Brain SPORE Developmental Awards
Factor Inhibiting HIF (FIH) is Essential for Inhibiting HIF-Mediated Gene Transcription in Glioblastoma Multiforme
Glioblastoma multiforme accounts for 38 percent of primary brain tumors in the United States. These tumors are characterized by extensive angiogenesis (new blood vessel growth) induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is mediated through the transcription factor hypoxia-inducible-factor (HIF-1), a key regulator that mediates the cellular responses to hypoxia.
Factor Inhibiting HIF-1 (FIH-1) is an inhibitor of the transcriptional activation of HIF-1. Dr. Datta's research is investigating the role of FIH in glioblastoma multiforme angiogenesis to help understand the molecular mechanism behind tumor growth and progression. This research could lead to the design of a new therapy targeting angiogenesis.
The FIH gene is located at chromosome 10q24. Because this region of the chromosome is often deleted in glioblastoma multiforme, the importance of the FIH gene in regulating glioblastoma multiforme growth is underscored, and emphasizes to Dr. Datta and his team the need to understand its role in this disease. Their results clearly establish the importance of FIH in regulating HIF-mediated gene transcription, for instance GLUT1 and VEGF-A, in human glioblastoma cells. Their data also suggests that FIH, unlike PTEN, can inhibit HIF-mediated gene transcription even in hypoxic conditions and hence is more potent in regulating GBM tumor growth and angiogenesis.
Early MRI Assessment of Glioblastoma Multiforme Response to Temsirolimus (CCI-779)
A novel, molecularly-targeted pharmaceutical agent, temsirolimus (CCI-779), has shown promise in the treatment of glioblastoma multiforme, in part by making possible a new standard of care — combination treatment with radiation therapy and temozolomide. Dr. Kaufmann's team is working to refine and assess physiological and anatomical magnetic resonance imaging (MRI) tools (chemical shift imaging, perfusion-weighted imaging, diffusion-weighted imaging, and an automated anatomical change detector) that could be used to detect early changes in glioblastoma multiforme morphology and biology, and to apply these tools in the evaluation of CCI-779 therapy in glioblastoma multiforme patients.
The research team believes that in a subset of patients with glioblastoma multiforme treated with CCI-779, early responses to therapy will be detected with chemical shift, perfusion-weighted, and diffusion-weighted imaging, prior to those responses detectable with the use of "standard" surveillance imaging. The researchers similarly think that in a subset of these patients an anatomical change detector will also mark early response. They hypothesize that these early detected responses will correlate with speed of tumor progression and overall survival. Patients enrolled in the NCCTG N027D trial of CCI-779 are currently being imaged for this study.
Immunotherapy for Glioblastoma
No effective therapy exists for patients with malignant glioma. The brain is perceived as an immuno-privileged site due to the restrictive blood brain barrier and not amenable to immune-based therapies. However, animal models and some human clinical trials indicate that malignant gliomas may be susceptible to directed stimulation of the immune system.
Specifically, autologous antigen-presenting cells known as dendritic cells have been combined with tumor-derived antigens and used as a vaccine in patients with recurrent glioblastoma or anaplastic glioma. These studies have documented occasional complete remission and one report of an increase in survivability. Importantly, the studies published thus far have also demonstrated that dendritic cell vaccination appears to be safe in patients with at least partially-resected tumors. Cumulatively, these data suggest that glioblastoma may be amenable to immunotherapy, but that additional work is needed to improve the efficacy of dendritic cell vaccines.
The specific aims of Dr. Dietz' research program are to:
Targeting cadherin-catenin signaling in glioma therapy
Malignant gliomas are the leading cause of central nervous system tumor-related death. The rapid growth and aggressive invasion into surrounding normal brain tissue are major factors in the poor clinical outcome of malignant gliomas. Current therapeutic interventions are of limited effectiveness primarily due to the diffuse nature of these tumors, which precludes their complete resection and hinders the effectiveness of classic radiation and chemotherapeutic treatments.
Recent evidence indicates that the invasiveness of solid tumors involves signaling events downstream of cell adhesion receptors. In particular, work in Dr. Anastasiadis' lab has established mesenchymal cadherins and their interacting partner p120 catenin, as key participants in the invasiveness of both breast and kidney cancer cells (Journal of Cell Biology,174:1087-96, 2006) and as potential therapeutic targets.
Cadherins and p120 are also essential for anchorage-independent growth and the maintenance of the transformed cellular phenotype (unpublished data). Consistent with these observations, p120 depletion inhibits both glioma cell migration and cell proliferation. Therefore, Dr. Anastasiadis' team hypothesizes that p120 signaling plays important roles in the aggressive behavior of malignant gliomas and furthermore, that inhibiting p120 signaling will limit glioma growth and invasiveness and increase the efficacy of current chemotherapeutic regimens. The objective of this project is to define the roles of p120 signaling in glioma growth and invasiveness and to identify inhibitors of p120 signaling that could improve the clinical outcome of glioma patients.
Specifically the investigators will:
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