Award Title: Hyperpolarised carbon-13 MRI for metabolic imaging of renal cell carcinoma
Funder: Cancer Research UK

Abstract: Background Hyperpolarised carbon-13 Magnetic Resonance Imaging (13C-MRI) is a new method for probing tissue metabolism non-invasively and has recently been translated into humans. The technique can measure the exchange of intravenously injected hyperpolarised 13C-pyruvate to 13C-lactate in real-time, catalysed by the enzyme lactate dehydrogenase. Our preliminary results with the method have demonstrated the formation of 13C-lactate in both normal human kidneys and in clear cell renal cell carcinoma (ccRCC): within the tumour, significant metabolic heterogeneity was demonstrated. This project will evaluate and develop the method as a clinical imaging tool in oncology. It will investigate metabolic imaging habitats as a measure of tumour heterogeneity and determine whether the technique can provide an early biomarker of successful response to neo-adjuvant therapy.  Aims 1. Develop models of hyperpolarised 13C-MRI in ccRCC tumours 2. Biological and technical validation of hyperpolarised 13C-MRI  3. Data modelling and imaging segmentation approaches for hyperpolarised 13C-MRI 4. Correlation with conventional imaging, textural features, tumour habitats and circulating tumour DNA  Methods Patients with ccRCC will be studied with multiparametric MRI and hyperpolarised 13C-MRI as a model of metabolic reprogramming. Patients will be imaged prior to surgery, as well as before and after neo-adjuvant therapy.  • Pre-operative imaging will be compared to tissue specimens to validate metabolic imaging with histology, immunohistochemistry, metabolomics and RNA-seq.  • Imaging-derived tumour habitats will be correlated with histology to evaluate the relationship between conventional/metabolic imaging and tumour heterogeneity. • Temporal changes in the metabolism of hyperpolarised 13C-pyruvate before and after neo-adjuvant therapy will be monitored as part of the WIRE study, to assess if hyperpolarised 13C-MRI can be used as an early imaging biomarker of treatment response. • Hyperpolarised 13C-MRI will be compared to conventional MRI, textural features of tumour heterogeneity and circulating tumour DNA to establish the temporal relationship between these biomarkers and their relative sensitivities for detecting response to therapy. • Novel pathways of pyruvate metabolism will be explored in tumours with loss-of-function mutations in the enzyme succinate dehydrogenase.  • Methods to model and analyse hyperpolarised 13C-MRI data will be developed.  How the results of this research will be used: This programme will develop hyperpolarised 13C-MRI as a clinical research tool and will explore whether it could be used more routinely in ccRCC. The technique has the potential to provide novel imaging biomarkers for assessing early response to treatment and may be used to non-invasively assess tumour metabolic phenotype and heterogeneity.

Lay Abstract: Background Hyperpolarised carbon-13 Magnetic Resonance Imaging (13C-MRI) is a new method for probing tissue metabolism non-invasively and has recently been translated into humans. The technique can measure the exchange of intravenously injected hyperpolarised 13C-pyruvate to 13C-lactate in real-time, catalysed by the enzyme lactate dehydrogenase. Our preliminary results with the method have demonstrated the formation of 13C-lactate in both normal human kidneys and in clear cell renal cell carcinoma (ccRCC): within the tumour, significant metabolic heterogeneity was demonstrated. This project will evaluate and develop the method as a clinical imaging tool in oncology. It will investigate metabolic imaging habitats as a measure of tumour heterogeneity and determine whether the technique can provide an early biomarker of successful response to neo-adjuvant therapy.  Aims 1. Develop models of hyperpolarised 13C-MRI in ccRCC tumours 2. Biological and technical validation of hyperpolarised 13C-MRI  3. Data modelling and imaging segmentation approaches for hyperpolarised 13C-MRI 4. Correlation with conventional imaging, textural features, tumour habitats and circulating tumour DNA  Methods Patients with ccRCC will be studied with multiparametric MRI and hyperpolarised 13C-MRI as a model of metabolic reprogramming. Patients will be imaged prior to surgery, as well as before and after neo-adjuvant therapy.  • Pre-operative imaging will be compared to tissue specimens to validate metabolic imaging with histology, immunohistochemistry, metabolomics and RNA-seq.  • Imaging-derived tumour habitats will be correlated with histology to evaluate the relationship between conventional/metabolic imaging and tumour heterogeneity. • Temporal changes in the metabolism of hyperpolarised 13C-pyruvate before and after neo-adjuvant therapy will be monitored as part of the WIRE study, to assess if hyperpolarised 13C-MRI can be used as an early imaging biomarker of treatment response. • Hyperpolarised 13C-MRI will be compared to conventional MRI, textural features of tumour heterogeneity and circulating tumour DNA to establish the temporal relationship between these biomarkers and their relative sensitivities for detecting response to therapy. • Novel pathways of pyruvate metabolism will be explored in tumours with loss-of-function mutations in the enzyme succinate dehydrogenase.  • Methods to model and analyse hyperpolarised 13C-MRI data will be developed.  How the results of this research will be used: This programme will develop hyperpolarised 13C-MRI as a clinical research tool and will explore whether it could be used more routinely in ccRCC. The technique has the potential to provide novel imaging biomarkers for assessing early response to treatment and may be used to non-invasively assess tumour metabolic phenotype and heterogeneity.

Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS