New imaging methods for detecting brain tumour response to treatment
Lead Research Organisation:
University of Cambridge
Department Name: Biochemistry
Abstract
Patients with similar tumour types frequently have markedly different responses to the same
therapy. The development of new treatments would benefit, therefore, from the introduction of imaging methods that allow an early assessment of treatment response, allowing rapid selection of the most effective treatment, with welfare benefits for the patient and cost benefits for the healthcare system. Beneficial responses to treatment are still largely assessed from imaging measurements of reductions in tumour size. However, this may take several weeks to become manifest.
Time is critical in the common brain tumour, glioblastoma multiforme, where the chance of being alive after 2 years is 16%. The aim of this research project is to develop imaging methods, which could be used in a hospital setting to detect the early responses of brain tumours to therapy. Firstly, by using a novel magnetic resonance (MR) method that detects a beneficial response to treatment through changes in chemical reactions within tumours. Secondly, by a novel image processing method in which a beneficial response to treatment is detected through changes in the wholeness of images. Here, MR images from patients are assessed.
A radiologist will perform the research under the guidance of an experienced research imaging scientist.
therapy. The development of new treatments would benefit, therefore, from the introduction of imaging methods that allow an early assessment of treatment response, allowing rapid selection of the most effective treatment, with welfare benefits for the patient and cost benefits for the healthcare system. Beneficial responses to treatment are still largely assessed from imaging measurements of reductions in tumour size. However, this may take several weeks to become manifest.
Time is critical in the common brain tumour, glioblastoma multiforme, where the chance of being alive after 2 years is 16%. The aim of this research project is to develop imaging methods, which could be used in a hospital setting to detect the early responses of brain tumours to therapy. Firstly, by using a novel magnetic resonance (MR) method that detects a beneficial response to treatment through changes in chemical reactions within tumours. Secondly, by a novel image processing method in which a beneficial response to treatment is detected through changes in the wholeness of images. Here, MR images from patients are assessed.
A radiologist will perform the research under the guidance of an experienced research imaging scientist.
Technical Summary
Aim
The aim of this research project is to develop non-invasive and clinically applicable imaging methods for detecting the early responses of brain tumours to therapy. Firstly, by using a novel magnetic resonance (MR) method that increases sensitivity in the MR experiment by >10,000x and which detects treatment response in rodent models through specific changes in tumour metabolism. Secondly, by a novel image processing method in which treatment response is detected through changes in image heterogeneity. Here, clinical MR images will be assessed.
Objectives
Objectives for the hyperpolarizer experiments are, using rat glioblastoma multiforme (GBM) controls and cases pre- and 1-5 days post-treatment (an alkylating cytotoxic, a tyrosine kinase inhibitor, a PI3K-akt-mTOR inhibitor, an anti-angiogenic) to measure [1-13C]lactate levels and lactate dehydrogenase catalyzed flux from [1-13C]pyruvate; [1,4-13C2]malate levels and fumarase catalyzed flux from [1, 4-13C2]fumarate; extracellular pH from H13CO3-.
The objective for the image analysis project is to develop and evaluate Minkowski Functional analysis for detecting treatment response in a clinical dataset acquired from patients with GBM treated with radiotherapy and concomitant and adjuvant temozolomide - in particular to differentiate pseudoprogression from true progression.
Design
MATLAB software will be used to segment and perform Minkowski Functional analysis on clinical MR images of patients with GBM.
Methodology
Cells will be cultured then implanted intracranially using stereotactic techniques. Syngeneic F98 cells will be implanted into Fischer rats and human GBM xenografts will be implanted into athymic rats. Hyperpolarized samples will be prepared using a Hypersense dynamic nuclear polarizer. Samples will be infused intravenously and MR spectroscopy will be used to measure the metabolites produced. Histopathology and immunohistochemistry will provide gold standard comparators for treatment response. Apoptosis and necrosis will be examined using TUNEL and haematoxylin and eosin. HIF-1, carbonic anhydrase IX, VEGF, CD31 and LDHA will be measured.
Scientific opportunities
Prof Brindle‘s laboratories include histopathology, flow cytometry, genomics, microscopy, transgenic rodent facilities and imaging. The latter includes fluorescent and bioluminescent imaging, high field MRI machines, Hypersense and prototype DNP hyperpolarizers, high-resolution ultrasound and micro PET/SPECT/CT. The laboratories comprise 22 research staff and students. In a recent CRUK quinquennial laboratory review, work on hyperpolarized 13C was rated outstanding, as was his proposed polarizer work for the next 5 years.
Medical opportunities
Honorary contracts for the National Hospital for Neurology and Neurosurgery, London and Addenbrookes, Cambridge are arranged to allow attendance at neuroradiology clinical sessions and brain tumour multi-disciplinary meetings.
The aim of this research project is to develop non-invasive and clinically applicable imaging methods for detecting the early responses of brain tumours to therapy. Firstly, by using a novel magnetic resonance (MR) method that increases sensitivity in the MR experiment by >10,000x and which detects treatment response in rodent models through specific changes in tumour metabolism. Secondly, by a novel image processing method in which treatment response is detected through changes in image heterogeneity. Here, clinical MR images will be assessed.
Objectives
Objectives for the hyperpolarizer experiments are, using rat glioblastoma multiforme (GBM) controls and cases pre- and 1-5 days post-treatment (an alkylating cytotoxic, a tyrosine kinase inhibitor, a PI3K-akt-mTOR inhibitor, an anti-angiogenic) to measure [1-13C]lactate levels and lactate dehydrogenase catalyzed flux from [1-13C]pyruvate; [1,4-13C2]malate levels and fumarase catalyzed flux from [1, 4-13C2]fumarate; extracellular pH from H13CO3-.
The objective for the image analysis project is to develop and evaluate Minkowski Functional analysis for detecting treatment response in a clinical dataset acquired from patients with GBM treated with radiotherapy and concomitant and adjuvant temozolomide - in particular to differentiate pseudoprogression from true progression.
Design
MATLAB software will be used to segment and perform Minkowski Functional analysis on clinical MR images of patients with GBM.
Methodology
Cells will be cultured then implanted intracranially using stereotactic techniques. Syngeneic F98 cells will be implanted into Fischer rats and human GBM xenografts will be implanted into athymic rats. Hyperpolarized samples will be prepared using a Hypersense dynamic nuclear polarizer. Samples will be infused intravenously and MR spectroscopy will be used to measure the metabolites produced. Histopathology and immunohistochemistry will provide gold standard comparators for treatment response. Apoptosis and necrosis will be examined using TUNEL and haematoxylin and eosin. HIF-1, carbonic anhydrase IX, VEGF, CD31 and LDHA will be measured.
Scientific opportunities
Prof Brindle‘s laboratories include histopathology, flow cytometry, genomics, microscopy, transgenic rodent facilities and imaging. The latter includes fluorescent and bioluminescent imaging, high field MRI machines, Hypersense and prototype DNP hyperpolarizers, high-resolution ultrasound and micro PET/SPECT/CT. The laboratories comprise 22 research staff and students. In a recent CRUK quinquennial laboratory review, work on hyperpolarized 13C was rated outstanding, as was his proposed polarizer work for the next 5 years.
Medical opportunities
Honorary contracts for the National Hospital for Neurology and Neurosurgery, London and Addenbrookes, Cambridge are arranged to allow attendance at neuroradiology clinical sessions and brain tumour multi-disciplinary meetings.
