Specialized Programs of Research Excellence (SPORE) Grant
National Institutes of Health
 
UCSF Brain Tumor SPORE
Principal Investigator: Mitchel S. Berger MD
Co-Principal Investigator: Clinical Science: Michael D. Prados MD
Co-Principal Investigator: Basic Science: Russell O. Pieper PhD
Total Project Period: 8/01/07-7/31/12
 
SPORE: Concept and Objectives*
Specialized Programs of Research Excellence (SPOREs) were conceived and implemented by the National Cancer Institute (NCI) in 1992 through a special appropriation from Congress to promote translational research focused on an organ-specific human cancer (e.g., breast cancer) or a highly related group of human cancer types (e.g., gastrointestinal). SPOREs are intended to foster interactions between basic scientists and applied scientists and to provide them with the flexibility to rapidly test new approaches to the prevention, early detection, diagnosis and treatment of human cancer. Translational research, for purposes of the SPORE program, is defined as research that uses knowledge of human biology to develop and test the feasibility of cancer-relevant interventions in humans and/or determines the biological basis for observations made in individuals with cancer or in populations at risk for cancer. The term "interventions" is used in its broadest sense to include molecular assays, imaging techniques, drugs, biologicals and/or other methodologies that are relevant to the prevention, early detection, diagnosis, prognosis or treatment of cancer. While the SPORE program initially funded four breast cancer SPOREs, two prostate cancer SPOREs and two lung cancer SPOREs, the program was expanded to include brain tumors beginning in 2002.
 
*Reproduced in part and adapted from the Web site: Guidelines. Specialized Programs of Research Excellence (SPOREs). Organ Systems Branch Office of Centers, Training, and Resources Office of Deputy Director for Extramural Sciences National Cancer Institute. (accessed 12/31/02).
 
SPORE Brain Tumor Research at UCSF
Since the 1940s, investigators in the UCSF Department of Neurological Surgery have been engaged in what today would be known as translational research. The creation of the BTRC in 1972 formalized this commitment to translational brain tumor research, strengthened the translational brain tumor research community, and led directly to the creation of what today is one of the premier neurological oncology programs in the United States. It was only logical, therefore, in response to the announcement of NIH funding for Specialized Programs in Research Excellence in brain tumors, that the BTRC would take the lead in formulating an application highlighting the best of translational brain tumor research at UCSF. In meetings over a nearly 2-year period, BTRC investigators and the UCSF brain tumor community as a whole developed and evaluated over 15 translational projects. After consultation with an external advisory board that consisted of experts in the SPORE process and translational brain tumor research, including Margaret Temporo, Howard Fine, and Webster Cavenee, four projects were selected and the application was created and submitted. The hard work, commitment, and dedication of all those involved in the SPORE process, as well as the dedicated translational researchers who came before them, was rewarded by the funding of this proposal beginning in August 2002.
 
Today, five translational projects are supported by the SPORE grant. All are shared efforts between applied and basic scientists, and all are focused on improving the diagnosis and treatment of brain tumors by applying laboratory advances in the clinical setting. They represent a diversity of research areas, including population science, research neuroimaging, molecular research of signaling pathways important in glioma, and developmental therapeutics with novel delivery systems. Because the future of brain tumor research at UCSF and nationwide relies upon the recruitment of new investigators to the field, a Career Development Research Program is also included in the SPORE to identify, support, and encourage new and young investigators doing translational brain tumor research. A Developmental Research Program is also included to provide initial funding of promising projects, which over a 2-year period may develop into full SPORE projects. Finally, an Administrative Core and Tissue Bank Core are included to provide administrative support and access to tissues required for the success of the translational projects proposed.
 
