Current Research Grants
Prognostic Value of MRSI Parameters for Patients with Gliomas
Principal Investigator: Sarah J. Nelson
P50 SPORE CA 97257

Abstract
DESCRIPTION (provided by applicant): This application represents the efforts of interdisciplinary teams of investigators from the Neuro-Oncology Program of the UCSF Cancer Center to apply their knowledge and expertise to translational research focused on brain tumors. The heart of the proposal is four translational research projects, each driven by pairs of applied and basic researchers, and each intended to create novel tools and therapies potentially useful in the treatment of human brain tumors. Project One focuses on the use of population science to find factors important in glioma patient survival. Project Two focuses on the use of sophisticated spectroscopic techniques to improve diagnosis and surgical resection of tumors. Project Three focuses on the development of liposomal drug delivery to improve the therapy of gliomas, while Project Four intends to characterize signal transduction cascades as a means of guiding glioma therapy. The proposal also includes support mechanisms for Career Development Research Programs, Developmental Research Programs, and 2 Cores that will support all aspects of the work proposed. Each project draws on the extensive experience of the investigators in the brain tumor field and on the long history of the UCSF Department of Neurosurgery and the UCSF Brain Tumor Research Center in translational research. The projects will be additionally strengthened by collaborations between researchers and other scientists in the UCSF Cancer Center, and (particularly in the case of Project Three), with scientists involved with the existing UCSF Breast Tumor SPORE. Finally, as a leading center of brain tumor clinical trials in America, an infrastructure already in place in the Department of Neurosurgery will allow the rapid clinical translation of important scientific breakthroughs. The UCSF Brain Tumor SPORE is led by Mitchel Berger, MD, a nationally recognized leader in neurosurgery and translational brain tumor research. The clinical Co-PI of this proposal is Michael Prados, MD. Dr. Prados is head of the North American Brain Tumor Consortium, and a Principal Investigator of the Pediatric Brain Tumor Consortium. He is a recognized leader in the development and implementation of clinical trials, and is ideally suited to carry our findings to the clinic. The clinical expertise, along with the strong laboratory-based research climate at UCSF, suggest that the work proposed will lead to significant progress in the treatment of brain tumors. Current Research Grants Prognostic Value of MRSI Parameters for Patients with Gliomas Principal Investigator: Sarah J. Nelson P50 SPORE CA 97257 Abstract DESCRIPTION (provided by applicant): This application represents the efforts of interdisciplinary teams of investigators from the Neuro-Oncology Program of the UCSF Cancer Center to apply their knowledge and expertise to translational research focused on brain tumors. The heart of the proposal is four translational research projects, each driven by pairs of applied and basic researchers, and each intended to create novel tools and therapies potentially useful in the treatment of human brain tumors. Project One focuses on the use of population science to find factors important in glioma patient survival. Project Two focuses on the use of sophisticated spectroscopic techniques to improve diagnosis and surgical resection of tumors. Project Three focuses on the development of liposomal drug delivery to improve the therapy of gliomas, while Project Four intends to characterize signal transduction cascades as a means of guiding glioma therapy. The proposal also includes support mechanisms for Career Development Research Programs, Developmental Research Programs, and 2 Cores that will support all aspects of the work proposed. Each project draws on the extensive experience of the investigators in the brain tumor field and on the long history of the UCSF Department of Neurosurgery and the UCSF Brain Tumor Research Center in translational research. The projects will be additionally strengthened by collaborations between researchers and other scientists in the UCSF Cancer Center, and (particularly in the case of Project Three), with scientists involved with the existing UCSF Breast Tumor SPORE. Finally, as a leading center of brain tumor clinical trials in America, an infrastructure already in place in the Department of Neurosurgery will allow the rapid clinical translation of important scientific breakthroughs. The UCSF Brain Tumor SPORE is led by Mitchel Berger, MD, a nationally recognized leader in neurosurgery and translational brain tumor research. The clinical Co-PI of this proposal is Michael Prados, MD. Dr. Prados is head of the North American Brain Tumor Consortium, and a Principal Investigator of the Pediatric Brain Tumor Consortium. He is a recognized leader in the development and implementation of clinical trials, and is ideally suited to carry our findings to the clinic. The clinical expertise, along with the strong laboratory-based research climate at UCSF, suggest that the work proposed will lead to significant progress in the treatment of brain tumors.

