the DNA repair pathway and they may have an effect on the tumor vasculature [3,4,5,6,7]. We have shown that hypoxia can lead to decreased HRR in vitro leading to an acquired “BRCAness” which translated into increased sensitivity to PARP-1 inhibition in hypoxic tumour cells. This “contextual” synthetic lethality as the tumour cell kill in vitro was associated with an effect of the microenvironment rather than an innate genetic susceptibility, per se. Whether the effect of prolonged PARP-1 inhibitor exposure leads to a reciprocal modification of the tumour microenvironment has not been studied

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Results

Conclusion