Specific Translational Research Objectives
 
Project 1: San Francisco Bay Area Adult Glioma Survival Study
Principal Investigator: Margaret Wrensch PhD
Clinical Co-Principal Investigator: Michael Prados MD
Three important goals of clinical research pertinent to glioma are to choose the best treatment available for each patient, to enhance stratification of patients 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 characteristics of tumors and patients that better define glioma subtype and prognosis. This project will address this need by examining survival in relationship to several tumor markers that define genetic subtypes of gliomas, and 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 patients' characteristics, including a variety of polymorphisms in DNA repair and carcinogen metabolizing genes, personal and family medical histories, diet, smoking and alcohol consumption before diagnosis, and other demographic factors such as education. Finally, this project proposes to validate results obtained in 100 newly diagnosed patients with glioblastoma multiforme on clinical trial protocols at UCSF. The survival information derived from this project 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: Prognostic Value of MRSI Parameters for Patients with Glioma
Principal Investigator: Sarah Nelson PhD
Clinical Co-Principal Investigator: Susan Chang MD
The objective of this project is to determine whether quantitative parameters derived from magnetic resonance spectroscopy imaging (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 patients' characteristics and are expected to have a significant impact on 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). This project 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: Development of Novel Targeted Therapeutics for Brain Tumor Treatment
Principal Investigator: John Park MD
Clinical Co-Principal Investigator: Mitchel Berger MD
Newer, more targeted therapies are needed for brain tumor treatment. Radiation therapy and chemotherapy are 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 also through selective and efficient targeting to the tumor cells themselves. Based on our previous work, we have developed immunoliposome technology for receptor-targeted, intracellular drug delivery. We are now applying this technology to brain tumor treatment. In this project, liposomes will be designed to carry various toxic small molecules or nucleic acid constructs that are potent agents against brain tumors. These liposomes will then be targeted to glioma cells by linkage to antibody fragments specific for tumor cells expressing epidermal growth factor receptor (EGFR) or mutant EGFR. In close collaboration with Dr. Krys Bankiewicz, these liposomes and immunoliposomes will be administered into the brain by using convection-enhanced delivery. Further development will be directed toward moving the most promising constructs into clinical trials in coordination with the Neuro-Oncology Service of the UCSF Neuro-Oncology Program. This approach is expected to selectively increase drug delivery to brain tumors and to have a significant impact on the therapy of otherwise untreatable gliomas. Dr. Park is also a Principal Investigator of a project in the UCSF Breast Tumor SPORE that concerns the creation of immunoliposomes specifically designed for use in the treatment of metastatic breast cancer.
 
Project 4: Exploiting the PI3-Kinase Pathway in Human Glioma Therapy
Principal Investigator: David Stokoe PhD
Clinical Co-Principal Investigator: Daphne Haas-Kogan MD
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 this pathway are in clinical trials, although to date it is not known which tumor will respond to which kinase pathway inhibitor. Our goal is to use the molecular profile of individual tumors to guide therapy with molecularly targeted treatments that will improve survival for patients with glioma. To achieve it, we must identify the most promising target for therapeutic inhibition, define the population most likely to benefit from treatment with signaling inhibitors, and validate the ability of molecular features to guide the choice of signaling inhibitor in individual patients. To identify the signaling molecule whose inhibition is likely to affect survival, elements within the PI3-kinase cascade will be analyzed in diffuse gliomas of all grades. We will characterize molecules that function upstream and downstream of PI3-kinase for each tumor and correlate those molecules with each other and with patients' survival. We will also define the patients most 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 enrolled in phase I clinical trials that include signaling inhibitors. The status of elements within the PI3-kinase pathway will be retrospectively correlated with tumor response to the novel agent. We plan a phase II trial to examine the value of molecular profiling in selecting treatment for individual patients with glioma. The choice of signaling inhibitor tested will rest on prevalence of the targeted aberration, the strength of its association with patients' survival, and clinical response data from completed phase I trials. To enhance the specificity of agents that inhibit the PI3-kinase pathway, we will incorporate into 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. We will test delivery and efficacy of these agents in xenograft models of human gliomas with the goal of incorporating them into the multimodality treatment of patients.
 
Project 5: Heat Shock Protein Vaccine Development
Principal Investigator: Andrew Parsa MD, PhD
Clinical Co-Principal Investigator: Russell Pieper PhD
This project evaluates biological factors affecting the successful application of a brain tumor vaccine and will provide helpful data to optimize clinical trials of future vaccines. The project evolved from Career Development and Developmental Research Awards to Andrew Parsa MD, PhD and Russell Pieper PhD. Dr. Parsa was originally funded by a UCSF Brain Tumor SPORE Career Development Award to study the immuno-modulatory actions of B7H1, a cell surface protein he showed to suppress T-cell function and play a role in the escape of gliomas from immunosurveillance. As these studies were being completed, results from a separate UCSF Brain Tumor SPORE Developmental Project awarded to Dr. Pieper showed that levels of pAkt were strong predictors of the response of glioma cells to pro-apoptotic agents. By collaborating, these two investigators were able to show that high levels of pAkt enhances B7H1 expression in vitro, and thereby suppress apoptosis induced by the immune system as well as by exogenous agents. Given that B7H1 played a key role in the sensitivity of gliomas to immune-based cell killing, pAkt levels could influence the sensitivity of immune-mediated cell killing stimulated by vaccines, and a better understanding of the relationship between pAkt levels and B7H1 expression in the clinical setting might provide the means for development of better vaccines and better stratification of patients for such therapy. The development of a heat shock protein vaccine in the Parsa lab (supported by a UCSF Brain Tumor SPORE Developmental Research Award and a partnership with Antigenics, Inc) provides the opportunity to address the role of pAkt-mediated B7H1 regulation in vaccine responsiveness.
 
