Combined use of AZD0530 and fulvestrant in breast cancer.

Introduction

Project background

Our previous research has revealed a key role for Src kinase in the acquisition of anti-hormone resistance in breast cancer, where it promotes an aggressive behaviour (increased invasion and migration) and contributes to anti-hormone insensitivity. Subsequently, we have shown that pharmacological inhibitors of Src, when used alongside the anti-hormone tamoxifen, can prevent acquisition of tamoxifen resistance. Thus targeting of Src signalling seems to provide a valuable new therapeutic strategy in oestrogen receptor (ER)-positive breast cancer cells when used alongside existing antihormonal therapies.

Recently fulvestrant, a new class of endocrine agent, has been introduced to the clinic as both a second line treatment for patients experiencing disease progression on tamoxifen and an appropriate option after failure of aromatase inhibitors. However, preclinical and clinical studies have demonstrated that resistance to fulvestrant can again be acquired. Interestingly, our data has revealed that acquired fulvestrant resistance in breast cancer cells is also accompanied by a significant increase in Src kinase activity suggesting that Src inhibition may also be of benefit to other classes of antihormone aside from tamoxifen. This hypothesis is supported through our preliminary data demonstrating that combining Src inhibition with fulvestrant is additive in the suppression of breast cancer cell growth compared with each as a single agent, although the mechanism underlying this is currently unknown. In addition to this, we have also observed that inhibition of Src activity in fulvestrant-resistant breast cancer cells greatly suppresses their invasive behaviour and partially restores endocrine response.

Aims of Project

In this project, we propose to investigate further the role of Src in endocrine response and failure and determine the effectiveness of Src inhibition in (i) delaying or preventing fulvestrant resistance in ER-positive breast cancer cells when given in combination with fulvestrant and (ii) the restoration of endocrine response in fulvestrant-resistant breast cancer cells.

Funder

AstraZeneca UK Ltd.

Project Value

£59,724

Additional Information

Relevance of research

Although antihormones bring benefit to a significant number of breast cancer patients, their success in the clinic is limited by the ability of breast cancer cells to acquire resistance to these agents, leading to disease relapse and progression. Data from this project will complement our existing studies, revealing the function of Src in multiple forms of antihormone resistance and thus its potential role as a generic target in breast cancer. These studies will generate important data to support the use of Src inhibitors in breast cancer though which acquired resistance to antihormones may be circumvented.