Related Articles

Response to Fractioned Radiation Therapy by MRSI
Principal Investigator: Sarah J. Nelson
R01 CA59880

Abstract
DESCRIPTION (provided by applicant): Magnetic Resonance Spectroscopic Imaging (MRSI) is an in vivo molecular imaging technique that has been proposed for defining tumor burden for patients with gliomas. The current funding cycle has demonstrated that MRSI is superior to conventional MR imaging for predicting outcome and following response to Gamma Knife Radiosurgery (GK-RS) in recurrent gliomas. The objective in the next funding cycle is to make this technology more generally applicable by investigating the application of MRSI to the evaluation of fractionated radiation therapy. This treatment is used as a follow-up to surgical resection for almost all newly diagnosed malignant gliomas. New approaches such as Intensity Modulated Radiation Therapy (IMRT) have made it possible to treat irregular 3-D volumes accurately and reproducibly in a highly conformal manner. Critical factors for realizing the potential of IMRT and for understanding its limitations are the ability to determine whether treatment failure is due to inadequate targeting or to an intrinsic lack of sensitivity to radiation. This represents a complex problem in gliomas because of the heterogeneity of the lesion and the spatial variations in radiation dose to the tumor and surrounding brain tissue. Specific Aim 1 will address the optimization of data acquisition and reconstruction parameters. This will include the investigation of the use of a 3T MR scanner rather the standard 1.5T clinical system for obtaining the anatomic and metabolic data. Specific Aim 2 will involve the development of algorithms for quantitative analysis of the MRSI data and correlation with serial MR images. The final Specific Aim will apply the new technology to the serial evaluation of 60 patients with malignant gliomas who are being treated at UCSF with fractionated radiation therapy. Using the MRSI data to guide and evaluate such focal therapy is expected to have a major impact upon treatment effectiveness and ultimately upon patient outcome.

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Tools for Improved Radiation Treatment Planning using MRSI
Principal Investigator: Sarah J. Nelson
R21 CA110171

Abstract
DESCRIPTION (provided by applicant) The objective of this study is to combine the efforts of MR scientists and radiation oncologists at the University of California at San Francisco (UCSF) with engineers at General Electric Medical Systems (GEMS) in developing data acquisition, reconstruction and post-processing capabilities for integrating Magnetic Resonance Spectroscopic Imaging (MRSI) data into radiation treatment planning for cancer patients. The motivation for this translational research has come from recent improvements in radiation treatment delivery systems that are able to conform dose very precisely to irregularly shaped 3-D targets. MRSI research studies at UCSF have shown that the spatial extent of the metabolic abnormality is often significantly different from the lesion observed with conventional MR imaging and that this is likely to have a major impact upon target definition. As a result of the studies at UCSF and supporting data from other institutions, the Radiation Therapy Oncology Group (RTOG) has proposed a multi-center clinical trial of the value of MRSI in targeting gliomas. A prerequisite for performing this study is the translation of the technology into robust tools that are available on clinical MR scanners and that integrate MRSI into the treatment planning process in a timely and efficient manner. This requires active participation from the manufacturer of the MR scanner. The scientists and clinicians at UCSF have already demonstrated the ability to form a partnership with GEMS in developing MRSI packages. This experience will now be directed towards a developing a prototype package for integrating MRSI into radiation treatment planning of brain tumors. Although this R21 project will focus on a single tumor site, the package will be constructed in a modular fashion so that the tools developed can be adapted to other types of tumors and used in conjunction with multiple imaging and treatment platforms.

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Multimodal MRI and Spectroscopy of Irradiated Brain
Principal Investigator: Sarah J. Nelson
CA105944

Abstract
Proton magnetic resonance spectroscopic imaging has been demonstrated to have significant clinical potential for the noninvasive localization brain tumors. In vivo spectroscopic measurements have revealed changes in brain metabolites that can be used to classify tissues as healthy or cancerous. However, it has been shown that radiation therapy changes the metabolite levels in healthy tissue, thus making it more difficult to distinguish between healthy tissue and tumor using spectroscopy alone. To overcome this problem, this research will study the integration of spectroscopy with diffusion and perfusion imaging into an automated tissue classification system. The time- and dose-response of radiation-induced changes in healthy brain tissue will be assessed by analyzing serial spectroscopic, diffusion, and perfusion imaging data from patients undergoing radiation therapy. The abnormality of a given volume of tissue will then be defined as the difference between the measured and expected values for a given parameter. An overall abnormality index will then be computed from a combination of spectroscopic, diffusion, and imaging parameters. It is hypothesized that this will improve the accuracy in identifying tumor in post-radiotherapy examinations compared with conventional imaging or MRSI alone. This will allow clinicians and researchers to better understand patterns of failure following radiotherapy of high grade gliomas, and adjust accordingly.

