Brain Tumor/ Cancer
The Department of Neurological Surgery is currently conducting the following studies in Brain Tumor/ Cancer:
High Throughput Screening for the Identification of Kinase-Related Proteins Involved in the Enhanced Malignancy of Aged Glioma Stem Cells
Principal Investigator: Robert Rostomily, MD
Funded By: Fred Hutchinson Cancer Research Center (FHCRC)
Human glioblastoma represents a uniformly fatal disease, affecting persons in their 5th to 7th decades of life. Despite extensive research, outcome remains poor with median survival approximating 12 months even with cytoreduction, chemotherapy, and radiotherapy. Recently, the cancer stem cell hypothesis has provided tantalizing evidence of the existence of glioblastoma cancer stem cells and that these cells are responsible for the universal recurrence of tumors seen after clinical institution of therapy.
Our lab has developed a model of aging glioblastoma cancer stem cells in mice and shown that the age of the cancer stem cell is critical to the cancer’s overall malignancy. The mechanisms of this increased malignancy are, however, poorly understood. As such, via RNA interference technology and small compound library screening, we propose to use High Throughput Screening to identify kinase-related protein pathways critical to the proliferation of these cancer stem cells and then validate these siRNA targets with known compounds in vitro. Data from this project will provide the pilot data necessary to perform further studies on aging cancer stem cell proliferation, migration, and invasion.
TWIST1 as a Target for Inhibition of Glioma Invasion
Principal Investigator: Robert Rostomily
Funded By: National Institutes of Health (NIH)
Glioblastomas (GBM) are the most malignant and common intrinsic brain tumor. Despite aggressive treatment, the disease is uniformly fatal and patients survive on average less than a year. Our inability to improve disease outcome is due in large part to gaps in our understanding of what mechanisms activate GBM invasion. We first identified the role of TWIST1 in GBM invasion and its high correlation with human GBM malignancy. Its critical function in carcinoma invasion and metastasis by activation of epithelial
mesenchymal transition (EMT) suggested that it may function through similar mechanisms to promote GBM invasion. Here we present novel data demonstrating the potential role of the secreted matrix protein POSTN, Akt activation and TWIST1 binding protein interactions in TWIST1 pro-invasive signaling in GBM.
We hypothesize that a TWIST1 regulatory mechanism signaling through POSTN and specific Akt isoforms that is in turn regulated by TWIST1 binding partners promotes GBM invasion and malignancy. To address this hypothesis and show the therapeutic potential of targeting this TWIST1 signaling network we will"
- Determine how inhibition of TWIST1 in human GBM stem cells and in a cre/lox conditional TWIST model
influences tumor invasion and malignancy in vivo
- Define the impact of inhibiting POSTN and specific Akt isoforms to abrogate TWIST1 pro-invasive signaling in vivo
- Identify TWIST1 binding partners that regulate TWIST1 invasion in concert with regulation of POSTN and Akt.
By demonstrating the importance of this network for GBM invasion, we will further validate the relevance of EMT mechanisms in non-epithelial derived cancers. As such, these studies are expected to revolutionize concepts of GBM invasion and accelerate generation of sorely needed therapies that target the most lethal biological feature of these dreaded cancers.