This proposal describes a 5-year-long career development program whose goal is to prepare Dr. Phillips for the role of an independent academic investigator. The project sponsor, Dr. Zena Werb, will provide the principle guidance. Dr. Werb is an internationally recognized expert on the tumor microenvironment and has a distinguished record of training independent scientists. The project co-sponsor, Dr. David Rowitch, is an internationally recognized expert on brain tumor development with a demonstrated commitment to training clinician-scientists. In addition to Drs. Werb and Rowitch, the members of the advisory committee will provide additional scientific and career development related guidance. The research program will address the hypothesis that microglia and macrophages accelerate brain tumor progression and infiltration. Microglia and macrophages are a significant component of the brain tumor microenvironment;however, their activation phenotype and function are unclear. In this project, the role of microglia and macrophages in the development of infiltrating glial tumors will be assessed in three specific aims. First, I will examine the activation patterns of microglia and macrophages in infiltrating glial tumors over time. Studies will be performed using a robust murine model for infiltrating glioma and the results will be confirmed in human tumor tissue. Second, I will determine whether microglia and macrophages promote tumor cell infiltration. Using novel imaging technology I will monitor the dynamic interactions of immune cells and tumor cells. Third, I will determine the in vivo significance of the microglial and macrophage response to brain tumor by depleting it or modifying it. The research training will also include a formal didactic program in research ethics, tumor biology, advanced molecular techniques, and tumor immunology. The UCSF Pathology Department is fully committed to Dr. Phillips'career development and UCSF provides an ideal setting for the training of independent physician scientists. Relevance: In 2007, it is estimated that 20,500 individuals will be diagnosed with cancer of the brain and nervous system in the United States. Despite current therapies infiltrating gliomas, the most common type of primary brain tumor, continues to progress and is often fatal. The research proposed in this project will yield important insight into the factors in the microenvironment that contribute to brain tumor progression and infiltration and potentially may aid in the development of new therapies for glioma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS063456-05
Application #
8287633
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$156,552
Indirect Cost
$11,596
Name
University of California San Francisco
Department
Pathology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Swartling, Fredrik J; Bolin, Sara; Phillips, Joanna J et al. (2014) Signals that regulate the oncogenic fate of neural stem cells and progenitors. Exp Neurol 260:56-68
Phillips, Joanna J; Aranda, Derick; Ellison, David W et al. (2013) PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma. Brain Pathol 23:565-73
Mukherjee, Joydeep; Phillips, Joanna J; Zheng, Shichun et al. (2013) Pyruvate kinase M2 expression, but not pyruvate kinase activity, is up-regulated in a grade-specific manner in human glioma. PLoS One 8:e57610
Phillips, Joanna J; Huillard, Emmanuelle; Robinson, Aaron E et al. (2012) Heparan sulfate sulfatase SULF2 regulates PDGFR* signaling and growth in human and mouse malignant glioma. J Clin Invest 122:911-22
Elkhaled, Adam; Jalbert, Llewellyn E; Phillips, Joanna J et al. (2012) Magnetic resonance of 2-hydroxyglutarate in IDH1-mutated low-grade gliomas. Sci Transl Med 4:116ra5
Goldhoff, Patricia; Clarke, Jennifer; Smirnov, Ivan et al. (2012) Clinical stratification of glioblastoma based on alterations in retinoblastoma tumor suppressor protein (RB1) and association with the proneural subtype. J Neuropathol Exp Neurol 71:83-9
Park, Ilwoo; Bok, Robert; Ozawa, Tomoko et al. (2011) Detection of early response to temozolomide treatment in brain tumors using hyperpolarized 13C MR metabolic imaging. J Magn Reson Imaging 33:1284-90
Phillips, Joanna J; Misra, Anjan; Feuerstein, Burt G et al. (2010) Pituicytoma: characterization of a unique neoplasm by histology, immunohistochemistry, ultrastructure, and array-based comparative genomic hybridization. Arch Pathol Lab Med 134:1063-9
Littlepage, Laurie E; Sternlicht, Mark D; Rougier, Nathalie et al. (2010) Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res 70:2224-34