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University of California, San Francisco Principal Investigator - Mitchel S. Berger, MD
PROJECT 1 Three important goals of clinical research pertinent to glioma are to choose the best treatment available for each glioma patient, to enhance patient stratification so that new treatments can be more quickly and accurately evaluated, and to provide better information to patients and their families on what they can expect as a result of their disease. Unambiguous diagnosis is a cornerstone for each of these goals. Currently, however, glioma diagnosis is primarily based on assessments of tumor morphology, which are inherently subjective. There is an urgent need to identify tumor and patient characteristics that better define glioma subtype and patient prognosis. This proposed study will address this need by examining survival in relationship to several tumor markers which define genetic subtypes of gliomas, and which are thought to be potentially important in prognosis. In addition to consideration of known prognostic indicators such as age, the study also will consider survival as a function of patient characteristics including a variety of polymorphisms in DNA repair and carcinogen metabolizing genes, personal and family medical histories, diet, smoking and alcohol consumption prior to diagnosis, and other demographic factors such as education. Finally, this study proposes to validate results obtained from aim 2 in 100 newly diagnosed GM patients on clinical trial protocols at UCSF. The survival information derived from this study is expected to be useful to clinicians in planning and refining treatments while information from other factors will be useful in providing patients with a clearer picture of their probable outcomes based on their individual characteristics.
PROJECT 2 The objective of this study is to determine whether quantitative parameters derived from MRSI data are predictive of response to therapy for patients with gliomas. This is an important clinical question because gliomas are heterogeneous, infiltrative tumors with poorly defined margins. Although histological grade has been shown to be predictive of outcome in large scale clinical trials, there is considerable variability between tumors of the same grade in terms of response to therapy and time to progression. The identification of new factors that predict treatment response are critical for tailoring therapy to individual patient characteristics and are expected to have a significant impact upon the criteria used to select patients for future clinical trials. In our laboratory, we have used MRSI to derive a number of different quantitative parameters that are valuable for defining the metabolic activity and spatial extent of tumor. These include a choline to N-acetylaspartate index (CNI), a choline to creatine index (CCrI), a creatine to N-acetylaspartate index (CrNI) and a lactate plus lipid index (LLI). The present study will determine if these indices provide information that is clinically relevant for the management of gliomas and will determine, using patients on clinical trial protocols at UCSF, if there is a basis for integrating the technology into the design of future clinical trials.
PROJECT 3 High-grade gliomas remain a surgically incurable disease, largely because of infiltratative growth into surrounding normal brain. Radiotherapy and chemotherapy limited by inadequate tumor specificity, inherent and/or acquired resistance, and the inability to achieve effective exposure within the brain without causing excessive systemic toxicity. Better therapies must achieve efficient delivery of agents not only to the brain but via selective and efficient targeting to the tumor cells themselves. As part of our effort in the UCSF Breast Tumor SPORE, we have developed immunoliposome technology for receptor-targeted, intracellular drug delivery. We now seek to apply this technology to brain tumor treatment. In this proposal, liposomes will be desinged to contain a variety of toxic small molcules and nucleic acids. These liposomes will then be targeted to glioma cells by linkage to single chain antibodies specific for tumor cells expressing EGFR or mutant EGFR. These immunoliposomes will then be targeted to the brain using convention enhaned delivery. Following optimization and evaluation, we intend to move the most promising constructs into clinical trials in co-ordination with the Neuro-Oncology Service of the UCSF Neuro-Oncolgy program. This approach is expected to selectively increase drug delivery to brain tumors and to significantly impact on the therapy of otherwise untreatable gliomas.
PROJECT 4: Dysregulation of the phosphoinositide 3-kinase (PI3-kinase) signaling pathway plays a key role in the development of gliomas. Novel agents that inhibit elements within the PI3-kinase pathway have entered clinical trials, although to date there is no way to predict which tumor will respond to which kinase pathway inhibitor. The broad long-term objective of the proposed work is to utilize the molecular profile of individual tumors to guide therapy with effective, molecularly targeted treatments that will improve survival for glioma patients. To achieve this goal we must identify the most promising target for therapeutic inhibition, define the patient population likely to benefit from treatment with signaling inhibitors and validate the ability of molecular features to guide the choice of signaling inhibitor in the treatment of individual patients. To identify the signaling molecule whose inhibition is most likely to impact on patient survival, elements within the PI3-kinase cascade will be analyzed in diffuse gliomas of all grades. Molecules such as EGFR and PDGFR, that function upstream of PI3-kinase, and molecules such as mTOR and PKB that function downstream of PI3-kinase, will be characterized for each tumor and correlated with each other and with patient survival. In addition, we will define the subset of patients who are likely to benefit from inhibition of the PI3-kinase pathway. To validate the ability of molecular features to guide the choice of signaling inhibitor, we will analyze tumors from patients who are enrolled in currently open phase I clinical trials employing signaling inhibitors. The status of elements within the PI3-kinase pathway will be retrospectively correlated with tumor response to the novel agent. Furthermore, we propose a phase II trial in which we will prospectively examine the value of molecular profiling in selecting appropriate treatment for individual glioma patients. The choice of signaling inhibitor to be tested in this protocol will rest on the prevalence of the targeted aberration, the strength of its association with patient survival and any clinical response data that may arise from the completed phase I trials. In order to enhance the specificity of agents that inhibit the PI3-kinase pathway, we propose to incorporate into glioma therapy agents that target central elements of this signaling cascade. To this end we have developed approaches to specifically inhibit PI3-kinase or its immediate downstream effector PDK1. The delivery and efficacy of these agents will be tested in xenograft models of human gliomas with the goal of incorporating them into the multimodality treatment of glioma patients.