Evaluation of Non-invasive Biomarkers using in vivo High Field MR Imaging and Spectroscopy
Principal Investigator: Sarah J. Nelson
UC Discovery Grant: Itl 10148

Abstract
The objective of this proposal is to develop and implement high field Magnetic Resonance Imaging (MRI) and multi-nuclear Magnetic Resonance Spectroscopic Imaging (MRSI) methods for measuring quantitative, non-invasive biomarkers for basic and translation research. This will integrate the expertise of researchers from UCSF and UCB who are members of the Institute for Quantitative Biomedical Research (QB3) with engineers at the California based research and development laboratories of General Electric Healthcare Technologies (GEH). The increase in signal to noise ratio and higher spectral resolution associated with whole body 3T and 7T scanners is critical for the practical implementation of techniques that visualize the functional and metabolic properties of tissue and for achieving the improvements in sensitivity and specificity necessary for diagnosis and monitoring response to therapy. The study will expand and extend upon preliminary results, data reconstruction algorithms and post-processing software that have been developed as part of an ongoing UC Discovery grant between these partners and have clearly demonstrated the benefits of the 3T scanner, especially when used in conjunction with multi-channel radiofrequency coils and parallel imaging techniques. Advances in the hardware and software associated with the 3T and 7T scanners will allow even greater benefits in terms of the acquisition capabilities. Other studies that will contribute to the identification of new biomarkers will be based upon 1-D and 2-D high resolution magic angle spinning spectroscopy (HR-MAS) of ex vivo samples from human and animal tissues. These will be used to investigate the potential of using P-31 metabolites and C-13 labeled tracers for in vivo applications. The long term goal of the partnership between UCSF, UCB and GEHT is to provide new tools for quantifying changes in normal physiology and abnormalities associated with common diseases such as cancer, osteoporosis, arthritis and multiple sclerosis. In addition to addressing a large number of problems that are important to the California economy, the investigators participating in this study will develop training programs for students and postdoctoral fellows in the design and practical applications of high field, whole body MR scanners with respect to biological and biomedical research.

Non-Technical Abstract

3D MR Spectroscopic Imaging of the Newborn Brain
Principal Investigator: Daniel Vigneron
R01NS40117

Abstract
Brain injury in term and preterm neonates is a serious problem. Of the approximately 42,000 infants born yearly in the United States with a birth weight less than 1500 g, approximately 85 percent survive and, of these, 5-10 percent exhibit major motor deficits and another 25-50 percent exhibit developmental and visual difficulties. Hypoxia and ischemia frequently occur during the birth process; however, the amount of brain damage in these patients and the long-term neurologic outcome varies considerably from patient to patient. There is a need, particularly in this group, to identify new clinical diagnostic tools that will improve early prediction of neurodevelopmental abnormalities and therefore allow for pharmacological interventions. The goal of this bioengineering research project is to develop and implement advanced Magnetic Resonance spectroscopic imaging techniques to detect the distribution of metabolite levels throughout the brain of neonates. Studies by ourselves and others have indicated an important role for single voxel MRS in the assessment of the neurologic status of neonates, especially premature infants and those with suspected neonatal hypoxia. However, these techniques provide very limited coverage of the brain and at poor spatial resolution. In this study, we propose to develop and optimize MRSI techniques to provide, for the first time, a study of the 3D distribution of metabolite levels in the newborn brain. This information will define the normal variation in metabolite levels with anatomic location and post-conceptional age. The database of normal MRSI spectra will improve our understanding of brain development and provide a reference for detecting abnormal metabolism in neonatal patients with neurologic damage. Current methods are inaccurate for assessing the cerebral metabolism of newborns. Through this project, we aim to develop a noninvasive metabolic imaging technique to address this important problem.