Last Updated: 09/13/10
UCSF Brain Tumor SPORE:
Principal Investigator:
Mitchel S. Berger MD
Co-Principal Investigators:
Michael D. Prados MD
Russell O. Pieper PhD
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, 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.
In August of 2007 the UCSF Brain Tumor SPORE was renewed, and new funding was provided for the continuation of the original 4 SPORE projects as well as a new firth project. All projects 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, Administrative, Tissue, Animal, and Biostatistics/Clinical Cores are also included to provide administrative support and access to tissues and animal models 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 Investigators:
Michael Prados MD
John Weincke, PhD
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 addresses 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. The project builds on successes in the first SPORRE funding period and proposes to: 1) continue to accrue patients and specimens to provide additional subjects for all validation studies; 2) address the hypotheses that emerged in the initial SPORE funding period that immune factors such as IgE levels and immune-related polymorphisms influence the survival of patients with glioma. For these studies measurements of serum IgE funded through the R01, as well as measurements of inflammatory mediators related to IgE (serum soluble CD23 and soluble CD14, tumor expression of CD23 and IL13RA2, and constitutive SNPs within IL4, IL13, ILAR, IL13RA1, and IL13RA2), will be compared to patient survival data generated in this and the previous funding period; 3) explore the hypothesis that MGMT polymorphisms, and tumor p53 mutation and/or expression influence the association of tumor MGMT promoter methylation and survival in patients treated with temozolomide; and 4) assess the prognostic significance of promising markers derived from aims 2 and 3 in GBM patients enrolled in UCSF Neuro-Oncology clinical trials. The information derived from this project is expected to 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
In the initial funding period, MRSI in conjunction with perfusion weighted (PW) and diffusion weighted (DW) imaging were sued to evaluate physiologic imaging parameters in gliomas of various grades. These studies confirmed the differences between the spatial extent of the anatomic, metabolic and physiologic lesions, and led to the identification of choline, lactate, and apparent diffusion coefficient as predictors of the biological behavior of gliomas of all grades and as measures of therapeutic response. The work also highlighted the need for validation of physiologic imaging parameters with respect to histological findings and specific clinical endpoints. Therefore this SPORE renewal project will determine whether MRSI, PW-MRI, and DW-MRI parameters can determine whether low- grade glioma (LGG) have transformed to higher-grade tumors, and whether these techniques can predict subsequent biological behavior of the tumor. This is an important clinical question because although nearly all LGG undergo malignant transformation, clinical outcome is heterogenous and non-invasive parameters of subsequent tumor grade or biological behavior are lacking. Repeated tissue sampling remains the standard evaluation of recurrent LGG but is limited due to surgical risk and sampling error. In this renewal proposal, patients with recurrent LGG will undergo image-guided tissue acquisition based on specified MRSI parameters with subsequent molecular morphologic assessment. Short-term metabolic and physiologic changes that occur in response to subsequent therapy in these patients will also be examined with respect to patient outcome. This information will form the basis for integrating the technology into a clinical trial of rapamycin for recurrent LGG that is planned as one of the specific aims of Project 4 in this SPORE renewal.
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. In the initial funding period, this project developed a variety of useful liposomal therapeutics, including an EGFR-targeted liposomes, an entire new class of nanoliposomal agents for improved drug delivery, a nanoliposmal agent encapsulating gadolinium that is suitable for imaging of tumors as well as drug delivery, and a variety of drug-encapsulated nanoliposomes. Project investigator also partnered with a company in Taiwan that created GMP-grade liposomes encapsulating CPT11, and used funds from a SPORE Supplemental Award to move the agent through the FDA approval process and to receive approval to initiate a clinical trial of liposomal CPT11 at UCSF. In the current renewal application, the investigators intend to work with the Neuro-Oncology Service of the UCSF Neuro-Oncology Program to pursue clinical implementation of liposomal CPT11, as well as to generate additional novel multifunctional nanoparticles which following convection-enhanced delivery in connection with Dr Krys Bankiewicz, can be used for integrated imaging and therapy. 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.
PROJECT 4: EXPLOITING THE PI3-KINASE PATHWAY IN HUMAN GLIOMA THERAPY
Principal Investigator:
David Stokoe PhD
Clinical Co-Principal Investigators:
Daphne Haas-Kogan MD
William Weiss, 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. Work completed in the previous funding period showed that pAkt levels in connection with EGFR status were a strong predictor of glioma response to EGFR pathway inhibitors. The correlations noted will be more critically investigated in the present proposal in studies of a series of human GBM xenografts, and in a prospective clinical trial in which high grade glioma patients will be selected by pAkt status prior to erlotinib therapy. The work completed in the initial funding period also led to a second important finding, namely that methylation of the PTEN promoter was associated with increased pAkt levels and mTOR activation in low-grade gliomas. These results suggest that mTOR inhibitors such as rapamycin, in addition to being useful in treating GBM, might also be useful in the treatment of low-grade gliomas. This idea will be tested in a second prospective phase II clinical trial included in the present proposal. Finally, in the previous funding period, the investigators in this project, in collaboration with William Weiss, MD, PhD (a previous UCSF Brain Tumor SPORE Developmental Project awardee), investigators in the UCSF Chemistry and Cancer Program, and investigators in the UCSF Breast and Prostate SPOREs, initiated a project designed to create new and specific inhibitors of the PI3 kinases that link EGFR to downstream components of the pathway and may contribute to glioma growth and progression. This project has also been highly successful, and specific inhibitors of various PI3K isoforms have been identified, synthesized, and tested in a preliminary manner in vitro. The present proposal, which has been expanded to include Dr. Weiss as a co-investigator, will evaluate the efficacy promising PI3K inhibitors alone and in combination with erlotinib in pre-clinical models. Because various PI3K inhibitors have already been created in GMP form, the work proposed has direct potential to lead to new clinical trials.