 
Career Development Awardees
 
Soonmee Cha PhD
Assistant Professor of Neuroradiology and Neurological Surgery
Principal Investigator, BTRC
Project Title: Validation of neuroimaging biomarkers of gliomas using molecular and genetic analysis of image-guided tissue biopsy
 
J. Graeme Hodgson PhD
Assistant Professor of Neurological Surgery
Principal Investigator, BTRC
Project Title: Characterization of microRNAs in astrocytomas
 
Andrea Pirzkall PhD
Assistant Adjunct Professor of Radiation Oncology
Project Title: Characterization of tumor heterogeneity in patients with newly diagnosed glioblastoma multiforme using MR-based metabolic and physiologic imaging: implications for optimizing radiation therapy and targeted therapy in general
 
Previous Career Development Awardees
 
Nalin Gupta MD, PhD
Assistant Professor of Neurological Surgery
Principal Investigator, BTRC
Project Title: Tumor-associated inflammation as a new target for glioma therapy
Funding Agency: National Cancer Institute/SPORE
Project Summary: Transformed astrocytes and conventional radiation therapy or chemotherapy independently activate components of the general inflammatory response through direct cytotoxic effects and a number of poorly defined interactions with the host microenvironment. Some of these interactions contribute to the injury of normal tissue by worsening brain edema and by activating mediators of inflammation. No effective therapeutic agent has been developed specifically to treat the effects of inflammation in patients with brain tumors. Preliminary data implicate a specific cytokine, monocyte chemoattractant protein (MCP-1), as a key participant in the inflammatory response. MCP-1 is produced by many cell types, functions as a "homing factor for cells involved in the inflammatory response (macrophages), and is consistently overexpressed in malignant glioma. The receptor for MCP-1, CC chemokine receptor 2 (CCR2) is also overexpressed in malignant glioma. These findings suggest that cytokines may also function as positive regulators of growth in tumor cells.
 
Frederick Gorin PhD
Neurosurgery, University of California, Davis
Project Title: The development of novel therapeutic agents directed towards preventing tumor recurrence in malignant gliomas
Funding Agency: National Cancer Institute/SPORE
 
Gabriele Bergers PhD
Assistant Professor of Neurological Surgery
Principal Investigator, BTRC
Project Title: Hypoxia and Neovascularization: Cause or Consequence of Glioblastoma Multiforme Progression?
Funding Agency: Sidney Kimmel Foundation/National Cancer Institute/SPORE
Co-Investigator: Dr. Randall Johnson
Project Summary: A specific feature of glioblastoma multiforme (GM) progression is the formation of a necrotic center due to reduced oxygen and nutrient levels. Consequently, these hypoxic conditions are able to trigger the formation of new blood vessels by inducing hypoxia-inducible transcription factors (HIF-1), which in turn induce proangiogenic molecules, including vascular endothelial growth factor (VEGF-A) and its receptors, allowing the tumor to co-opt and progress. We hope to reveal the biological significance of hypoxia and VEGF in GM progression by generating tumors that are unable to induce HIF-1 α or VEGF and comparing their characteristics. This will help to elucidate hypoxia-induced tumor-promoting pathways that are distinct from the hypoxia-induced VEGF pathways and help shed light on the importance of these factors in GM progression.
 
Tracy Richmond McKnight PhD
Assistant Professor of Radiology
Principal Investigator, BTRC
Project Title: Correlation of MRS Features of Glioma with Tumor Markers
Funding Agency: National Cancer Institute/SPORE
Project Summary: Magnetic resonance spectroscopy (MRS) is currently used to aid in the clinical management of patients with glial tumors. Magnets with field strength greater than 1.5 Tesla are beginning to be used for both clinical and research purposes. We will investigate the difference between the high-field MRS signature of normal and transformed cells in culture by using high-resolution magic angle spinning (HRMAS) MRS. Recent data from our laboratory show that normal brain, oligodendroglioma, and astrocytoma each have different MRS profiles. We have designed a series of HRMAS experiments to investigate whether such differences are observed in cultured cell models of normal and transformed brain, and whether the MRS signature is more reflective of the genetic features or morphologic features of the cells.
 
