A novel imaging biomarker for detecting treatment response in high-grade glioma

The most common brain cancer, glioblastoma, has an extremely poor prognosis, with a median life expectancy of 15 months from diagnosis. This poor prognosis reflects the aggressive nature of this cancer and also the variable way in which it behaves following treatment. Patients can show markedly different responses to the same treatment. New treatments need to be developed and introduced into the clinic quickly. The development of these new treatments would benefit from the introduction of imaging methods that allow an earlier assessment of treatment response, which would allow clinicians to better and more quickly select the most effective treatment. Current imaging techniques only allow us to assess the size of a tumour, however, this is not ideal as it may take several weeks or even months for a tumour to decrease in size following an effective treatment. In some cases a tumour may even increase in size despite a positive response to the treatment. Tumour metabolism can show an earlier change following treatment than tumour size. However, the most widely used metabolic imaging technique in the clinic, PET measurements of the uptake of a radioactive glucose analog, are ineffective in brain tumours because of the high uptake in the normal brain tissue surrounding the tumour.

The aim of this research project is to develop a new imaging method that uses a non-radioactive tracer, known as deuterium, which can be imaged with MRI. With this method deuterium-labelled glucose is used and its conversion to another metabolite, lactate, is measured, which does not accumulate in normal brain. We will test this imaging technique in rat models of the disease, which are created by implanting patient's tumour cells into their brains. We will use this new imaging technique to monitor the growth of these tumours and then their response to the current standard-of-care treatment, as well as a new treatment.

Potential applications and benefits
If successful, this research could be beneficial for patients and clinicians.
1. Patients will benefit from earlier diagnosis and detection of their cancer's response to treatment. We hope this will lead to a reduction in morbidity and mortality and an increase in survival.
2. Clinicians will benefit from detection of early response to treatment allowing for timely selection of the most appropriate treatment regime. This has associated cost benefits for the healthcare system and welfare benefits for the patients.
3. Pharmaceutical companies will be able to better assess the efficacy of their new drugs. The current estimated figure for developing a new medicine and bringing it to market is $500 million. This imaging modality may allow a more streamlined drug development process, which could bring down the cost of drugs for the healthcare system.

Aim
Detecting changes in tumour metabolism can give an earlier indication of treatment response when compared to conventional imaging. This project will explore deuterium magnetic resonance spectroscopic imaging (MRSI) as a novel, non-invasive imaging modality to detect and quantify treatment response in glioblastoma multiforme (GBM).

Objectives
1. We will investigate the potential of dynamic 2H MRSI for measuring tumour glycolytic and oxidative fluxes following administration of [6,6'-2H2] glucose to rats with orthotopically implanted xenografts derived from GBM patients.
2. We will use dynamic 2H MRSI measurements of glycolytic and oxidative fluxes to detect response to conventional chemoradiotherapy, as well as treatment with a novel blood brain barrier penetrating phosphatidylinositol 3-kinase (PI3K) inhibitor.

Methodology
GBM cells taken from patients will be cultured then implanted intracranially into athymic rats and tumour growth will be monitored using 1H MRI. [6,6'-2H2] glucose will be administered and dynamic 2H MRSI used to measure the time-dependent levels of 2H-labelled glucose, lactate, and glutamate/glutamine. Measurements will be made before and after treatment. Mass spectrometric imaging, histopathology and immunohistochemistry will provide gold-standard comparators for treatment response.

Scientific opportunities
Professor Brindle is a world leader in the field of metabolic imaging in cancer and has a multidisciplinary team with a wealth of experience in translational research. The CRUK Cambridge Institute has excellent facilities for histopathology, flow cytometry, genomics, microscopy, transgenic rodent and specialised imaging facilities. Prof. Brindle has an excellent track record of supervising clinical research fellows.

Medical opportunities
Honorary contracts at Addenbrooke's Hospital will be arranged to attend neuro-oncology multi-disciplinary meetings and outpatient clinics.