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.
CORES:
The UCSF Brain Tumor SPORE includes four cores essential to the accomplishments of the SPORE.
CORE 1 — ADMINISTRATIVE CORE
The UCSF Brain Tumor SPORE Administrative Core is directed by Mitchel Berger, MD, with Russ Pieper, PhD and Michael Prados, MD serving as basic and clinical co-directors of the core, respectively. Jacquelyn Johnson is the SPORE Administrator and reports directly to Dr. Berger. The Administrative Core provides support for all SPORE investigators including communication with the National SPORE program staff, preparation of progress reports and competitive renewal applications, financial oversight and organization of research meetings, annual retreats, meetings of the External Advisory Board and meetings of the Steering Committee.
CORE 2 — TISSUE CORE
Scott VandenBerg, MD, PhD, an experienced neuropathologist and an expert in the optimal handling, cataloging, and distribution of brain tumor samples, is the Director of the Brain Tumor SPORE Tissue and Outcome Core. At present, over 10,000 frozen brain tumor specimens are available in the Tissue Core, and the Tissue Core has distributed over 450 samples to SPORE investigators in the past three years. Samples and outcomes information are also available to SPORE investigators on over 1000 brain tumor patients. The Tissue and Outcomes Core assists SPORE researchers with sample preparation and evaluation (e.g., review by core pathologists for histopathologic features and confirmation of tumor presence; extraction of DNA, RNA and protein; and preparation of custom tissue microarrays as well as custom immunohistochemistry). It also coordinates with tumor banks at other institutions to obtain and distribute additional material for SPORE projects.
CORE 3 — BIOSTATISTICS AND CLINICAL CORE
The Biostatistics and Clinical Core is co-directed by Kathleen Lamborn, PhD, and Michael Prados, MD. Dr. Lamborn was the Director of the UCSF Cancer Center Biostatistics Core for six years, and has worked with laboratory and clinical investigators of the BTRC since 1988 in providing her expertise in study design, analysis and statistical interpretation of data. Additional biostatistical support is provided by Ivan Smirnov, PhD. Dr. Smirnov has been with the BTRC since 1998 and is responsible for the technical aspects of the tissue bank database systems, for linking data across the multiple systems, and for providing informatics support for analysis of micro-array data. The Biostatistics component of the Biostatistics and Clinical Core provides service to all the projects and to the Tissue and Animal Cores.
Dr. Prados is the clinical co-leader of the Biostatistics and Clinical Core. He is a nationally and internationally recognized neuro-oncologist and is the PI of the North American Brain Tumor Consortium (NABTC), one of the leading adult brain tumor clinical trials groups in America. He is also the UCSF PI of the Pediatric Brain Tumor Consortium and is the Director of the Translational Science Division of the BTRC. Dr. Prados works closely with investigators in this SPORE application to plan and design clinical trials that test SPORE-generated hypotheses, and as head of the clinical component of the Biostatistics and Clinical Core provides the expertise necessary to carry out the multiple clinical trials proposed in this application.
CORE 4 — PRE-CLINICAL ANIMAL CORE
David James, PhD, is the head of the recently established UCSF Brain Tumor SPORE Animal Core. The Animal Core, under Dr. James’ guidance, assists in experimental design involving animals, works with project investigators to test therapeutics in vivo, and maintains a well-characterized repository of brain cancer cell lines and primary tumors optimized for propagation in immune-deficient rodents. The core also ensures data reproducibility, compliance with local and federal regulatory guidelines for tumor-bearing animals, and maximum resource usage through coordinated animal purchasing and housing. The core also introduces new technologies to facilitate animal studies and shares these with the SPORE community.
CAREER DEVELOPMENT AWARDEES
Claudia Petritsch, PhD
Research Assistant Professor of Neurological Surgery
Principal Investigator, BTRC
Project Title: Identification of novel diagnostic markers and therapeutic approaches to premalignant and malignant lesions of high-grade oligodendroglioma.
Anita Lal, PhD
Assistant Professor of Neurological Surgery
Principal Investigator, BTRC
Project Title: Predicting the prognosis of atypical meningiomas using molecular signatures.
Elva Diaz, PhD
Assistant Professor, UC-Davis Dept. of Pharmacology
Project Title: Novel role of the Mad family member Mad3 in tumorigenesis.
Manish Aghi, MD, PhD
Assistant Professor of Neurological Surgery
Principal Investigator, BTRC
Project Title: Identifying and overcoming mechanisms of glioblastoma resistance to antivascular treatment.
Previous 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
DEVELOPMENTAL RESEARCH AWARDEES
David James, PhD
Professor of Neurological Surgery
Principal Investigator, BTRC Project Title: Temozolomide plus p53 inhibitor salvage therapy for the treatment of recurrent GBM.
Sabrina Ronen, PhD
Associate Professor of Radiology
Project Title: Metabolomic biomarkers of PI3K inhibition in glioma.
Karen Aboody, MD
Associate Professor, Divisions of Hematology and Hematopoietic Cell Transplantation, City of Hope
Project Title: NSC-mediated glioma therapy: pre-clinical optimization of therapeutic efficacy for clinical trials
Previous 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