Developmental Research Awardees
 
Joseph Costello PhD
Assistant Professor of Neurological Surgery
Principal Investigator, BTRC
Project Title: Reversing hypomethylation and aberrant gene activation in glioblastoma multiformes via folate
 
James Rubenstein MD, PhD
Assistant Professor of Medicine in Residence, Divison of Hematology/Oncology
Project Title: CSF biomarkers of brain tumors
 
Russell Pieper PhD
Associate Professor and Vice Chair of Neurological Surgery
Principal Investigator, BTRC Project Title: Determining and predicting tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity in primary glioblastoma multiforme
 
Previous Developmental Research Awardees
 
Joseph Costello PhD
Assistant Professor of Neurological Surgery
Principal Investigator, BTRC
Project Title: New targets for therapy of glioblastoma multiforme unmasked by demethylation
Funding Agency: National Cancer Institute/SPORE
Project Summary: Methylation is required in normal brain cells for chromosome stability and the repression of gene expression. Glioblastoma multiforme (GBM) tumorigenesis is known to be accompanied by a genome-wide loss of methylation, but the exact genomic regions affected and the downstream consequences of demethylation are not known. We propose that the loss of methylaion occurs in part on gene promoters, which leads to gene reactivation that in turn has two possible consequences, depending on the type of gene that is affected. First, if the promoter gene is a positive regulator of cell growth (i.e., an oncogene), then the hypomethylation-induced gene reactivation will contribute to increased cell proliferation. Second, if the promoter gene is normally silent in all types of normal brain-cell types, then the gene activation will result in expression of a protein that is not present in normal brain cells and is tumor-specific; such demethylation of genes silent in normal brain cells has been shown in studies of melanoma in which the melanoma antigen (MAGE) gene is activated by tumor-specific hypomethylation.
 
Collin Collins PhD
Cancer Center
Project Title: Identification of chimeric transcripts in brain tumors using end sequence profiling
Funding Agency: National Cancer Institute/SPORE
 
Russell Pieper PhD
Associate Professor and Vice Chair of Neurological Surgery
Principal Investigator, BTRC Project Title: Determining and predicting tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity in primary glioblastoma multiforme
Funding Agency: National Cancer Institute/SPORE
 
Andrew T. Parsa MD, PhD
Assistant Professor of Neurological Surgery
Principal Investigator, BTRC
Project Title: Antigen-Specific Modeling of Glioma Immunotherapy
Funding Agency: National Cancer Institute/SPORE
Co-Investigator: Abul K. Abbas MD
Collaborators: Drs. Lawrence Fong, Sang-Mo Kang, Lewis Lanier
Project Summary: Immunotherapy depends on evoking an immune response with tumor-related antigens. Clinical protocols designed to treat glioma to date have been uniformly unsuccessful, suggesting that the preclinical model systems used to test them are inherently flawed. Our preliminary results established the need for a more appropriate model system for studying mechanisms of efficacy in glioma immunotherapy. Our project is designed to study basic tenets of immunology while providing readily translatable treatment plans. A murine model of glioma generated from transgenic strains engineered to overexpress oncogenic V12Ha-ras in astrocytes will be used. In the murine system, V12Ha-ras can cause expansion of MHC restricted specific T-cells readily detected by tetramer analysis. For the first time, we have a relevant glioma model for immunotherapy to investigate the following: T-cell trafficking in the CNS; antigen presenting cells in the CNS; epitope spreading in antiglioma immunity; in-vivo loading of dendritic cells.
 
William A. Weiss MD, PhD
Assistant Professor of Neurology, Neurological Surgery, & Pediatrics
Principal Investigator, BTRC
Project Title: Stem Cells as Delivery Agents in the Treatment of Glioma
Funding Agency: National Cancer Institute/SPORE
Collaborators: Drs. Arturo Alvarez-Buylla, Evan Snyder, Karen Aboody
Project Summary: We have generated a model for oligodendroglioma by over-expressing the oncogenic form of the epidermal growth factor receptor v-erbB in oligodendroglial cells of transgenic mice. These mice develop infiltrating oligodendrogliomas that are initiated using a gene that is commonly overexpressed in human oligodendroglioma. Our hypothesis is that this mouse model for spontaneously arising oligodendroglioma provides a valuable preclinical model for the treatment of patients with glioma. Neural stem cells are ideally suited for delivery of antitumor agents in the brain; they are migratory and specifically hone to human tumor xenografts. We propose to test whether neural stem cell lines and primary neural stem cell populations are effective vehicles for delivery of therapy in a mouse model for spontaneously arising glioma.