Title: Can we exploit breast cancer sodium for diagnostic and therapeutic benefit?
Funder: Cancer Research UK

Abstract: Background: Metastatic breast cancer is incurable and there is an urgent need for new therapies. The ionic composition of breast tumours, particularly sodium (Na+), is critical for regulating tumour growth, invasion and metastasis. It is possible to block specific Na+ transporters and channels with existing drugs. Targeting the ionic microenvironment of breast tumours by combining such treatment with advanced 23Na-MR imaging represents a novel approach in the fight against breast cancer. Aims: We will investigate the mechanistic basis for elevated Na+ in breast tumours, in order to establish the utility of Na+, and its conductance routes, as diagnostic indicators and therapeutic targets. We will address three areas: (1) effect of chemotherapy on tumour Na+ level in mice; (2) effect of Na+ transport blockers on tumour Na+ level in mice; and (3) non- invasive 23Na-MR breast imaging in volunteers and patients. Methods: We will construct a bespoke radio frequency coil for our preclinical scanner to enable 23Na- MRI. We will test the effect of neoadjuvant chemotherapy on tumour Na+ in mice bearing xenografts to validate our imaging protocol. We will test the involvement of Na+ channels and transporters in regulating tumour Na+ by treating mice with eslicarbazepine acetate and cariporide. We will monitor the effect of treatment on other tumour properties using standard 1H-MRI, cellular electrophysiology and Na+ dyes to aid interpretation. We will install a breast 23Na coil on a human MRI system to allow non-invasive 23Na-MRI evaluation in healthy volunteers and breast cancer patients to test the hypothesis that Na+ correlates with tumour grade. How results will be used: This work will enable us to translate ion conductance blockers into a window study using approved drugs such as eslicarbazepine acetate. Further work will also be undertaken to characterise Na+ as a biomarker of sensitivity to such inhibitors.

Lay abstract: Background: Metastatic breast cancer is incurable and there is an urgent need for new therapies. The ionic composition of breast tumours, particularly sodium (Na+), is critical for regulating tumour growth, invasion and metastasis. It is possible to block specific Na+ transporters and channels with existing drugs. Targeting the ionic microenvironment of breast tumours by combining such treatment with advanced 23Na-MR imaging represents a novel approach in the fight against breast cancer. Aims: We will investigate the mechanistic basis for elevated Na+ in breast tumours, in order to establish the utility of Na+, and its conductance routes, as diagnostic indicators and therapeutic targets. We will address three areas: (1) effect of chemotherapy on tumour Na+ level in mice; (2) effect of Na+ transport blockers on tumour Na+ level in mice; and (3) non- invasive 23Na-MR breast imaging in volunteers and patients. Methods: We will construct a bespoke radio frequency coil for our preclinical scanner to enable 23Na- MRI. We will test the effect of neoadjuvant chemotherapy on tumour Na+ in mice bearing xenografts to validate our imaging protocol. We will test the involvement of Na+ channels and transporters in regulating tumour Na+ by treating mice with eslicarbazepine acetate and cariporide. We will monitor the effect of treatment on other tumour properties using standard 1H-MRI, cellular electrophysiology and Na+ dyes to aid interpretation. We will install a breast 23Na coil on a human MRI system to allow non-invasive 23Na-MRI evaluation in healthy volunteers and breast cancer patients to test the hypothesis that Na+ correlates with tumour grade. How results will be used: This work will enable us to translate ion conductance blockers into a window study using approved drugs such as eslicarbazepine acetate. Further work will also be undertaken to characterise Na+ as a biomarker of sensitivity to such inhibitors.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS