Specialized Programs of Research Excellence (SPORE) Grant Projects
UCSF Brain Tumor SPORE
Principal Investigator: Mitchel S. Berger MD
Clinical Science Principal Investigator: Michael D. Prados MD
Basic Science Principal Investigator: 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).
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, four 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 Objectives
Project 1: San Francisco Bay Area Adult Glioma Survival Study
Principal Investigator: Margaret Wrensch PhD
Co-Principal Investigator: John Wiencke PhD
During the most recent phase of the UCSF Brain SPORE, neuroepidemiologists in the BTRC identified the first germline and acquired somatic genetic variations associated with survival in patients with glioblastoma (GBM). Over the next four years, the project will extend these groundbreaking advances by identifying additional genetic variations associated with survival in patients with low-grade glioma and GBM, and by integrating survival genes identified by genome-wide association studies (GWAS) with IDH mutation and other molecular characteristics. Patients with grade II and III tumors have substantially longer survival times than patients with GBM, and GWAS of these lower grade tumors offer a chance to uncover new inherited factors important for survival. This research team will also apply these results to long-standing completed clinical trials to begin to assess the generalizability of their findings to clinical trial populations.
Project 2: Prognostic Value of MRSI Parameters for Patients with Glioma
Principal Investigator: Sarah Nelson PhD
Co-Principal Investigator: Susan Chang MD
Co-Principal Investigator: Joseph Costello PhD
Project 2 is focused on identifying noninvasive imaging parameters as biomarkers of malignant transformation in diffuse low-grade glioma and to use these parameters to select regions for characterizing the genetic mutations associated with recurrent disease. The studies will have a significant impact on the management of these patients by providing objective criteria to predict when a lesion transforms to a more malignant phenotype, whether and where to intervene surgically, and how to select the next-line therapy. This is an important problem because patients with tumors that recur from a prior lowgrade glioma have different outcomes depending on histological subtype, grade, and molecular/ cytogenetic features. The mechanisms of malignant transformation are unclear and treatment strategies are often pursued without histological confirmation of recurrent tumor.
Neuroimaging specialists are using state-of-the-art spectroscopic techniques to directly assess the ability of spectroscopic markers to predict time to progression and overall survival in low-grade glioma patients. The project also includes a first ever analysis of the genetic mutations that drive low-grade glioma formation and progression and which may serve as biomarkers of the disease.
Project 3: Novel Approaches for Improving Pediatric BRAFV600E Glioma Patient Outcomes
Principal Investigator: C. David James PhD
Co-Principal Investigator: Michael Prados MD
Co-Principal Investiagor: Theodore Nicolaides MD
Other than surgery and radiation, there are currently no effective treatments for glioma in children. Available treatments only provide shortterm relief from the cancer, while substantially contributing to patient morbidity. This SPORE project is based on work by BTRC investigators showing thata large fraction of pediatric brain tumors contain a mutation in the gene encoding BRAF – called the BRAFV600E mutation. In preclinical studies, the mutation was shown to sensitize these tumors to clinically available mutant BRAF inhibitors and mutant BRAF/cyclin-dependent kinase inhibitor combinations. glioma cell surface, induces CD8+ T-cell apoptosis and is positively regulated by PI(3)K.
Going forward, the goals of the project are to: determine the impact of the PI(3)K/ Akt/mTOR/B7-H1 pathway on expansion of regulatory T-cells and locally suppressive macrophages; investigate the utility of inhibiting PI(3)K/Akt/ mTOR/B7-H1 as a means of augmenting immunotherapy in the pre-clinical setting; and initiate a first of its kind, NCI cooperative group-sponsored, large-scale phase II clinical trial to examine the impact of PI3K activation and B7-H1 expression on response to active immunotherapy in patients with recurrent GBM. Over the next four years, the investigators will address mechanistic aspects of inhibitor action; will initiate pre-clinical studies comparing the efficacy of mutant BRAF inhibitors in combination withdifferent mechanism-based inhibitors; and will initiate clinical trials of mutant BRAF inhibitors alone and in combination with other agents. The first clinical trial will be investigating the BRAF inhibitor vemurafenib. This is the first pediatric project of any NIH SPORE.
Project 4: Overcoming Local and Peripheral Immune Suppression in Glioma to Facilitate Effective Glioma Therapy
Principal Investigator: Andrew Parsa MD, PhD
Co-Principal Investigator: Russell Piper PhD
This innovative immunology project builds on findings from our previous cycle of SPORE funding that identified key factors contributing to the failure of vaccinebased therapies in brain tumors. BTRC investigators demonstrated that the protein B7-Homologue 1 (B7-H1), which is expressed on the glioma cell surface, induces CD8+ T-cell apoptosis and is positively regulated by PI(3)K. Going forward, the goals of the project are to: determine the impact of the PI(3)K/ Akt/mTOR/B7-H1 pathway on expansion of regulatory T-cells and locally suppressive macrophages; investigate the utility of inhibiting PI(3)K/Akt/ mTOR/B7-H1 as a means of augmenting immunotherapy in the pre-clinical setting; and initiate a first of its kind, NCI cooperative group-sponsored, large-scale phase II clinical trial to examine the impact of PI3K activation and B7-H1 expression on response to active immunotherapy in patients with recurrent GBM.