The candidate: Dr. Terreia Jones is an Assistant professor in the Department of Clinical Pharmacy at the University of Tennessee Health Science Center (UTHSC). She completed her residency training in clinical pharmacy practice at the VA Medical Center (Memphis, TN) and her fellowship training focused in the pharmacogenetics of anti-leukemia therapy at St. Jude Children's Research Hospital (Memphis, TN). Dr. Jones is now building a research program focused in neuro-oncology under the mentorship of a world-renowned brain cancer biologist and neurosurgeon, Dr. Eric C. Holland. The goals of Dr. Jones'career development are centered on her desire to become a successful clinical brain cancer scientist which include: establishing strong collaborations in the neuro-oncology field, 2) publishing high-impact publications relevant to brain cancer, and 3) securing extramural funding to support her research. Key elements of her research career development plan include extended visits to Memorial Sloan Kettering Cancer Center to acquire experimental techniques in her mentors laboratory;attending and presenting at recurring institutional seminars (at the University of Tennessee Health Science Center, St. Jude Children's Research Hospital and Memorial Sloan Kettering);and frequent meetings with her advisory committee that consists of well-establish brain cancer scientists for guidance and support. The research resulting from this award will be presented at scientific meetings annually and is expected to generate a minimum of 4 - 8 manuscripts over the tenure of the award and lead to a successful R01 submission. Environment: The UTHSC has committed to provide the necessary infrastructure to nurture Dr. Jones'career development and has provided an excellent environment in which to train, both physically in the form of exceptional lab space and equipment. There are a number of relevant seminars between the UTHSC and St. Jude campuses that will enhance her knowledge in cancer biology. She has the overwhelming support of her administration, working under a Department Chair and Dean who embrace competitive science in clinical pharmacy. The University's support has been integral in helping Dr. Jones establish a fruitful relationship with Dr. Holland thus far. As detailed in the applicatin, the Dean and Chair both commit to protecting 75% of her time to dedicate to her career development. Dr. Larry Pfeffer (co-mentor and Director of the UTHSC Center for Cancer Research), will assist Dr. Eric C. Holland and the mentoring team in providing Dr. Jones with the mentorship and resources that she needs to ensure her success. Research: Malignant gliomas account for the vast majority of primary brain tumors, with glioblastoma (GBM) being the most frequent, malignant and deadly overall. Over the past several decades there have been only modest improvements in survival and only a few significant advances in the therapeutic management for GBM. Corticoisteroids such as dexamethasone (Dex) have remained the standard of care for resolving brain tumor-associated neurological symptoms for decades, so prevalent that they can be thought of as part of the disease process itself. However, it remains unclear which cell population(s) and molecular factors are most affected by this therapy. Nor is it clear what effect Dex has on the effectiveness of the standard DNA damaging therapy for GBM such as radiation or alkylating agents. Our data from homogenized tumors and IHC studies from mice treated with Dex show that Dex suppresses the expression of genes and proteins involved in cell proliferation. If Dex decreases cell proliferation of the tumor cells themselves (Olig2+ cells) it is possible that it may decrease the efficacy of anti-neoplastic therapy. This study will provide valuable insight into the mechanism of how Dex works and potentially lead to a paradigm shift in how neurologic symptoms are managed in glioma. We will address the hypothesis that Dex inhibits tumor cell proliferation either in a direct cell autonomous manner or indirectly through microglia;and because of its anti-proliferative effect, it may compromise the effectiveness of standard cytotoxic therapy. We will use a variety of sophisticated genetically engineered mouse models of GBM and leverage in vitro co-culuture models to address the following specific aims: 1) To determine whether Dex inhibits proliferation in the tumor cell population in vivo;2) To determine the transcriptional effects of Dex on tumor-associated microglial cells and their secreted products;3) To determine whether Dex antagonizes the anti-tumor effect of standard therapy;and 4) To determine whether compounds targeting microglia function in vivo can lead to a comparable edema reduction as Dex.
Glioblastoma is the most frequent, malignant and deadly primary brain tumor overall. Corticoisteroids such as dexamethasone have remained the standard of care for resolving brain tumor-associated symptoms for decades (so prevalent that they can be thought of as part of the disease process itself);however, no one knows whether dexamethasone alters the effectiveness of the standard DNA damaging therapy for glioblastoma such as radiation or alkylating drugs. This study will provide valuable insight into the mechanism of how dexamethasone works and potentially lead to a paradigm shift in how neurologic symptoms are managed in brain cancer.