Title: Plasma tumor-specific DNA as a biomarker for glioma
Principal Investigator: Kyle D. Weaver, M.D.
Recent advances in brain tumor research suggest the imminent development of effective treatments. Unfortunately, our ability to safely and accurately diagnose brain tumors and evaluate treatment response lags behind. It is imperative that these diagnostic deficiencies be corrected in concert with treatment advances.
It is well known that many cancers secrete their genetic material (DNA) into the blood. This DNA carries a unique tumor “fingerprint” and is not found a healthy person’s blood. It can be used to estimate amount of tumor, assess treatment response, and predict survival in some cancers, and only requires a blood draw, but has not been evaluated in brain tumors. We have demonstrated that brain tumors shed their unique DNA into the blood just as other tumors do.
We plan to develop this tumor-specific DNA in the blood into a biomarker to assist with the diagnosis of tumors and assess the response to therapy. To do so, we will identify patients needing an operation to remove a brain tumor. A piece of tumor will be removed for genetic fingerprinting and a blood sample taken to determine if it contains brain tumor DNA also. If so, the patient will be followed with MRI scans and blood draws. The type and amount of brain tumor DNA in the blood will be correlated with the patient’s clinical condition, amount of tumor on MRI, and survival. This will allow the development of a new, genetic test to better care for brain tumor patients and precisely guide their treatment.
Title: Cellular Therapies for Malignant Gliomas
Principal Investigator: Moneeb Ehtesham, M.D.
Our research focuses on the development of effective cell-based strategies to treat malignant brain tumors. High grade gliomas, the most common primary brain tumors, are characterized by their highly infiltrative nature and often recur despite aggressive resection of the primary tumor mass with adjunct radio- and chemotherapy. Our work focuses on developing the use of progenitors and immune cells as tools to track down and specifically target infiltrative glioma cells in the brain. The goal of this laboratory is to develop these experimental approaches into translationally relevant treatment paradigms. We are also interested in elucidating chemokine signaling mechanisms that govern the migratory capacity of glioma cells as well as neural progenitors in the brain. Furthermore, our group also seeks to investigate signaling mechanisms that may govern aberrant progenitor cell proliferation in the context of gliomagenesis.
Title: In vitro timing of intrauterine repair of myelomeningoceles.
Principle Investigator: Dr. Noel Tulipan; Dr. Michael Drewek, resident
After initial success with pioneering procedures developed by this department to attempt primary closure of myelomeningoceles in utero, this project is the next step in refining this technique. It addresses the question of timing for in utero repair of neural tube defects by characterizing the toxic effects of human amniotic fluid on the unprotected fetal rat spinal cord in cell culture. This model has shown that at [24 weeks] of gestation, amniotic fluid exerts a maximal toxic effect on embryonic spinal cord cells, and therefore dictates consideration as to timing of in utero repair of humans with prenatally diagnosed myelomeningocele defects.
Of pride to the Department is the fact that Dr. Michael Drewek has won a national award for his part in this research as a resident interested in pediatric neurosurgery. He received this award after presenting his results at the American Association of Neurological Surgeons Meeting in Philadelphia last fall.
Title: Investigation of an amino acid kinase, KGX, as a tumor suppressor factor in glioma transformation
Principle Investigator: Dr. Steven Toms
Co-investigators: Jennifer Pietenpol, Ph.D., Dept. of Toxicology, Vanderbilt University, Bryan R. G. Williams, Ph.D., Chairman, Department of Cancer Biology, The Cleveland Clinic Foundation
KGX is an 814 amino acid kinase which maps to human chromosome 10q24, the area of the highest loss of heterozygosity for glioblastoma multiforme (GBM) as well as prostate cancer. The kinase exhibits homology with other human mitogen activated protein kinases as well as kinases in yeast and Drosophila. In vitro kinase assays using recombinant KGX exhibit strong kinase activity versus histone and myelin basic protein. Yeast two-hybrid assays revealed TAFII31 to be a potential binding partner. In vitro binding assays have confirmed this relationship as well as the binding relationship between KGX and p53. Transient transfections of KGX into NIH3T3 cells have confirmed that over-expression of KGX and KGX mutants alter the transcription of a p53 dependent reporter construct.
Investigation is currently underway in three areas:
- We are undertaking transfections of eukaryotic cell lines in order to determine if KGX phosphorylates either TAFII31, p53, or other elements of the RNA polymerase holoenzyme mediating p53 directed transcription.
- We are beginning a mutation analysis of GBM cell lines and tumor samples to determine if KGX may be a tumor suppresser in this tumors.
- We are investigating the usefulness of a polyclonal antibody for immunohistochemistry.
We hope to determine within the next year if KGX is, in fact, a tumor suppresser and the exact nature of its relationship with p53. Future studies with this gene will center on its role in cell cycle its role in the response to radiation and other DNA damaging agents, as well as its role in other malignancies.
Title: Investigation of the free electron laser in peripheral nerve welding in rats
Principle Investigator: Dr. Peter Konrad
Co-investigator: Dr. Duco Jansen, Department of Biomedical Engineering
Fixed wavelength lasers have been tried unsuccessfully in the past to "weld" peripheral nerves together for repair of damaged segments or transected nerves. A key point in the failure of this technique has been the failure to maintain tensile strength in the initial post-operative recovery period. A unique advantage is the minimal scar tissue produced by laser assisted annealing of perineural proteins during the welding process. Recent advances in the development of "biological soldering compounds" may provide a solution to the problem with tensile strength. Potentially, the free electron laser may reveal a unique wavelength which can optimize coaptation of fascicles within the peripheral nerve as well as maximize strength after welding to provide optimal functional recovery of damaged peripheral nerves. Translation of this research into surgery on humans at the Free Electron Laser Facility is a paramount goal of this project.
Title: Optical detection of functional activity in neural tissue
Principle Investigator: Dr. Peter Konrad
Co-investigator: Dr. Anita Mahadaven-Jansen, Department of Biomedical Engineering
Recent advances in fiber optic detection and transmission have allowed accurate and high-resolution imaging of the nervous system to occur across a broad spectrum of wavelengths. Research at several center have revealed the capability to "see" electrophysiological activity at a cellular and tissue level. This project attempts to investigate the acquisition of images of natural or evoked electrical activity of the brain, spinal cord, and/or peripheral nerves in animal models and humans. Critical to the practical application of this technique is the ability to acquire such functional images in real time without the administration of electrically coupled dyes. Based on other work by Dr. Mahadaven-Jansen, we feel that this is feasible with enhanced imaging techniques trained to observe bio-fluorescence. Ultimately, such techniques would provide visual, real-time feedback to neurosurgeons operating in areas of the nervous system in which critical functions are to be preserved or ablated. This is a natural extension of image guided neurosurgery.