DEVELOPMENTAL PROJECT 1 Gliomas are among the most common malignancies of childhood and in adults. We have generated a model for oligodendrogliomas by over-expressing the oncogenic forms of EGFR (v-erbB) in oligodendroglial cells of transgenic mice. These animals develop oligodendrogliomas that are highly infiltrative, occur anywhere in the craniospinal axis, may be multiple in number, and show heterogeneity both in genetic complexity and in histopathologic grade. Their similarity to human oligodendrogliomas suggests that this mouse model for spontaneously arising oligodendrogliomas can serve as a valuable pre-clinical model for the treatment of patients with glioma. We intend to test whether neutral stem cells and primary neural stem cell populations are effective vehicles for delivery of therapy in a mouse model of spontaneously arising glioma, and to explore the utility of neural stem cells for delivery of anti-angiogenesis therapy in this mouse model.
CAREER DEVELOPMENT AWARD 1 Glioblastoma Multiformae (GBM) is a tumor with a devastating outcome and little in the way of non-surgical treatment modalities. A hallmark of GBM is the occurrence of high levels of neo-vascularization, paradoxically coupled to profound tumorigenic hypoxia. We hypothesize that reduction in oxygen and nutrient levels trigger two survival mechanisms in GBM cancer cells. First, they become more motile and migrate into normal tissues towards existing blood vessels. Second, they induce the formation of new blood vessels in hypoxic areas. Interference with any of these parameters should block vascularization and consequently tumor growth. We hope to reveal the biological significance of hypoxia and VEGF in GBM progression by generating tumors that are unable to induce HIF-1a or VEGF and compare their characteristics by morphological, cellular and molecular criteria. This project will therefore test the hypothesis that hypoxia and consequential VEGF induction is a critical event in GBM progression. The specific aims of the project are to investigate the impact of HIF-1a deficiency on GBM growth and invasiveness, and to investigate the impact of VEGF-A-deficiency on GBM growth and invasiveness.
CAREER DEVELOPMENT AWARD 2 The goal of the proposed project is to perform immunohistochemical assays of cellular proliferation, cellularity, and vascular volume on tissue biopsies from patients with glial tumors who underwent magnetic resonance spectroscopic imaging (MRSI), diffusion-weighted imaging, and perfusion imaging prior to surgery. The purpose of the study is to determine the relationship between the in vivo and ex vivo markers of malignancy and incorporate the information into optimized MR parameters that reflect the physiological features of malignant brain tissue. We propose to use the optimized MR parameters to generate image maps that highlight regions with the highest likelihood of containing aggressive tumor. We will develop a protocol for the interactive display of the image maps as color overlays on the anatomical MRIs used with the surgical navigation system so that the surgeon can retrieve functional information on specific brain regions on demand.
CORE 1 - ADMINISTRATIVE CORE The Administrative Core supervises the activities of the Brain Tumor Spore and provides fiscal management, administrative support, and the framework by which researchers can communicate and share data. These activities include the organization of weekly research meetings, an annual retreat, and meetings of the External Advisory Board and the SPORE steering committee, and meetings with other existing SPOREs at UCSF. The Administrative Core also provides the means by which project progress can be evaluated. The Administrative Core will also provide the infrastructure to administer the Career Development Program and the Developmental Research Program, and to provide accurate financial reporting for each investigator.
CORE 2 - TISSUE CORE The Neurological Surgery Tissue Bank is an organized repository of malignant and nonmalignant tissues from patients undergoing craniotomy for removal of tissue. Procedures have been designed to comply with the stringent requirements for informed consent, patient confidentiality, multiple users (requiring tissue conservation) and prioritization. This bank is directed by Dr. Deen, who meets with a Core Committee to consider requests for tissue, establish and review policy, resolve problems and address evolving issues relating to all issues pertaining to the Core's activities. The Tissue Bank Core in this grant application will provide services to each of the projects in the SPORE. Its aim is to distribute brain tumor tissue samples to SPORE investigators and to create tissue arrays from a variety of brain tumor types. These tissue arrays will be made available for research activities within and outside UCSF. Specifically, we propose to 1) collect and distribute tissue samples in support of the SPORE projects; 2) create and distribute tissue arrays from glioblastoma, oligodendroglioma, and meningioma tumors; and 3) supply clinical correlative/follow up data on distributed samples and arrays.
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