Program Project Grant

Treatment of Malignant Brain Tumors

Principal Investigator: Mitchel S. Berger MD
Total Project Period: 07/1/07 - 06/30/12

Brain tumors affect more than 17,000 people in the United States each year, and cause more than 13,000 deaths. Although brain tumors are a prominent cause of cancer death in young adults and children, they are most common among middle-aged and older adults, and the incidence in people older than 65 years of age is increasing. Glioblastoma multiforme (GM) and anaplastic astrocytoma (AA)-the most malignant brain tumors with the poorest prognosis-comprise a significant proportion of these tumors.

The overall goal of this program is to integrate advances in technological development of physiologic neuro-imaging and tissue biomarkers in the management of patients with brain tumors and to translate this knowledge to optimize delivery of novel agents into the brain parenchyma.

Project Summaries

Project 1: Improved Management of Glioblastoma by Integrated Imaging and Tissue Analysis
Principal Investigator: Sarah Nelson PhD
Project Summary: The previous cycle of the BTRC Program Project Grant was focused on determining which noninvasive metabolic and physiological imaging parameters are valuable for characterizing newly diagnosed and post-treatment glioblastoma (GBM) and to link these metrics with ex vivo metabolic profiles and histological characteristics. Diffusion-weighted imaging, perfusion imaging, and MR spectroscopy parameters can provide useful information on tumor burden and response to treatment.

Over the next cycle of the Program Project Grant (2013-2017), investigators will validate the metrics defined in the previous funding cycle and applying them to routine clinical practice. These metrics include the myoinositol/ choline index derived from MR spectroscopy, which was shown to be a relevant biomarker for gliosis. More than 250 patients with newly diagnosed and post-treated glioblastoma have been enrolled in image-guided biopsy studies to correlate histologic, genomic, and metabolic characteristics with physiological imaging features.

Project 2: Image-guided Genomics to Understand Tumor Heterogeneity and Evolution
Principal Investigators: Susan Chang MD and Joseph Costello PhD
Project Summary: The goal of this investigation is to evaluate newly diagnosed and posttreated glioblastoma with specific emphasis on the genomic features of tumor heterogeneity and evolution. Changes in the tumor from time of initial diagnosis to progression occur at the molecular level – both as part of the natural history of the disease and as an effect of therapies. Determining the genetic changes at the time of progression and correlating them to physiologic and metabolic imaging could more accurately reflect the biological behavior of recurrent glioblastoma. The information gleaned from these studies will be especially useful for evaluating agents that target specific dysregulated pathways within a given tumor. If the activated pathways change from initial diagnosis to recurrence, patients will need to be enrolled in new protocols that are appropriate for the new molecular signature of their tumor.

Project 3: Hyperpolarized 13C MRSI Monitoring of Pyruvate Metabolism to Assess Drug Action
Principal Investigators: Russell Pieper PhD and Sabrina Ronen PhD
Project Summary: The final group of experiments in the BTRC Program Project Grant explores ex vivo, in vivo, and clinical development of hyperpolarized 13C imaging as a biomarker of drug delivery and response to therapy. UCSF is one of the only institutions with this technology and this study will represent the first-ever application of hyperpolarized 13C imaging to patients with brain tumors.

Preliminary studies in glioblastoma models indicate that response to therapeutic agents such as temozolomide, PI3K/ mTOR inhibitors, and histone deacetylase inhibitors is associated with a drop in the activity of enzymes involved in pyruvate metabolism, including pyruvate kinase and lactate dehydrogenase. This manifests in a tumor-specific decrease in the conversion of hyperpolarized 13C pyruvate to 13C lactate and a drop in the ratio of hyperpolarized lactate to pyruvate (Lac/Pyr) detectable by 13C MRS and MRSI within the first week of treatment. Hyperpolarized 13C Lac/Pyr may therefore serve as a novel biomarker of response to therapy and could allow clinicians to rapidly assess early response to treatment and make critical decisions regarding changes in drug therapy faster. Clinical evaluation of hyperpolarized 13C imaging will be performed in conjunction with the first project funded by the Program Project Grant, which is vetting new imaging parameters in clinical studies.